Implications of the monoclonal character of human atherosclerotic plaques. Evidence for the monoclonal nature of human atherosclerotic plaques is reviewed. Eighty percent of discrete raised atherosclerotic plaques are of single phenotype. Interpretations alternative to single-cell orgin, based on patch size, selection due to linked genes, or repetitive sampling do not seem to explain the apparent monoclonality. Search for carriers in serum of mutagens, such as may be present in cigarette smoke, show them to be the lipoproteins, and the presence and possible role of intrinsic mutagens, e.g., cholesterol-alpha-oxide, are presented. The possible role for other factors implied by the monoclonal hypothesis, e.g., the mechanism by which estrogen therapy may increase coronary attacks, is discussed.


Excitation conduction in Auerbach's plexus of rabbit small intestine. Excitation conduction in Auerbach's plexus of the rabbit small intestine was investigated by analyzing its evoked potentials as the response to a single electrical stimulus given to this plexus. When the conduction distance was 1 mm, two spike waves were recorded. Conduction velocities of nerve impulses were 0.3-0.5 m/s, and chronaxie was 0.06-0.11 ms. When the distance between stimulating and recording electrodes was further increased, evoked potential waves became multiple and small, until beyond 15 mm in the longitudinal direction and beyond 3 mm in the circular direction they could no longer be recorded. Evoked potentials recorded at a distance greater than 2 mm were reduced in their amplitude, and some potential waves were abolished after repeated stimulation with high frequency above 50/s, and also after hexamethonium application and lack of oxygen. It was concluded that in Auerbach's plexus nerve impulses spread through multiple pathways, conducting mainly on the longitudinal axis of the small intestine, and that some impulses make synaptaic transmission at ganglia.


Lack of adaptation of pancreatic colipase in rats and mice. A new automated potentiometric method for the determination of colipase was developed, taking advantage of the reactivation of purified lipase, in the presence of bile salt and at pH 6.5. High-fat and high-starch diets induced an opposite regulation of lipase and amylase in the rat pancreas. At the same time, the level of colipase was not influenced by nutrition. During fasting and in alloxan diabetes, the specific activity of lipase almost doubled, that of amylase decreased sharply, and colipase was not affected in the rat pancreas. In obese-hyperglycemic mice, suffering from obesity, hyperinsulinism, and moderate diabetes, there was also no regulation of pancreatic colipase. Thus, at variance with a number of hydrolases, there was no dietary or hormonal adaptation of colipase. However, this was probably without any bearing on intraluminal lipolysis. Indeed, comparison of lipase and colipase activities in pancreas and in small intestine suggests that colipase concentration is not a limiting factor of intraluminal lipolysis. The molecular mechanism of this assumption is discussed on the basis of in vitro studies.


Tracer kinetic analysis of Cori cycle activity in the rat: effect of feeding. Turnover rates of blood glucose and lactate, along with the rates of their interconversion, were calculated from changes of their specific activities in rats infused with [U-14C] glucose and [U-14C] lactate based on a simple flux model of the Cori cycle. In the fasted state, most (75%) of the glucose metabolized was converted to lactate, whereas only a small fraction (35%) of the lactate metabolized was converted to glucose. Of the glucose metabolized, 27% returned from the lactate pool to the glucose pool. Feeding stimulated the outflow of glucose carbon from the Cori cycle via the action of secreted insulin. Insulin-induced stimulation of blood glucose removal was associated with increased glucose production, whereas anti-insulin serum-induced stimulation of glucose production was associated with increased glucose removal. It is argued that a "compensatory" mechanism independent of insulin and epinephrine might be in operation to minimize the glycemic changes that would otherwise occur in response to drastic metabolic changes.


Activation of the Cori cycle by epinephrine. The effect of epinephrine on Cori cycle activity has been studied by a tracer kinetic technique. The subcutaneous injection of epinephrine into fasted adrenodemedullated rats activated gluconeogenesis and increased glucose utilization. Most of the glucose utilized in epinephrine-treated rats was converted to lactate, and the conversion to the metabolites other than lactate was markedly suppressed by epinephrine. As a result, not only hyperglycemia and hyperlactacidemia developed, but also the contribution of the Cori cycle to glucose metabolism increased after epinephrine. The glucose-alanine cycle, which is roughly one-third as active as the Cori cycle, was only slightly activated by epinephrine. No evidence was obtained, in vivo and in vitro, for the increased formation of lactate from muscle glycogen which decomposed in response to epinephrine. It is suggested that, in epinephrine-treated rats, blood glucose was converted to blood lactate predominantly while muscle glycogen selectively yielded the metabolites other than blood lactate. This suggests compartmentalization of glycolytic pathway in the peripheral tissues of epinephrine-treated rats.


Comparison of pancreatic responses to portal and systemic secretin and VIP in cats. This study was designed to compare pancreatic bicarbonate responses to secretin and vasoactive intestinal peptide (VIP) administered either by peripheral or portal route in 24 anesthetized cats. Continuous intravenous infusion of graded doses of secretin (rang from 0.04 to 0.68 nmol/kg per h), stimulated pancreatic volume flow and bicarbonate outputs dose dependently and not statistically differently when given into the peripheral or portal vein. VIP infused in graded doses (range from 0.60 to 9.62 nmol/kg per h) into the peripheral vein produced pancreatic volume flow and bicarbonate outputs not statistically different from those obtained with secretin. In contrast, the biological activity of VIP administered intraportally was reduced by 60% at lower VIP doses (0.60 and 1.20 nmol/kg per h) and by 40% at 2.40 nmol/kg per h, whereas at higher doses it was not significantly changed. This study provides evidence that VIP in the cat is a secretin-like full agonist of pancreatic bicarbonate secretion and that it is only partially inactivated by the liver.


Influence of vagal cooling on esophageal function. Experiments were performed on adult opossums to determine the effect of decreased vagal activity on the esophageal peristalsis and lower esophageal sphincter (LES) relaxation associated with pharyngeal stimulation (PS) and esophageal balloon distension (ED). The cervical vagi were exposed and cooled (individually and bilaterally) to 3 degrees C using Dry Ice and alcohol-chilled saline. Unilateral vagal cooling had no effect on the esophageal peristalsis or LES relaxation associated with PS or ED. Similarly, bilateral vagal cooling did not alter the peristalsis and sphincter relaxation induced by ED. Bilateral vagal cooling, on the other hand, significantly decreased the incidence of peristalsis and the sphincter relaxation associated with PS. Studies were also performed to examine the effect of unilateral and bilateral vagotomy of esophageal function. Neither right nor left cervical vagotomy affected esophageal peristalsis or LES relaxation, regardless of the model of stimulation. Bilateral vagotomy, however, diminished the esophageal response to PS but was without effect on the peristalsis and LES relaxation produced in response to ED. From the studies we condlude: 1) the vagus nerve is of primary importance in regulating the esophageal response to PS, and 2) local neuromuscular factors within the esophageal wall appear sufficient to initiate and maintain an esophageal response to distension.


Daily rhythms of lipogenesis in fat and lean white-throated sparrows Zonotrichia albicollis. Lipogenesis was assayed at 6 times a day in the migratory white-throated sparrow Zonotrichia albicollis by measuring the incorporation of label in liver and body lipid 4 h after injection of [3H] acetate. There were daily rhythms of 3H incorporation by liver lipid both in fat birds in the vernal migratory condition and in lean birds in the summer photorefractory condition. Most of the liver lipid incorporation of 3H was restricted to the late afternoon and early evening in both the fat and lean birds. In addition, the total liver incorporation was similar for both groups. On the other hand, nearly twice as much 3H was incorporated in the body lipid of fat birds as in that of lean birds, and a daily rhythm was present only in fat sparrows. Injections of prolactin given simultaneously with [3H] acetate early during the day (at a time when daily injections of the hormone can cause severe losses in body fat stores) drastically reduces liver and body lipid incorporation of 3H. However, injections of prolactin during the afternoon (when daily injections of the hormone produce large increases in body fat stores) have no apparent influence on the incorporation of label. Our results indicate that a principal difference between lean and fat birds resides in a greater capacity in fat birds to transport triglycerides from the liver, in which they are produced, to the body storage depots. The daily rhythm of prolactin in some temporal relations may cause fattening by increasing the transport capacity or cause loss in fat stores in other temporal relations by directly inhibiting hepatic lipogenesis.


Changes in protein and nucleic acid synthesis in rat gastric mucosa after pentagastrin. The trophic effects of gastrin on gastrointestinal tissues have been shown to be physiologically important. This study was designed to investigate the sequence of changes in macromolecular synthesis in the rat gastric mucosa following a single dose of pentagastrin. The earliest response was an increase at 1-2 h of poly (A) messenger RNA (mRNA). This increase dropped after 4 h but remained slightly elevated even 12 h after pentagastrin. By 6 h there was a large increase in protein synthesis that lasted until 12 h. Accompanying this rise in protein synthesis was a large increase in ribosomal (rRNA) and transfer RNA (tRNA), which peaked at 12 h. The changes in both fractions of RNA and protein were over by 18 h. No significant increase in secreted protein was noted, but there was a slight, transient decrease at 1 h. Pentagastrin stimulated all forms of RNA, but the largest increase was seen in the rRNA fraction. After multiple doses, parallel increases in rRNA and tRNA were seen. The stimulation of protein synthesis could be abolished by actinomycin D, and was, therefore, RNA dependent.


Effect of hypophysectomy on calcium transport by rat duodenum. To examine the effect of hypophysectomy on intestinal calcium absorption, studies were performed on immature rats 7, 14, and 21 days after hypophysectomy. Duodenal calcium transport was measured in vitro utilizing everted gut sacs and in vivo by a luminal perfusion technique. Hypophysectomy produced no differences in the ability of everted gut sacs to transport calcium. Similarly, when in vivo transport data were expressed on the basis of intestinal length, no significant differences were noted. However, when transport data were expressed on the basis of mucosal weight, increases in absorption and lumen-to-plasma fluxes were apparent in hypophysectomized animals. No differences were seen in plasma-to-lumen fluxes. The results indicate that when the transport data are corrected for mass of intestinal mucosa, the duodenum from hypophysectomized animals absorbs calcium more avidly due to an increase in lumen-to-plasma flux.


Effect of angiotensin II and glucocorticoids on plasma angiotensinogen concentration in the dog. The increase in plasma angiotensinogen concentration produced by angiotensin II infusion in the dog is accompanied by an increase in plasma corticosteroid concentration and is prevented by adrenalectomy. The present study was undertaken to test the possibility that the angiotensinogen response to angiotensin is mediated via an increase in glucocorticoid secretion. Infusion of angiotensin II (3-6 mug/h for 5 h) into the third cerebral ventricle of five dogs increased plasma corticosteroid concentration from 3.5+/-0.6 to 11.8+/-1.5 mug/dl (P less than 0.025) but did not increase plasma corticosteroid concentration from 2.7+/-0.4 to 7.8+/-1.5 mug/dl (P less than 0.05) but again failed to increase plasma angiotensinogen concentration. On the other hand, more prolonged glucocorticoid treatment with dexamethasone produced a significant increase in plasma angiotensinogen concentration within 24 h. Intravenous infusion of angiotensin II (50 mug/h for 5 h) in five acutely hypophysectomized dogs receiving a cortisol infusion caused only a small increase in plasma corticosteroid concentration (5.0+/-0.5 TO 6.9+/-0.6 mug/dl, P less than 0.02) but increased plasma angiotensinogen concentration from 967+/-122 to 1,358+/-204 ng/ml (P less than 0.02). These results indicate that although glucocorticoids can increase plasma angiotensinogen concentration, the angiotensinogen response to angiotensin II is not dependent on increased glucocorticoid secretion.


Insulin secretion in hypoglycemia after adrenal vein ligature or splachnicotomy. During bonito insulin-induced hypoglycemia in dogs, pancreatic venous dog insulin concentration (IRI), radioimmunoassayed differentially from bonito insulin, was progressively diminished in response to local glucose infusion (0.6 mg/kg - min) for 4 min into the superior pancreaticoduodenal artery. Basal arterial plasma glucose was significantly lower after bilateral splanchnicotomy (BSNC) than after bilateral adrenal vein ligature (BAVL). During local glucose infusion in both normoglycemia and hypoglycemia, the increment of pancreatic venous IRI was significantly greater after BAVL or BSNC than in the controls, and the increment of pancreatic venous glucose was also significantly greater after BAVL than in the controls or after BSNC. It is suggested that under the stress of major surgery the splanchnic nerves partially suppress insulin secretion in normoglycemia as well as in hypoglycemia, and epinephrine released from the adrenal medulla may interfere with glucose-mediated insulin secretion in profound hypoglycemia.


Effect of isoproterenol on amino acid levels and protein turnover in skeletal muscle. The effect of isoproterenol on amino acid concentrations in perfusate and skeletal muscle was studied during a 3-h perfusion of the isolated rat hemicorpus. The beta-adrenergic agonist inhibited the accumulation  of alanine, threonine, phenylalanine, tyrosine, lysine, arginine, leucine, and valine and increased the loss of glutamate, aspartate, serine, and isoleucine from the pool of free amino acids in perfusate and muscle. The loss of glutamate was accompanied by a greater accumulation of glutamine. Changes in alanine levels showed the greatest response with a net accumulation of 98 mumol in the controls becoming a net loss of 54 mumol in the experimentals. These changes in amino acid levels were accounted for in part by a 20% decrease in protein degradation. Protein synthesis was not affected by isoproterenol. In addition to an effect on degradation,  it appeared that isoproterenol affected amino  acid levels by increasing alanine utilization and causing formation of glutamine instead of alanine. Other effects of the drug included increased rates of lactate production, muscle glycogen breakdown, and oxygen consumption, whereas no effects were observed on ATP and creatine phosphate levels. Pyruvate content of muscle was maintained at a higher level in the presence of the drug than in control perfusions.


Effects of prostaglandin E2 and prostaglandin inhibitors on adrenal regeneration hypertension. The effects of prostaglandin E2 (PGE2) and a prostaglandin inhibitor, indomethacin, on the development of adrenal regeneration hypertension (ARH) were investigated. Weanling female rats underwent right adrenonephrectomy and left adrenal enucleation. PGE2 was injected subcutaneously daily in dosages of 0, 20, 40 and 80 mug/day. Indomethacin, 1 mg/kg, was administered twice daily by gavage. Blood pressures were determined by a tail and cuff plethysmographic method at 3, 5, and 7 wk after surgery. Increases in dosage of PGE2 produced a progressive reduction in mean blood pressures, heart, and kidney weights. Indomethacin produced significant increases in mean blood pressure, heart, kidney, and adrenal weights. The effects of aspirin and indomethacin on the blood pressures of rats with right adrenalectomy, left adrenal enucleation, and intact kidneys were studied. Administration of asprin twice daily (25 or 50 mg/kg) produced a fall in blood pressure, body and heart weight. Administration of 1 mg/kg twice daily of indomethacin resulted in a significant increase in blood pressure at 3 wk, and 0.1 or 1 mg/kg caused significant increases at 5 wk. The heart, kidney, and adrenal weights also showed increases with indomethacin administration. This study suggests that a deficiency of renal PGE2 may be involved in the etiology of ARH.


Phosphaturic effect of furosemide: role of PTH and carbonic anhydrase. The first objective of this study was to examine the effects of furosemide on renal phosphate excretion in the presence and absence of a constant level of parathyroid hormone (PTH) while extracellular fluid volume was held constant. In the absence of PTH, furosemide did not significantly increase fractional phosphate excretion (FEP%, 4.2 +/- 2.7 to 6.2 +/- 1.9%; five dogs). In the presence of PTH, furosemide increased FEP% from 23.4 +/- 3.7 to 33.8 +/- 6.0% (P less .025; five dogs). Thus, the phosphaturia induced by furosemide was dependent on the presence of PTH. The second objective was to evaluate the hypothesis that furosemide exerts its phosphaturic effect through carbonic anhydrase inhibition, and therefore we tested for additivity of the phosphaturic effect of furosemide, and acetazolamide. In the presence of a constant level of PTH, acetazolamide increased FEP % from 24.5 +/- 1.8% to 40.7 +/- 5.1% P less than .025, five dogs. The subsequent administration of furosemide did not further increase FEP%, delta 3.3 +/- 8.9%; NS. Thus, the phosphaturic effect of furosemide was not additive to that of acetazolamide, indicating that acetazolamide and furosemide may share similar mechanisms for inhibiting phosphate reabsorption.


Antidiuretic hormone and the distribution of renal cortical blood flow. The radioactive microsphere method was used to study the distribution of cortical blood flow in anesthetized dogs during water diuresis and during antidiuresis. Infusion of antidiuretic hormone (ADH) at rates ranging from 0.33 to 0.5 mU/kg-min into dogs previously volume expanded with 3% dextrose resulted in an increase in urinary osmolality and a significant increase in fractional flow in the inner cortex. Mean arterial pressure, glomerular filtration rate, and renal plasma flow were unaltered by the infusion of ADH at these doses, suggesting that absolute, as well as fractional, blood flow to the inner cortex increased in response to ADH. In three additional experiments, termination of an infusion of ADH in hydropenic dogs and subsequent induction of water diuresis was accompanied by a shift in fractional cortical blood flow away from the inner cortex. The redistribution of cortical blood flow in response to ADH at a time when the kidney is producing a more concentrated urine supports the hypothesis that this vascular effect of ADH may have functional significance in the urinary concentration ability of the kidney.


Effect of NaCl on composition and volume of cells of the rat papilla. The composition and volume of the cells of an isolated rat papilla were measured in media in which NaCl was varied from 150 to 600 mM; KCl, from 2 to 20 mM; or which contained mannitol, 300 mM. Change in NaCl from 150 to 600 mM reduced cell volume by 25%, increased cell Na+ content by 250% but had no significant effect on cell potassium concentration or content. Increases in K+ concentration in the media did not affect cell water or cell sodium, but the cell potassium rose by an amount approximately 3 times the increase in the medium concentration. Mannitol reduced cell volume; the cell content of sodium and potassium did not alter, but the concentration of Na+ and K+ altered reciprocally with the change in cell volume. Similar changes were observed with liver slices. This study indicated that papillary cells maintain osmotic equilibrium by the accumulation of sodium. This accumulation may influence the metabolic activity of the medullary and papillary cells.


Effects of saline and albumin on plasma and urinary catecholamines in dogs. Volume expansion by infusion of saline and 25% albumin has been compared in dogs to differentiate volume- and salt-induced catecholamine changes previously observed in humans. Plasma and urinary norepinephrine (NE) and epinephrine (E) decreased following both saline (urinary) NE+E, from 17.3 +/- 3.4 to 6.8 +/- 1.5 ng/min; P less than 0.005) and albumin (from 29.9 +/- 3.4 to 12.5 +/- 2; P less than 0.001) infusion. Urinary dopamine increased in saline-expanded dogs (from 3.4 +/- 0.6 to 4.4 +/- 0.8 ng/min, P less than 0.05), but did not significantly change in control and albumin-expanded dogs; whereas plasma free dopamine remained uninfluenced by saline or albumin. The mean renal clearance of dopamine more than doubled (from 110 +/- 37 to 272 +/- 96 ml/min; P less than 0.05) in response to saline expansion, but did not significantly change in response to albumin expansion or in control animals. A significant correlation between the increase of urinary dopamine and the tubular rejection fraction of sodium was found in saline-expanded dogs (P less than 0.05), or when all experiments (saline, albumin expansion, and control dogs) were considered together (P less than 0.001). The data indicate that : 1) the increase in urinary dopamine excretion (concomitant with sodium excretion) is related to the saline infusion rather than to the suppression of the sympathetic nervous system induced by plasma volume expansion; 2) this increased urinary dopamine originates probably in the kidney. Dopamine may thus be somehow related to regulation of urinary sodium excretion, either as an endogenous natriuretic factor or a response reflecting natriuresis.


Effect of secretin on renal blood flow, interstitial pressure, and sodium excretion. Most renal vasodilators are natriuretic. However, secretin increases renal blood flow (RBF) markedly but produces only a very slight increase in sodium excretion (UNaV). To investigate this observation further, the relationship between vasodilatation, interstitial pressure (IP), and UNaV was studied in dogs. Intrarenal infusion of secretin increased RBF (delta=107+/-19 ml/min). The IP, as measured from chronically implanted polyethylene matrix capsules, was not significantly changed (delta=-0.3+/-0.5 mmHg). UNaV was slightly, although significantly, increased (delta=19+/-4 mueq/min). Following a similar increase in RBF with an intrarenal infusion of acetylcholine (ACh), IP and UNaV increased markedly (delta=8.2+/-0.8 mmHg and 174+/-23 mueq/min, respectively). Neither secretin nor ACh) altered glomerular filtration rate or blood pressure. Both secretin and ACh produced comparable increases in peritubule capillary(delta=5+/-1 and 7.5+/-1.4 mmHg, respectively) and free-flow tubule pressure (delta=7+/-2 and 9.5+/-1.4 mmHg, respectively). In summary, the usual relationship between vasodilatation and IP was dissociated during secretin infusion, whereas the relationship between IP and natriuresis was not dissociated.


Evidence for a peritubular-to-luminal flux phosphate in the dog kidney. The possible presence of a direct influx of phosphate into the tubular lumen of the dog kidney was examined by two different techniques. A 0.3-ml bolus of 32PO4 and [3H]inulin was injected into the renal artery of dogs with and without phosphate loading. The mean urinary transit time (TT) for PO4 was consistently less than the TT for inulin in nonphosphate-loaded dogs. Following phosphate loading the TT for phosphate approached but did not equal the TT for inulin. In contrast, after microinjections of 32PO4 and [3H]inulin into proximal tubules, the urinary TT of PO4 was significantly longer than the TT of inulin. The application of 32PO4 and [3H]inulin to the surface of the left kidney was associated with a greater recovery of 32PO4 from the left kidney compared to that from the right kidney. The recovery of [3H]inulin was proportional to the glomerular filtration rate for both kidneys. Application of the 32PO4 and [3H]inulin to the surface of a muscle resulted in an equal recovery of phosphate and inulin from both kidneys. The results demonstrate the presence of a detectable tubular influx of phosphate.


Renal clearance studies in fetal and young guinea pigs: effect of salt loading. The maturation of renal function was investigated by clearance studies in 11 fetal, 9 young, and 4 adult guinea pigs undergoing salt loading (NaCl 1.5%, 75 mul min-1 100 g-1) and in 10 young and 4 adult animals under nondiuretic conditions. The fetal preparation described makes it possible to obtain two to four steady clearance periods for each animal. In the fetus, GFR increased significantly with age, but less than in the newborn. Fractional water and sodium reabsorption was generally low, and net renal secretion of potassium was observed in some cases. Fetal urine was sometimes slightly hypertonic. The effectiveness of the diuretic and natriuretic response following saline expansion was smaller in young than adult animals. The fractional excretion rate of solutes and water increased as a function of age in the young animal and the urinary Na/K concentration ratio showed a marked drop around birth. This latter observation suggests that during the first days of life the effect of saline expansion on the proximal tubule is partially blunted by enhanced sodium reabsorption from the distal nephron due to the high concentration of circulating aldosterone.


Effect of aortic clamping on proximal reabsorption and sodium excretion in the rat. It has been suggested that aortic clamping prior to expansion of the extracellular fluid volume prevents the natriuretic response normally seen in this setting. To further evaluate this finding, two groups of re-collection micropuncture studies were performed before and after 7.5% body wt expansion with Ringer solution. Group I, immediate-clamp studies, n, 11. After control collections, perfusion pressure to the left kidney was decreased to 75 mmHg followed by Ringer loading. Group II, delayed-clamp studies, n, 8. After control collections, Ringer solution was given for 40 min. Then the left renal perfusion pressure was reduced to 75 mmHg and the Ringer infusion was continued at the same rate. In the immediate-clamp group, there was no change in total kidney glomerular filtration rate (GFR) (1.16 vs. 1.11 ml/min), nephron GFR (40 vs. 39 nl/min), tubular fluid-to-plasma inulin ratio (2.40 vs. 2.28), or filtrate delivery out of the proximal tubule (18 vs. 18 ndium excretion were not significantly altered. In the delayed-clamp studies, there was also no change in total or nephron GFR, but the tubular fluid-to-plasma inulin ratio fell from 2.52 to 1.65 (P less than .001) and distal delivery rose 9 nl/min after expansion (P less than .001). Sodium excretion increased 3.83 mueq/min and fractional sodium excretion rose 2.28%, both values being markedly greater than in the immediate-clamp studies (P less than .005 for both). These results demonstrate that immediate clamping obviates the fall in proximal reabsorption and the natriuretic response to Ringer loading and suggests that intrarenal adjustments are a major determinant of the magnitude of the natriuretic response to expansion of the extracellular volume


Factors determining superficial nephron filtration in the mature, growing rat. Factors that determine and cause an increased glomerular filtration rate in superficial nephrons (sngfr) in the mature, growing rat were examined in 39 Munich-Wistar rats, ranging from 93 to 335 g in body weight, from 40 to 140 days in age, and in sngfr, from 15 to 78 nl/min. Hydrostatic pressure gradient (delta P) from glomerular capillary (PG) to Bowman's space (Pt) was measured in surface glomeruli and pertinent oncotic pressures (pi) by microprotein methods. Isoncotic plasma expansion (PV) prevented filtration-pressure equilibrium (EFP) and permitted calculation of glomerular permeability coefficient (LpA) where sngfr = EFP-LpA, and EFP = delta P - pi. Increased sngfr correlated best with nephron plasma flow (rpf) (r = 0.81, P less than 0.001) and LpA (r = 0.71, P less than 0.001). The rpf increased because of parallel reductions in afferent and efferent resistances (slope = 0.89 +/- 0.09, r = 0.86, P less than 0.001), which also produced a constancy of PG and deltaP with growth. The ratio of rpf to LpA remained constant with growth permitting EFP to remain relatively unchanged (r = 0.14, P greater than 0.4). The increase in LpA should permit filtration-pressure equilibrium to persist in the hydropenic rat in spite of increases in rpf with growth. deltaP was constant with increasing age and therefore did not contribute to the increase in sngfr.


Comparison of vascular effects of gastrointestinal hormones on various organs. Vascular effects of raising local arterial concentration of pentagastrin (2-1,500ng/ml), secretin (0.2-150mU/ml), and cholecystokinin (0.2-150mU/ml) in the duodenum, jejunum, heart, kidney, forelimb, spleen, and the skin and muscle of the forelimb were studied in 54 anesthetized dogs. Secretin produced similar vasodilation in all organs. The minimal increment in local blood secretin concentration for vasodilation ("concentration requirement") was between 7 and 32 mU/ml. Pentagastrin produced vasodilation only in the duodenum and jejunum and the concentration requirement was between 25 and 50 ng/ml. Cholecystokinin did not affect vascular resistance of the forelimb, skin, or muscle. In the heart, kidney, and spleen, cholecystokinin produced vasodilation but the concentration requirement was above 21-33 mU/ml. In contrast, vasodilation in the duodenum and jejunum appeared when cholecystokinin concentration was increased by only 2.5 mU/ml. Furthermore, almost all its vasodilating effect occurred below an increment of 10 mU/ml. Comparison of our data with the reported cardiovascular adjustments and blood concentration of gastrointestinal hormones following a meal suggests that cholecystokinin may contribute to postprandial intestinal hyperemia.


Angiotensin II antagonists in dehydrated rabbits without baroreceptor reflexes. Blood pressure effects of angiotensin II antagonists were studied in sham-operated and baroreceptor-denervated rabbits in the normal water-replete state or after 6 days of water deprivation (dehydrated). Experiments were performed in awake rabbits. Dehydrated rabbits had significantly higher plasma sodium concentrations, hematocrits, and plasma renin activities, but lower plasma potassium concentrations and body weights than water-replete rabbits. Administration of angiotensin II antagonists caused a significant decrease in mean arterial pressure in dehydrated rabbits (-16 mmHg in sham-dehydrated and -19 mmHg in denervated-dehydrated) but not in water-replete ones, whether the baroreceptor reflexes were intact or not (-1 mmHg in sham replete and -4 mmHg in denervated replete). The open-loop feedback gain of the renin-angiotensin system in blood pressure control was calculated as -1.6. The results demonstrate an important role of angiotensin II in blood pressure regulation during the high-renin, dehydrated state, but not during the normal renin, water-replete state. Abolishment of baroreceptor reflexes did not unmask an important role of normal levels of angiotensin II in blood pressure regulation.


Elevated systolic pressure following chronic low-level cadmiun feeding. Groups of 16 female Long-Evans rats received 0, 1, 2.5, 5, 10, 25, and 50 mg cadmium/liter dringking water (parts per million (ppm)), from the time they were weaned until they were 30 mo old. Systolic pressure was measured indirectly in triplicate at 6-mo intervals. Both 2.5 and 5 ppm cadmium consistently induced significant elevations in mean systolic pressure, ranging from 13 to 33 mmHg. At 6 mo, 10 and 25 ppm cadmium also induced significant elevations, whereas at 12 mo and subsequently 1 ppm cadmium induced significant elevations. With 10 ppm cadmium or less weight gain was normal and there was no evidence of cadmium toxicity. With 25 and 50 ppm cadmium weight gain was diminished, suggesting toxicity. Five rats with each level of exposure were sacrificed every 6 mo from a second population of similarly handled rats in order to determine renal cadmium concetrations. Cadmium intakes that had induced hypertension were associated with mean renal cadmium concentrations ranging from 5 to 50 mug/g kidney.


Comparison of arteries with longitudinal and circular venous muscle from the rat. Rat portal, mesenteric, renal, and femoral veins possess functionally responsive circular and longitudinal smooth muscle layers in vitro. In contrast to the dominant rhythmically active longitudinal muscle of portal veins, rat longitudinal mesenteric veins lacked rhythmic activity and developed maximal force equivalent to that of mesenteric circular muscle. Renal and femoral veins exhibited predominantly circular smooth muscle responses. Rat veins must be subjected to between 1 g (renal and femoral) and 4 g (circular portal and mesenteric) of passive forse for optimal responsiveness. Contractile response to vasoactive agent including carbamylcholine, serotonin, and norepinephrine was quantitatively different among veins. Femoral veins developed greater maximal force in response to norepinephrine than to KCL, and the responses to norepinephrine were not altered by cocaine. In contrast, cocaine markedly potentiated responses to norepinephrine in portal, mesenteric, and renal veins and, to a lesser extent, in the mesenteric artery. These data demonstrate heterogeneity in rat venous tissue and suggest that neuronal innervation may markedly influence responses to norepinephrine in some, but not all, rat blood vessels.


Norepinephrine release in isolated arteries induced by K-free solution. Helical strips from arteries with a rich sympathetic innervation (rat tail and femoral, and dog mesenteric arteries) develop a sustained contracture when exposed to a K-free physiological salt solution (PSS). The contracture can be blocked by phentolamine and does not occur in arteries whose nerve terminals have been destroyed with 6-hydroxydopamine. The temporal relationship between force development and efflux of NE was determined. Helical strips of rat tail arteries or dog mesenteric arteries were incubated in PSS containing 1-norepinephrine-7-3H([3H]NE). They were then transferred to a superfusion system which allowed isometric recordings and collection of the superfusate for the estimation of [3H]NE content. Following exposure to a K-free PSS force development paralleled NE release and both parameters were potentiated by ouabain. These data demonstrate that this neurogenic mechanism plays a most important role in the K-free contracture of the vascular smooth muscle studied. It is in accord with the observation that NE is released by adrenergic nerves following inhibition of Na+-K+-ATPase.


Opposing central and peripheral effects of atropine on parasympathetic cardiac control. Cardiac vagal efferent (CVE) activity was recorded from fine strands of the cervical vagus of chloralose-urethane-anesthetized dogs weighing an average of 14.6 kg. In spontaneously breathing animals atropine sulfate in doses of 0.003-1.5 mg significantly increased CVE activity even when the activity was corrected for changes in blood pressure. A 50% average increase (P less than 0.001) in mean activity was observed at a dose of 0.15 mg. The increase was not abolished by vagotomy as long as the animals were allowed to breathe spontaneously. The peripheral effect of atropine was characterized by the relationship between CVE activity and measured heart period changes. A 50% peripheral blockade was achieved at a dose of 0.06 mg; a dose of 1.0 mg produced essentially complete (greater than 90%) blockade. The results quantitatively demonstrate that atropine exerts a powerful central stimulating effect on CVE activity while simultaneously blocking vagal heart rate effects at the periphery.


Mechanism of action of isoproterenol on venous return. The systemic vascular effects of isoproterenol infused in a dose of 1 mug-kg-1-min-1 was studied in 10 anesthetized dogs. A right heart bypass preparation allowed the separation of venous return into splanchnic and extrasplanchnic flows. Each channel was drained by gravity into an external reservoir. Venous return was then pumped into the pulmonary artery. During the infusion of isoproterenol, the pump was set at sufficient speed to maintain a constant level of blood in the external reservoir. Venous resistances and compliances of both channels were calculated from transient and steady-state volume shifts that occurred after rapid drops in splanchnic and then extrasplanchnic venous pressures. Isoproterenol affected both arterial and venous systems. Venous return increased from 1.62+/-0.11 to 2.40+/-0.19 liter/min (P less than 0.001) while arterial pressure fell from 97.5+/-3.8 to 70.2+/-5.9 mmHg (P less than 0.01). The compliances of the splanchnic and extrasplanchnic channels did not change significantly from their control values of 0.025+/-0.004 and 0.024+/-0.002 liter/mmHg. The venous resistance of the extrasplanchnic channel also did not change from its control value of 5.0 mmHg-liter-1-min-1; however, the splanchnic venous resistance decreased from 16.3+/-3.2 to 9.4+/-2.8 mmHg-liter-1-min-1 (P less than 0.001). The effective splanchnic back pressure, estimated by measuring the level to which hepatic venous pressure had to be raised to cause a change in portal pressure, decreased from 3.9 to 3.0 mmHg (P less than 0.01).


Left atrial size and geometry in the intact dog. Multiple determination of size, shape, and diameter of the left atrium were made during the control state and under conditions of varied ventricular outflow resistance in intact anesthetized dogs with markers chronically attached to the mitral annulus and the valve cusps. Measurements were made from left atrial angiograms (120 frames/s) obtained after injections of contrast medium into the pulmonary artery. Changes in atrial size were characterized by symmetrical circumferential diameter changes and eccentric variations of anteroposterior axis due almost entirely to valve ring displacement. With normal aortic pressure, maximal atrial area averaged 11.0+/-3.1 cm2. When aortic pressure was increased maximal area increased to 12.9+/-3.7 cm2 and percent emptying decreased, whereas maximal and minimal atrial areas were similar to control values during decreased aortic pressure. These findings suggest the possibility that atrial emptying may be near maximal at the resting control state.


Function of lateral reticular nucleus in central cardiovascular regulation in the cat. The role of the lateral reticular nucleus (LRN) in central cardiovascular regulation was investigated in cats. In 15 cerebellectomized and nine intact chloralosed cats stimulation of 115 histologically verified sites in the LRN elicited increases in arterial pressure and heart rate; the latter was abolished by propranolol but not by bilateral cervical vagotomy. The pressor response was significantly greater in intact animals. Electrical activity was recorded from the right inferior cardiac nerve (ICN) during stimulation fo the LRN  and of a vasomotor region in the posteromedial hypothalamus (PMH). Stimulation of sites in the LRN and in the PMH, on both sides, elicited a response in the right ICN that was consistently abolished during baroreceptor excitation. Medullary transection 3 mm rostral to the LRN did not abolish the  ICN response to LRN stimulation. The conclusions are drawn that stimulation of the LRN elicits cardiovascular responses probably due to excitation of groups of neurons in this nucleus located in a descending sympathetic pathway originating in the PMH and that these responses can be inhibited by excitation of baroreceptors. In view of the known functional connections of the LRN with the somatomotor system it is suggested that this nucleus may play a major role in somatosympathetic reflexes.


Arterial barostasis along the mouse tail between different steady-state flows. From its etymology, "barostasis" would denote homeostasis with respect to pressure in relation to the blood vascular system. Arterial pressure and flow were measured along the proximal half of the tail of the unanesthetized, intact mouse with a pneumatic cuff and just distally with a pneumatic plethysmograph at room temperatures near 20 and 25 degrees C. The pressure fell measurably from proximally to distally at both temperatures. From 20 to 25 degrees C barostasis was evident in that the local pressure changed relatively little proportionately in comparison with a considerable proportional increase in flow. As in other studies the occlusion of the circulation for some seconds was followed by a momentary increase in flow lasting less than a minute.


Phospholipid metabolism during renal regeneration after acute tubular necrosis. Renal function, structure, and membrane metabolism were studied during regeneration of proximal tubular cells in rats. A reversible syndrome of nonoliguric acute renal failure was induced by the intravenous administration of a low dose of mercuric chloride (1.0 mg Hg/kg). At day 1 there was a marked increase in serum urea nitrogen concentration (SUN), decrease in food intake, and a zone of proximal tubular cell necrosis in the inner cortex. By day 3 low cuboidal epithelial cells were seen, indicating that regeneration had been initiated despite decreased food intake and increasing SUN. Phospholipid synthesis for new membrane formation in regenerating cells was studied by using [14C] choline as a precursor of phosphorylcholine and cytidine diphosphocholine (CDP-choline), which are intermediates in the synthesis of renal choline-containing phospholipid. The rate of [14C]choline incorporation into phospholipids in inner cortical slices was lowest 1 day after mercury administration, then increased constantly for the next 4 days to reach a maximal value 104% above control. The rate declined slowly for the next 11 days and returned to normal by 28 days. The increased rate represented choline phosphoglyceride synthesis, since degradation was unchanged. The entire increment in choline radioactivity in regenerating tissue 2 and 3 days after mercury administration was in phospholipid or CDP-choline, which suggests that the increased number of choline molecules entering the growing cells were trapped in these two forms. The results indicate that renal regeneration is associated with a specific enhancement of the synthesis of choline-containing phospholipids. This anabolic response of the kidney occurs in the presence of systemic catabolism and progressive renal functional insufficiency.


Potassium and chloride conductances in normal and denervated rat muscles. The membrane conductance of rat muscles (mainly gastrocnemius (G) and soleus (S)) was measured by using the two-microelectrode technique and the current point clamp method. Thin muscle bundles were washed in Tris chloride and Tris propionate solutions containing 6 mM K. The current strength was always 5 x 10-9 A and the steady-state membrane voltage was about 5 mV. The average chloride conductance (gcl, in mumho/cm2) of normal muscles was 845 (G) and 1,025 (S). The potassium conductance (gk) was 99 (G) and 161 (s). In separate measurements, the contribution of the chloride conductance (gcl) to the total membrane conductance (gm) was 89% for normal G and S. Two weeks after denervation the average gcl decreased to 440 in G and 191 in S; gk increased to 205 in G and to 364 in S in the presence of 0.1 mM Ca in solution; the increase in gk was less when measurements were made in the presence of 3mM Ca and 1 mM Mg. The contribution of gcl to gm was 60% in G and 30% in S in 14-day denervated muscles. The coefficient of variation for gcl/gk in 30 normal and 46 denervated muscles was 0.91 and 0.46, respectively. The curve representing the voltage-current relationship of muscles washed in Cl-free solutions containing 60 mM K was S-shaped in normal and in denervated muscles, but the changes in slope were less marked in the latter.


Effects of cadmium and lead on adrenergic neuromuscular transmission in the rabbit. The effects of inorganic lead (PbCl2) and cadmium (DdCl2) on the pressor response of rabbit saphenous arteries produced by sympathetic nerve stimulation were examined. A 1- to 3-cm length of artery was removed, placed in a bath containing mammalian Ringer solution, and perfused with the same solution at a constant rate sufficient to maintain a 40-60 mmHg perfusion pressure. Increases in perfusion pressure resulting from electrical stimulation -f periarterial nerve endings were reduced or completely blocked by the addition of 5-20 muM lead or cadmium to the bathing solution for a period of 15-30 min. Responses to norepinephrine or to direct electrical stimulation of the muscle remained relatively unaffected. During lead or cadmium blockade, the response to nerve stimulation could be restored by a fourfold increase in calcium concentration. It is concluded that lead and cadmium reduce the response to sympathetic nerve stimulation primarily through an effect on presynaptic nerve terminals.


Effect of pulmonary edema on drug transport and binding in rat lung. The pulmonary absorption and uptake of (35S)phenol red ((35S)PR was measured in anesthetized rats with alpha-naphthylthiourea- (ANTU) induced lung edema. When (35S)PR solution was injected through a tracheal cannula in control animals and the percentage of the tracheal cannula in control animals and the percentage of the dose unabsorbed plotted semilogarithmically against time, an apparent first-order absorption rate was obtained. In contrast, in rats with ANTU-induced edema, the absorption time curve showed at least two different first-order components. Increasing the concentration of (35S)PR from 0.01 to 3 mM resulted in a decrease in the percentage absorption of the compound in controls compared with a relatively constant percentage absorption in edematous lungs. (35S)PR uptake by lung slices from ANTU-treated rats was decreased in the presence of IAA and a N2 atmosphere, and the dye accumulated at a faster rate and to a greater extent than in controls. The results suggest that although energy-dependent drug transport mechanisms remain intact, the porosity of the absorbing membranes and the extent of drug binding in the lung are increased markedly in the presence of edema.


Effect of hyperosmolarity on resting and developed tension in heart muscle. Simultaneous changes in weight, tension, and electrical activity were studied in the isolated perfused rabbit heart when the Ringer solution perfusion fluid was made hypertonic by the addition of sucrose, urea, glycerol, ethylene glycol, or formamide. The typical responses to each of the molecules was an initial drop in weight and tension followed by a return toward the base-line level. A 0.4 M concentration of sucrose, urea, or glycerol reduced the weight to 40 +/- 4.6, 48 +/- 3, and 52.2 +/- 3% of the initial value, respectively. The tension was simultaneously reduced to 23 +/- 3.5, 31 +/- 2, and 41 +/- 4% of its initial value. The tension drop produced by the solutes tested was linearly related to the amount of water lost by the heart. The falling phases of both tension and weight loss were closely correlated phases of both tension and weight loss were closely correlated in time a magnitude and were both related to the effectiveness of a particular molecule to move water out of the cells. In contrast, the subsequent rising phases of tension and weight were not as well correlated in time and magnitude. Whereas for most of the molecules used, the tension recovery was incomplete; urea, in contrast, caused an overshoot of the control tension level, thus pointing toward a unique inotropic effect of this compound. Resting tension rose for both urea and sucrose but not for the other compounds.


Neurotrophic regulation of insulin-sensitive amino acid uptake in rat fast muscle. Our object was to determine how innervation regulates muscle insulin sensitivity. Insulin-stimulated uptake of the nonmetabolized amino acid, 2-amino-isobutyric acid, was used as a measure of insulin sensitivity in denervated rat extensor digitorum longus muscles retaining either a similar 2.5-cm (""proximal denervation'') or a similar to 0.5-cm (""distal denervation'') length of distal nerve stump. Because both muscles were inactive in the first 24 h, any difference in insulin sensitivity could be due only to some trophic influence of the distal nerve stump. Fifteen hours after either type of denervation, 2-aminoisobutyric acid uptake was refractory to insulin. However, at 24 h, insulin sensitivity of distally denervated muscles (with or without a second ipsilateral proximal denervation) was normal, whereas that of proximally denervated muscles was still relatively insensitive. In the absence of insulin, the two types of denervated muscles at 24 h showed no difference in 2-aminoisobutyric acid uptake. Finally, organ culture of paired muscles with or without long nerve stumps showed corresponding differences in insulin-stimulated 2-aminoisobutyric acid uptake after 48 h in vitro. Thus, a neurotrophic factor, independent of impulse activity, stretch, or changes in blood flow, regulates one type of muscle insulin sensitivity.


Amine uptake and metabolism by endothelium of pig pulmonary artery and aorta. The uptake and metabolism of 5-hydroxytryptamine (5HT) and l-norepinephrine (NE) were measured in endothelial cells of pig pulmonary artery and aorta, as well as in lung slices. Evidence for oxidative deamination and for a saturable uptake mechanism, sensitive to cold, imipramine, and NA+-free medium was obtained for 5HT in lung slices and in the pulmonary as well as in the aortic endothelium, separated from the lumen by absorption to Millipore filters or by exposure to collagenase. For NE, however, a similar type of uptake could be deomonstrated in lung slices only. In the aortic and pulmonary endothelium, NE was metabolized, but its uptake was not influenced by imipramine, Na+-free medium, and high substrate concentration. The aortic and pulmonary endothelium have, therefore, similar properties and exhibit for 5HT, but not for NE, a type of uptake similar to that existing in lung capillaries.


Effects of luminal hyperosmolality on electrical pathways of Necturas gallbladder. The electrical properties of the transepithelial pathways of Necturaus gallbladder were studied with intracellular microelectrode techniques under control conditions and after exposure to hyperosmotic mucosal bathing media (addition of sucrose or other solutes). Doubling mucosal osmolality produces a large increase in the resistance of the intercellular shunt pathway (from 420 +/- 50 to 700 +/- 70 omega - cm2, P is less than 0.001) and a significant decrease in the resistance of the apical membrane of the cells (from 3,510 +/- 420 to 1,540 +/- 380 omega p cm2, P is less than 0.001). The basolateral membrane resistance remains unchanged. Both the apical and basolateral membranes depolarize (from 59.5 +/- 1.8 to 36.6 +/- 2.8 mV, P less than 0.0001, and from 61.8 +/- 1.7 to 32.2 +/- 3.0 mV,P is less than 0.001, respectively). The transepithelial diffusion potential resulting from NaCl concentration gradients due to the osmotic water flow does not explain the cell potential changes. Mucosal solution ion substitution experiments demonstrate increases of gk, gcl, and gna (ca. 2.5-fold, 4-fold, and 7-fold, respectively). Therefore, cell depolarization appears to be produced mainly by a reduction of apical membrane K permselectivity. The increase in the resistance of the shunt is attributable to reduction of the width of the lateral intercellular spaces, because of the osmotic serosa-to-mucosa water flow.


Fatty acid oxidation by isolated perfused working hearts of aged rats. It has been reported that mitochondria isolated from hearts of old rats have lower respiratory activity than mitochondria from young rats. In order to determine the physiological correlates of these changes, the metabolism of hearts from young and old rats has been compared in a perfused working heart preparation. The oxidation of [14C]palmitate to 14CO2, oxygen consumption, and nucleotide levels were measured under different cardiac workloads. The hearts from old animals performed less cardiac work and utilized less oxygen and palmitate in proportion to tissue mass, but the ratio of oxygen consumed to pressure developed was unaltered. There was a small but significant decrease in cardiac efficiency expressed as the ratio between the rate of oxygen consumed and ventricular pressure development. Tissue levels of total carnitine and long-chain acylcarnitine derivatives were greatly reduced in the older heart without significant change in free CoA, acetyl-CoA, or long-chain acyl-CoA. The adenine nucleotide levels were not significantly different in the two groups. The results appear consistent with the in vitro studies on isolated mitochondria.


Amino acid metabolism of dog jejunum before and during absorption of keto analogues. In fasting dogs, significant uptake by the jejunal wall from arterial blood was found for glutamine and eight other amino acids. Significant release into the mesenteric vein of ammonium, alanine, citrulline, and proline occurred, equal in nitrogen content to glutamine nitrogen taken up. The keto analogues of leucine, valine, and isoleucine, infused for 1 h into the lumen at initial concentrations of 10mM, disappeared from the lumen at 20.2 +/- 1.6, 18.6 +/- 2.0, and 15.7 +/- 2.8 mumol/cm in 1h, respectively. Eight fifteen and seventeen percent, respectively, of these absorbed quantities were released into mesenteric blood as leucine, valine, and isoleucine plus alloisoleucine, indicating significant amination of the keto acids by the gut wall. No significant changes were detected in the arteriovenous differences of any other amino acids or ammonium. The remainder of the absorbed analogues of valine and isoleucine appeared as such in the blood. In the case of the keto analogue of leucine, there was apparent degradation by the gut wall of 34% of the absorbed compound.


A potassium gradient in smooth muscle segment of the opossum esophagus. Sodium and potassium content were determined in the smooth muscle segment of the opossum esophagus. Extracellular space measurements were also made using inulin and mannitol as markers. The muscle also made using inulin and mannitol as markers. The muscle was sampled at five sites spaced equally along the esophageal segment. On site in the stomach was also examined. The mean tissue sodium content was 36.6 +/- 10.7 meg/kg, and the mean tissue sodium content was 83.5 +/- 2.9 meg/kg wet wt. The mean inulin space was 184 +/- 34 ml/kg, and the mean mannitol space was 249 +/- 20 ml wet wt. The tissue potassium content was found to decline from 48.4 /- 10.1 meg/kg at the proximal site to 23.6 +/- 8.0 meg k/g at the distal site. The slope of electrolyte values from sites 1 through 5 was significant for both potassium and sodium. Extracellular space volume did not differ significantly from one end of the smooth muscle segment to the other.


Actions of cholecystokinin octapeptide on smooth muscle of isolated dog intestine. Adult dogs were anesthetized and segments of small intestine were isolated and perfused via a mesenteric artery with Krebs-bicarbonate solution. Muscle responses along the circular and longitudinal axes were monitored with extraluminal strain gauge transducers. Agonists were administered as intraarterial bolus injections in volumes not exceeding 0.1 ml. Antagonists were dissolved in the Krebs perfusion solution. The C-terminal octapeptide of cholecystokinin (CCK-OP) produced dose-related tonic and phasic contractions of smooth muscle along the transverse axis and tonic and phasic relaxations along the longitudinal axis of the muscle segments. Smooth muscle responses to CCK-OP were reduced by atropine sulfate (0.1 mug/ml) and minimally affected by hexamethonium (10 mug/ml) perfusion. Tetrodotoxin (TTX, 5 ng/ml) selectively reduced muscle responses to dimethylphenylpiperazinium (0.5 mug) and CCK-OP (0.2 mug) but failed to alter responses to bethanechol (BeCh, 5 mug). Higher concentrations of TTX (10 ng/ml) abolished responses to CCK-OP. Depolarizing doses of nicotine (500 mug) selectively antagonized responses to 5-hydroxytryptamine (5HT, 5 mug) and CCK-OP (0.2 mug) but did not alter responses to BeCh (5 mug). Perfusion with tetraethylammonium (1 mg/ml) reduced muscle responses to depolarizing doses of nicotine and abolished the nicotine-induced antagonism of 5HT and CCK-OP. The intestinal smooth muscle response to CCK-OP in the dog is mediated through a neurogenic mechanism. CCK-OP interacts with a nonnicotinic receptor on postganglionic cholinergic neural elements in this preparation.


Bovine pancreatic peptide: action on gastric and pancreatic secretion in dogs. Bovine pancreatic peptide (BPP) is a straight chain peptide containing 36 amino acid residues that has recently been isolated from pancreatic tissue. At a dose of 40 mug/kg-h intravenously, it stimulated gastric acid secretion when given alone but inhibited the submaximal secretion induced by the C-terminal pentapeptide of gastrin. Basal pancreatic secretion of dogs was inhibited by BPP (1-10 mug/kg-h) inhibited pancreatic protein secretion but often showed a biphasic action on water-bicarbonate response, an initial augmentation followed by reduction. BPP (2-5 mug/kg-h) inhibited pancreatic water-bicarbonate and protein secretions induced by an infusion of secretin plus cholecystokinin. Des-tyrosyl-NH2 BPP lacking the C-terminal tyrosyl amide, failed to inhibit gastric acid induced by C-terminal pentapeptide of gastrin or pancreatic secretion induced by secretin. BPP had no hyper- or hypoglycemic, hyperkalemic, or diuretic actions in the dog.


[3H]inositol incorporation into phosphatidyl-inositol in work-induced growth of rat muscle. Unilateral tenotomy of the gastrocnemius muscle in normal rats caused rapid hyptertrophy of the soleus and plantaris muscles. The phospholipid content of hypertrophied muscles increased; the increase was proportional to the extent of hypertrophy and was distributed proportionally among the major phospholipid components. During the growth process, the hypertrophying muscles incorporated [3H]inositol into phosphatidyl-inositol more rapidly than did the contralateral, control limb muscles. The increased incorporation was evident 2 h after the operation and cannot be explained solely by an increased uptake of [3H]inositol. After growth had ceased, the incorporation of [3H]inositol into phosphatidyl-inositol gradually returned toward control levels. The increase in incorporation after tenotomy was prevented by simultaneous spinal section to abolish activity in the tenotomized limb muscles. By contrast, in rats that had been forced to swim for prolonged periods of time, there was no increased incorporation of [3H]inositol into phosphatidyl-inositol. It is concluded that the increased incorporation of [3H]inositol into phosphatidyl-inositol is related to increased muscle activity sufficient to produce compensatory hypertrophy.


Adaptation to calcium deprivation in the rat: effects of parathyroidectomy. The role of parathyroid hormone (PTH) in the adaptive response in gut calcium transport to calcium deprivation has been studied in the rat using both the in vitro everted duodenal sac and the in situ ligated duodenal segment technique. Intact or parathyroidectomized (PTX) young rats were placed on a low calcium (0.01%) diet for 7-, 14-, or 21-day adaptation periods and compared with control rats maintained on a high calcium (1.5%) diet. Prior PTX (3 days before the start of the adaptation period) abolished the adaptive response (enhanced calcium transport) induced by calcium deprivation for a 7-day adaptation period, but did not abolish a response after a 21-day period. A 14-day adaptation period gave equivocal results. It is concluded that PTH appears to be necessary for short-term (7-day) adaptation, but not for long-term (21-day) adaptation to calcium deprivation. However, if accessory parathyroid tissue is present, the data could be interpreted differently: the essentiality of PTH for the adaptive response might be independent of the length of the adaptation period. The data also contribute to a possible resolution of the controversy concerning the involvement of PTH in the regulation of intestinal calcium transport in the rat.


Function of the thin ascending limb of Henle of rats and hamsters perfused in vitro. In order too examine whether there is species difference in the function of the thin ascending limb of Henle (tALH), segments isolated from rat and hamster kidneys were perfused in vitro and compared to results obtained by identical techniques from rabbits. The net water flux and the transtubular potential difference were not different from zero. The osmotic water permeability of the rat and hamster tALH was unmeasurably small. Isotopic and electrically determined permeabilities for Cl- and Na+ were quite high in both species, with Cl- being approximately twice as permeable as Na+. Urea permeability across the tALH of both species was moderate. Solute permeability to NaCl, urea, and raffinose (10(-5) cm sec-1) of the tALH of both species was determined by measuring changes in osmolality of the collected fluid when each solute was added to the bath at the same osmolality. They were 82.2, 38.3, and 6.9, respectively. The relative permeabilities to various ions were estimated from the deflection of the transtubular potential difference when NaCl in the bathing medium was replaced by various salts. The following sequence of permeabilities was obtained across the tALH from both the rat and hamster: Cl- greater than or equal to Br- greater than or equal to SCN- greater than or equal to I- greater than or equal to Na+ = K+ greater than Li+ greater than choline+ greater than or equal to HCO3- greater than acetate- greater than or equal to cyclamate-. These data indicate that membrane characteristics of the tALH of rats and hamsters are similar to the previously published values of rabbits. The conclusion is drawn that the principle of the passive equilibrating model of the countercurrent multiplication system is operative in other mammalian species besides the rabbit.


Dissociation of renal blood flow and filtration rate autoregulation by renin depletion. Renal blood flow (RBF) and glomerular filtration rate (GFR) autoregulation during changes in renal artery pressure (RAP) were examined in dogs fed a "normal" diet (group 1, n = 10) and in renin-depleted dogs (group 2, n = 11) which received a high-sodium diet and deoxycorticosterone acetate (DOCA) injections for a minimum of 21 days prior to the study. Renal venous plasma renin activity was undetectable in group 2 by radioimmunoassay of angiotensin I and did not increase even when RAP was reduced to less than 70 mmHg. Autoregulation of RBF was not impaired by renin depletion. However, GFR autoregulation, which was very effective in group 1 dogs, was markedly impaired in group 2. Average GFR in group 2 decreased progressively to 58 +/- 7% of the control value as RAP was reduced in steps from the control value of 137 +/- 3 to 69 +/- 1 mmHg. In normal dogs, the filtration fraction either increased slightly or did not change when RAP was reduced in steps, whereas in renin-depleted dogs the filtration fraction decreased progressively during reductions in RAP. Thus, chronic sodium loading and DOCA administration causes renin depletion and dissociates the autoregulation of RBF and GFR. These data are consistent with the hypothesis that the renin-angiotensin system participates in the control of GFR, possibly by an efferent arteriolar mechanism.


Inhibition of probenecid uricosuria by pyrazinamide and para-aminohippurate. Both para-aminohippurate (PAH) and pyrazinamide inhibited the uricosuric response to probenecid administration. The mechanism of this inhibition of probenecid uricosuria was assessed in 18 male subjects. The decrease in uricosuria was assessed in 18 male subjects. The decrease in uricosuric response to probenecid observed after pyrazinamide administration or PAH infusion occurs by different mechanisms. Administration of PAH and probenecid together resulted in reduced excretion of both drugs. PAH was weakly uricosuric and did not appear to inhibit urate secretion. PAH inhibition of probenecid uricosuria is accounted for by inhibition of probenecid secretion. Probenecid excretion was not affected by pyrazinamide administration. Inhibition of probenecid-induced uricosuria by pyrazinamide is most likely due to inhibition of urate secretion. The urate secretory carrier inhibited by pyrazinamide appears to be independent of that responsible for secretion of probenecid and PAH. Probenecid secretion appears to be required for its uricosuric effect.


Renal sugar transport in the winter flounder. III. Two glucose transport systems. Teased renal tubules of the winter flounder (Pseudopleuronectes americanus) were employed to investigate the structural requirements for two pathways of D-glucose transport which take place preponderantly across the basal (antiluminal) face of renal cells. 1) An inhibition analysis of the equilibrating, Na-independent and phlorizin-sensitive transport of the nonmetabolizable methyl-alpha-D-glucoside (0.1 and 0.5 mM), with 20 glucose analogs (5 mM), was employed to establish the structural requirements for the substrate-carrier interaction: a (pyranose) ring, oxygen, or F at C1, C2-OH, C3-OH, and C4-OH (all axial, 1C model). Some interaction may also occur at C6-OH. D-Glucose shares this transport system. Hydrogen bonding between the oxygens and the carrier is suggested. 2) The phloretin- and phlorizin-sensitive, ouabain-insensitive transport of D-glucose, 2-deoxy-D-glucose, and D-mannose is associated with considerable phosphorylation. The three sugars mutually compete for a shared transport site. The specificity pattern characterizing the transport system defines the following structural requirements: a (pyranose) ring, a free C1-OH, C3-OH, and C4-OH (both axial) and possibly C6-OH. Hydrogen bonding between the carrier and the oxygens at C3, C4, and C6, and covalent bonding at C1 is suggested.


Absence of significant secretory flux of phosphate in the proximal convoluted tubule. The presence of phosphate secretion by the renal tubule in mammals has been controversial. Recently, in a micropuncture and microperfusion study, net secretion of phosphate was reported for the proximal tubule of rats which were infused with parathyroid hormone (PTH) and phosphate. Since the finding of net secretion of phosphate by the proximal tubule is in contradiction to other reports, the question was reinvestigated with the use of microperfusion techniques that were modified to allow identification of sample contamination. Studies were performed in intact dogs, phosphate- and PTH-loaded intact rats, and phosphate-loaded, acutely thyroparathyroidectomized rats. After exclusion of contaminated samples, no significant influx of phosphate was found in any of the three groups. Neither increased plasma phosphate concentration nor the infusion of parathyroid hormone unmasked a secretory process for phosphate. It is concluded that phosphate transport in the proximal tubule is essentially a unidirectional phenomenon, i.e., reabsorption is not opposed by significant backflux of phosphate.


Effect of potassium on utilization of (1-14C)palmitic acid in renal cortex of the rat. The renal cortex has an unusually high rate of palmitic acid utilization. The uptake, oxidation, and distribution of this fatty acid in the cortex, unlike other tissues, responds to variations in medium and tissue potassium content. This potassium dependency is mimicked and amplified by rubidium. These observations indicate that in the renal cortex, both potassium and rubidium promote the accumulation, oxidation, and esterification of palmitic acid.


Vasopressor role of ADH in the pathogenesis of malignant DOC hypertension. During the onset of malignant hypertension (MH) in rats treated with deoxycorticosterone trimethylacetate (DOC), plasma arginine vasopressin (AVP) concentrations increase tenfold as a consequence of hypovolemia and hyperosmolality. In benign hypertensive (BH) rats, plasma AVP is increased threefold in comparison with control animals. Plasma renin is markedly suppressed in both BH and MH animals. In MH rats, biologically active AVP antiserum lowers blood pressure (BP) transiently to normal or subnormal levels; in BH rats, a small BP-lowering effect of the AVP antiserum is seen. (Biologically active angiotensin II antiserum does not lower BP in MH rats.) The relationship between the height of BP and plasma AVP concentration in DOC hypertensive rats indicates, when compared with that relationship in diabetes insipidus rats infused with AVP, a marked enhancement of the vasopressor effect of AVP. These findings and the earlier observation of vasopressin-induced vascular damage by Byrom (F. B. Byrom, The Hypertensive Vascular Crisis. London: Heinemann, 1969) strongly suggest that ADH is involved as a vasopressor hormone in the pathogenesis of malignant DOC hypertension.


Renal responses to diuretic drugs in freshwater catfish Ictalurus punctatus. Renal tubules of freshwater teleosts consist of proximal, intermediate, distal, and collecting segments. Diuretic drugs were injected into freshwater channel catfish to define the mode of natriuresis and diuresis. Although the catfish lack a loop of Henle, ethacrynic acid (1 mg/kg), furosemide (1 mg/kg) and, to a smaller extent, hydrochlorothiazide (2 mg/kg) produced marked chloruresis and natriuresis. The amount of sodium and chloride reabsorbed decreased, and the decrease in fractional reabsorption of chloride was greater than that of sodium. All three drugs, however, elicited only mild diuresis. This finding suggests that these drugs inhibit sodium and chloride reabsorption in tubules which are highly impermeable to water, most likely along distal segments of the nephron. Ethacrynic acid and furosemide appear to inhibit both reabsorption and secretion of potassium. Acetazolamide (50 mg/kg) induced moderate diuresis which seemed to reflect increased glomerular filtration rate. Smaller doses of acetazolamide increased urinary bicarbonate excretion without the increase in filtration rate, suggesting a possible inhibition of carbonic anhydrase in the renal tubules.


Effect of albumin infusion on renal glucose reabsorption in the rat. Clearance and micropuncture techniques were employed to assess the relationship between renal glucose and sodium reabsorption in the rat. Late proximal tubular fluid was collected from surface nephrons before and at two intervals after the infusion of hyperoncotic albumin by a double recollection technique. Plasma glucose levels were maintained at 28-44 mM throughout. Proximal tubular reabsorptive rates for both glucose and sodium were elevated 20 min after the start of the hyperoncotic infusion. Continued infusion of the hyperoncotic albumin resulted in a natriuresis and a parallel fall in proximal glucose and sodium reabsorption. Changes in maximal glucose reabsorption rates for the whole kidney paralleled changes in glucose reabsorption in surface nephrons. The addition of calcium and magnesium to the hyperoncotic infusate diminished the natriuresis but did not alter the relationship between sodium and glucose reabsorption. These observations indicate a close relationship between proximal tubular glucose reabsorption and sodium reabsorption during hyperoncotic infusion.


Distribution of cardiac output in ovine pregnancy. Cardiac output and organ blood flows were measured in 6 nonpregnant and 24 pregnant ewes from 38 to 141 days of gestation employing radionuclide-labeled microspheres. From the nonpregnant state to term increases in cardiac output, from 73.7 +/- 4.6 ml/min-kg of maternal weight to 148 +/- 2.4 ml/min-kg, and heart rate, from 88.5 +/- 10.3 to 106 +/- 4.6 beats/min, were noted, while mean arterial blood pressure was unchanged. Near term, the blood flows to the uterus and mammary gland represented approximately 18% of cardiac output. The blood flow to nonreproductive organs increased from 76.6 +/- 6.8 ml/min-kg of nonreproductive tissue in the nonpregnant state to 132 +/- 3.5 ml/min-kg at 130-140 days' gestation (P less than 0.01). No significant changes in renal blood flow were detected.


Hypercapnia and right-duct lymph flow in pups and adult dogs. The effect of moderate hypercapnia on right-thoracic duct lymph flow, pulmonary hemodynamics, and lung water content was studied in seven 2- to 5-wk-old dogs and eleven adult dogs anesthetized with pentobarbital, paralyzed with succinylcholine, and maintained on intermittent positive-pressure ventilation. Following a 30-min control period in which arterial pH and blood gases were maintained within normal limits, the dogs were ventilated with 3-14% CO2 for 30 min; they were then returned to control conditions fro a 30-min recovery period. Hypercapnia was associated with a significant increase in lymph flow rate in both pups and adult dogs (P less than 0.05) and a significant increase in pulmonary artery and pulmonary artery wedge pressures in adult dogs (P less than 0.05). These data suggest that hypercapnia may increase the net flow of water out of the pulmonary vascular bed.


Instantaneous force-velocity-length relations in isolated dog heart. The mechanics of left ventricular contraction were investigated in terms of instantaneous mural force, mid-wall circumferential fiber shortening velocity (dL/dt), and fiber length (L) in seven servo-regulated hearts. The steady-state response of series of variably preloaded or afterloaded allasotonic contractions were utilized. Norepinephrine (0.55-1.38 mug/min) or propranolol (0.07-0.14 mg/min) were given to alter inotropic background. For any given contractile state and initial L, maximum dL/dt was not attained instantly but after a finite time of ejection (39 ms +/- 0.2 SE; range, 24-60) and from a lesser length (92% +/- 0.5 SE; range, 83-99) than present at end diastole. Beyond this initial period instantaneous dL/dt was dependent on both instantaneous force and length while independent of time after contraction and initial L. Instantaneous dL/dt also varied with contractile state, e.g., dL/dt was less after propranolol and greater after norepinephrine. Peak dL/dt for all conditions was a function of the extent of shortening (r = 0.90). Thus, the trajectory describing instantaneous force, velocity, and length provides a useful description of both the mechanical behavior and contractile state of the ventricular myocardium.


Evidence for the presence of adrenergic receptors in 3-day-old chick embryo. Effects of sympathomimetic amines without and with alpha and beta-adrenergic blocking agents on the heart rate and arterial and venous blood pressures in the 3-day-old chick embryo were studied. No chronotropic effect was observed. Norepinephrine caused a biphasic change in systolic and diastolic arterial pressures, the lower doses effecting a fall, and the higher doses a rise in these pressures. With phenylephrine a sharp rise in systolic, diastolic, and pulse pressures was seen. Isoproterenol caused a dramatic fall in systolic, diastolic, and pulse pressures. In the presence of phenoxybenzamine, the pressor effect of high doses of norepinephrine was reversed, the pressor effect of phenylephrine was abolished, and the hypotension with isoproterenol was enhanced. After propranolol, the hypotensive effect of low doses of norepinephrine was reversed, the pressor response to phenylephrine was unchanged, and the depressor effect of isoproterenol was abolished. These findings suggest the presence of functioning alpha- and beta-receptors in the 3-day-old chick embryo. Additionally, they suggest that the alpha-receptors develop more slowly in the chick embryo.


Some pressure and fluid dynamic characteristics of the canine epidural space. Pressure measured in teh epidural space of 50 dogs was consistently negative (subatmospheric). Acutely implanted epidural catheters gave an average reading of -2.72 mmHg (n = 44, SE = 0.18), whereas chronically implanted catheters gave more negative readings, averaging -5.8 mmHg (n = 6, SE = 0.49). Since the chronically implanted catheters permit healing, resolution of hemorrhage, and resealing of the epidural space to take place, resulting in equilibration of microcirulatory forces, these readings are believed to represent more closely the true epidural pressure. Also these results approximate closely the calculated and measured interstitial fluid pressures obtained by different  techniques in other loose areolar connective tissue systems. Compliance studies, using a double-lumen catheter for simultaneous recording and infusing in the epidural space, showed increasing compliance as the pressure rose into the positive pressure range, with an eventual plateau of the volume-pressure curve at the level of the concomitantly measured cerebrospinal fluid pressure (avg = +5.73 mmHg, n = 10, SE = 0.48). Intravenous volume loading using Tyrode solution caused a large rise in epidural pressure, and volume depletion with diuretics caused a significant drop in epidural pressure.


Vasopressin and angiotensin: reciprocal mechanisms controlling mesenteric conductance. Intravenous infusions of [Sar1-Ala8]angiotensin II, acute hypophysectomy, and acute intestinal denervation were carried out in 15 pentobarbital-anesthetized cats. Infusion of the angiotensin II antagonist caused only a small increase in superior mesenteric arterial conductance and a small decrease in arterial pressure in intact animals, but the changes were subypophysectomy alone caused only a small intestinal vasodilatation and little change in arterial pressure. However, the responses to hypophysectomy were much larger when the gland was removed during a prolonged infusion of the angiotensin II antagonist. Intestinal denervation caused only minor changes in mesenteric conductance and arterial pressure, and the responses to [Sar1-Ala8]angiotensin II and hypophysectomy were largely unaltered by the presence or absence of the intestinal innervation. The results suggest that the renin-angiotensin and vasopressin systems are reciprocal overlapping mechanisms that exert a significant vasoconstrictor influence on the intestinal resistance vessels in the anesthetized cat. In the absence of one control system, the other appears to compensate to maintain resistance.


Actions of bradykinin on isolated cerebral and peripheral arteries. The addition of bradykinin (BK) caused a dose-related contraction in helical strips of canine cerebral, internal carotid, external carotid, and femoral arteries, while the peptide elicited a relaxation in canine coronary, renal, and mesenteric arteries contracted with 5+ or prostaglandin F2alpha. In contrast to canine cerebral arteries, human cerebral arteries contracted with K+ or prostaglandin relaxed with BK. Contractile responses of canine cerebral arteries to BK were not influenced by phentolamine, diphenhydramine, and methysergide, but were attenuated by aspirin and indomethacin. Contractions induced by K+ were not or only slightly inhibited by these anti-inflammatory agents. Polyphloretin phosphate failed to reduce BK-induced contractions. Relaxing effects of BK on canine coronary arterial strips were not altered by atropine, propranolol, metiamide, and aminophylline, but were inhibited by aspirin and indomethacin. Adenosine-induced relaxation was unaffected by the latter two agents. It may be concluded that adrenergic, cholinergic, histaminergic, and adenosine-related mechanisms are not involved in the genesis of BK-induced contraction and relaxation. Contractile responses of canine cerebral arteries to BK do not appear to derive from prostaglandins released, but rather from a direct action on vascular smooth muscle cells.


Contraction and resting stiffness of isolated cardiac muscle: effects of inotropic agents. The purpose of this study was to test the hypothesis that either hypoxia and its combined effects with extracellular calcium (Ca), digoxin, and ouabain, or these positive inotropic agents acting alone or in combination, influence contraction and resting stiffness of isolated papillary muscle. Stiffness was measured utilizing the sinusoidal forcing function technique. Neither an increase in extracellular calcium concentration (from 2.5 to 4.0 mM) nor digoxin or ouabain in either Ca concentration altered contraction or resting stiffness in the well-oxygenated environment. Resting stiffness for any given resting tension was increased at the end of hypoxia only in the presence of digoxin, and this occurred in both 2.5 mM Ca (P less than 0.02) and in 4.0 mM Ca (P = 0.05). Contraction stiffness for any given tension was increased in 2.5 mM Ca by hypoxia alone (P less than 0.05) and by hypoxia in the presence of digoxin (P less than 0.005) and ouabain (P less than 0.02), but was not increased in any experiments conducted in 4.0 mM Ca. The conclusions from these data are that certain experimental conditions of the study evoked different directional changes in stiffness and contractility. Further, changes in contraction stiffness are not always paralleled by changes in resting stiffness.


Humoral factor depletion and reticuloendothelial depression during hemorrhagic shock. Circulating opsonic activity and reticuloendothelial system (RES) phagocytic function were determined in anesthetized rats subjected to hemorrhagic shock. Animals were hemorrhaged to and maintained at 40 mmHg arterial blood pressure until they spontaneously took back 5% or 40% of the maximum bled volume. The phagocytic index, as determined by colloid clearance kinetics, was decreased in both groups following reinfusion of the shed blood. The reduction in phagocytic index was associated with decreased liver, unchanged spleen, and increased lung test colloid localization. Plasma opsonic activity, as determined by liver slice bioassay, was decreased 50-60% at 5% and 40% uptake of the maximum shed volume, decreased further 15 min after reinfusion in both groups, and tended to recover 1 h after reinfusion in the 5% uptake group. In vitro hepatic phagocytic activity of liver slices from shocked animals in the presence of normal rat plasma was decreased only in the 40% uptake animals after reinfusion when the arterial blood pressure had decreased to 50 mmHg. These data indicate that the depression of RES phagocytic function during hemorrhagic shock is associated with and may be mediated, in part, by decreased circulating opsonic activity.


Thermally induced myocardial preservation and necrosis in deprived fetal mouse hearts. Cultured fetal mouse hearts deprived of oxygen and glucose were used to examine the effect of temperature on the mechanical, biochemical, and ultrastructural responses of the deprived myocardium to assess the utility of this in vitro model for studying myocardial necrosis, preservation, and repair. After 4 h of deprivation at 4, 24, 37, or 42 degrees C, 1) beating had ceased;2) ATP levels were decreased by 22% for 4 degrees C insults, 69% for 24 degrees C, 89% for 37 degrees C, and 97% for 42 degrees C; 3) CPK and LDH levels were unchanged; and 4) ultrastructural changes were observed. After 24 h of recovery from deprivation, 1) beating resumed, except for 42 degrees C;2) ATP levels were 102% of control for 4 degrees C; 99% for 24 degrees C; 62% for 37 degrees C; and 4% for 42 degrees C; 3) LDH content was decreased by 0% at 4 degrees C; 6% at 24 degrees C; 35% at 7 degrees C; and 70% at 42 degrees C; and 4) CPK content decreased similarly. Hypothermia protected deprived myocytes while hyperthermia accelerated cell necrosis. Combining deprivation with thermal insult in this in vitro model provides a spectrum of myocardial damage for studying the effect of interventions on repair processes and on metabolic changes in jeopardized myocardium.


Blood vessel-hormone interactions: angiotensin, bradykinin, and prostaglandins. Isolated Krebs-perfused rabbit-mesentery blood vessels release a prostaglandin E-like substance (PGE) when treated with angiotensin II, angiotensin I, arachidonic acid, or bradykinin. The specific competitive antagonist [Sar1,Ile8]angiotensin II, was found to inhibit angiotensin II-induced PGE release. The angiotensin antagonist did not block PGE release by bradykinin, whereas indomethacin blocked PGE release induced by all agonists. SQ-20881, the converting-enzyme and bradykininase inhibitor, decreased the PGE release by angiotensin I, enhanced the release by bradykinin, and did not affect release by angiotensin II. Pressor and depressor responses were obtained in mesenteric preparations constricted by epinephrine to a pressure of 60 mmHg. Angiotensin II induced an initial increase in mesenteric vascular resistance followed by a depressor response below basal pressure. The pressor responses were enhanced by indomethacin and the depressor responses were eliminated. Bolus injections of both bradykinin and arachidonic acid produced decreases in perfusion pressure, but indomethacin completely inhibited only the arachidonic acid-induced responses while only diminishing bradykinin-induced responses. The ability of angiotensin to increase mesenteric vascular resistance and to release PGE which decrease vascular resistance is discussed.


Carbon monoxide exchanges between the human fetus and mother: a mathematical model. A mathematical model was developed to calculate maternal and fetal carboxyhemoglobin concentrations, [HbCO], as functions of time during and after exposure of the mother to various inspired CO concentrations. Effects of variation in alveolar ventilation rates, pulmonary and placental fiffusing capacities, cardiac output, endogenous carbon monoxide production and other factors were studied. Following a change in the inspired CO concentration, fetal HbCO lags behind maternal HbCO by several hours. During CO uptake, fetal HbCO eventually overtakes maternal, and approaches an equilibrium value as much as 10% higher than the mother's. During CO washout the fetal levels again lag behind the mothers. Results indicate that treatment of pregnant women who have elevated HbCO levels with 100% oxygen reduces the time necessary to reduce the maternal HbCO level as expected, but that the rate of fetal CO elimination is not increased as much as that of the mother. Changes in maternal and fetal HbCO were also calculated for a representative exposure to changing inspired CO levels produced by fluctuating levels of air pollution. Finally, the effects of carboxyhemoglobin on fetal oxygenation were studied, including the effects of high altitude and exercise.


Carbon monoxide uptake and elimination in fetal and maternal sheep. We studied the relation of carboxyhemoglobin concentration in the fetus, [HbCOf], to that of the pregnant mother, [HbCOm], and inspired CO concentrations in unanesthetized sheep. We exposed ewes with catheters chronically implanted in maternal and fetal blood vessels to varying inspired CO concentrations. At 30 parts per million (ppm) CO, [HbCOm] increased from base-line levels of about 1.1% to about 4.6% over a course of 8-10 h. [HbCOf] increased more slowly from base-line values of 1.8% to steady-state values of 7.4% by 36-48 h. At 50 ppm, steady-state [HbCOm] = 7.2% and [HbCOf] = 11.3%. At 100 ppm, steady-state [HbCOm] = 12.2%, [HbCOf] = 19.8%. The increase in [HbCOm] resembled a simple exponential process with a half-time of 1.5 h. The time for [HbCOf] to reach half its final value was 5 h. The decay curve for CO elimination showed similar reactions, with fetal washout occurring slower than in the mother. Elevated [HbCOf] significantly decreased the PO2 values in the fetal descending aorta and inferior vena cava. These decreases in PO2 values can cause hypoxia and fetal death.


Cardiovascular effects of radioactive microsphere suspensions and Tween 80 solutions. The cardiovascular effects of two concentrations of Tween 80 (polyoxyethylene sorbitan mono-oleate), a surface-active agent commonly used to prevent aggregation of radionuclide-labeled microspheres, were examined in conscious dogs. Two types of adverse reactions were noted. The first (Type A) consisted of reductions in cardiac dimensions as well as hypotension and tachycardia. The second (Type B) was less severe and involved only a decrease in cardiac dimensions with no change in left ventricular systolic pressure or heart rate. A 10% dextran solution with .05 +/- .02% Tween 80 injected into the left atrium caused systemic and/or cardiac alterations in all four dogs studied. Administration of a lower concentration of Tween 80 (0.01 +/- 0.005%), which was the minimum concentration necessary to prevent aggregation of microspheres, induced adverse reactions in 6 of 41 dogs studied. Subsequent administration of this concentration of Tween 80 on the same day rarely induced adverse reactions. Thus, care must be exercised in application of microsphere techniques to organ blood flow measurements when Tween 80 is used to prevent microsphere aggregation, since this surface-active agent causes profound alterations in cardiac dynamics in concentrations normally employed in experiments involving microsphere techniques.


Selective coronary embolization in closed-chest dogs. A method is described for occluding a branch of the canine left coronary arterial system, without the use of X-ray equipment or the need for a surgical thoracotomy. For the creation of experimental myocardial infarction, either a solid embolus or a diffusible medium is introduced into the coronary vessels via a rigid cannula which is inserted through a carotid artery. This technique produces infarcts of reproducible size with a minimum of equipment and surgical complication.


Occlusion cuff for routine measurement of digital blood pressure and blood flow. A miniaturized blood pressure cuff made of plastic material and applicable to fingers and toes is described. The cuff was compared to rubber cuffs and to bladder-free cuffs. It was found to be more reliable than the former type and much easier to use than the latter type. It is recommended for use in conjunction with a mercury-in-Silastic strain gauge for routine measurement of digital blood pressure and blood flow in patients with arterial disease.


Coupling of signals to brown fat: alpha- and beta-adrenergic responses in intact rats. The present study examines the effects of alpha- and beta-adrenergic antagonists (phentolamine and propranolol, respectively) and agonists (phenylephrine, isoproterenol) on the neurally induced temperature changes and membrane potentials of interscapular brown adipocytes. These studies, performed in vivo with anesthetized rats, indicate that both alpha- and beta-adrenergic components are associated with the biphasic temperature changes observed following sympathetic activation of the tissue. Specifically, the initial transient temperature decrease seen after brown fat stimulation appeared to reflect vasoconstriction mediated primarily via alpha-receptors, while the subsequent rise in tissue temperature was associated primarily (though perhaps not entirely) with beta-adrenergic pathways. In contrast, the redistribution of ions across the membrane of the brown adipocyte, a phenomenon manifested as a membrane depolarization, was elicited by phenylephrine (an alpha-agonist) as well as by isoproterenol (a beta-agonist), with the magnitude of the isoproterenol-induced depolarization being comparable to that of the phenylephrine-induced effect.


Epinephrine effects on branchial water and urea flux in rainbow trout. In isolated trout heads, perfused at constant pressure, epinephrine (10(-6) M) was found to double water and urea efflux but increased Ringer perfusion rate by only 33%. Drastic changes in perfusion rate (by clamping) produced smaller changes of both efflux rates. Epinephrine-stimulated increase in water and urea efflux, and perfusion rate, was blocked by propranolol (beta-blocker) but not by phentolamine (alpha-blocker). Both blockers together canceled out all epinephrine effects. Epinephrine increased water influx across isolated unperfused gill arches, the effect again being blocked by propranolol but not by phentolamine. Both blockers together canceled any epinephrine effect. We conclude that epinephrine alters branchial vascular flow and functional surface area via alpha- and beta-adrenergic receptors, but also increases branchial permeability to water and probably urea, via beta-adrenergic receptors. To test the validity of the perfused head technique, water and urea efflux rates were compared with in vivo values.


Prolactin and fetal osmoregulation: water transport across isolated human amnion. The addition of human or ovine prolactin to the fetal side of the human amnion is associated with a latent decrease in membrane permeability. The specificity of this effect of prolactin is observed when equimolar concentrations of human placental lactogen and human growth hormone were used in place of ovine prolactin and failed to influence water transport. Likewise, the extracellular transport of p-aminohippurate across human amnion was unaffected by the addition of ovine prolactin. Tritiated water transport under these circumstances, however, remained impaired. The addition of antibody to ovine prolactin completely blocked the effect of this polypeptide on membrane permeability. Permeability to tritiated water remained unchanged when synthetic arginine vasopressin was added to the fetal side of the amnion. The results imply an active role for prolactin on water transport across human amnion. Moreover, the latent period between the addition of the polypeptide and its subsequent influence on permeability suggests a biologic effect of this hormone. That this effect is related to ion transfer remains to be shown.


Sympathetic nervous system involvement in the lateral hypothalamic lesion syndrome. The role of the sympathetic nervous system in the lateral hypothalamic syndrome of body-weight loss was investigated. Bilateral electrolytic lesions of the lateral hypothalamus (LH) were performed in 90-day-old male albino rats. In experiment 1, the splanchnic nerves were resected at 35 days (right) and 70 days (left) postlesion. In experiment 2, bilateral adrenal demedullations were performed in a second group of rats with LH lesions (LH rats) at 35 days postlesion. The results indicated that lesions of the lateral hypothalamic area lowered body-weight maintenance levels to approximately 87% of nonlesion control values. Bilateral splanchnicetomy produced a significantly greater body-weight loss in nonlesion animals than in LH rats. Following adrenal demedullation, nonlesion rats also reduced body-weight levels whereas LH rats significantly increased weight-maintenance levels. In addition, the adrenal glands of LH rats with sham demedullations weighed significantly more than the adrenals of nonlesion-sham demedullated animals. These data are discussed in relation to metabolic-autonomic mechanisms that may play a role in LH lesion-induced weight loss.


Model for transport in the central nervous system. A pharmacokinetic model relating the flux of substances between blood, the compartment consisting of the cerebrospinal fluid (CSF)-extracellular space (ECS) of brain, and brain was developed. Transport equations for diffusion, active transport, and bulk flow of CSF between these three compartments were postulated, and kinetic constants were experimentally obtained. The appropriate differential equations were solved on a digital computer to predict concentrations in CSF and brain as a function of the plasma concentration. The ability of the model to predict correctly CSF and brain concentrations of ascorbic acid and mannitol with only knowledge of the plasma concentrations in both steady-state and nonsteady-state conditions was experimentally tested in rabbits. Ascorbic acid was chosen as a model substance that is actively transported into the CSF-ECS of brain and also into brain cells whereas mannitol enters CSF and brain by diffusion. The model made accurate predictions when the assumptions were not violated. Second, the model showed that the experimentally determined Michaelis-Menten transport constant (KT = 0.8 mg=dl-1) for ascorbate transport from blood into the CSF-ECS of brain optimizes ascorbate homeostasis in brain.


Drinking following intracarotid infusions of hypertonic solutions in dogs. Eight dogs were prepared with bilateral carotid loops and trained to stand quietly in a modified Pavlov stand. In each of the dogs, 0.3, 0.45, and 0.6 M NaCl were infused, split between the two carotids at a rate of 0.6 ml-kg-1-min-1 for 10 min and the effect on drinking assessed. A graded increase in drinking was obtained with increased osmolality of the saline (R = 0.59, N = 32, P less than 0.001). Infusion of 0.3 M NaCl was associated with an increase in jugular venous osmolality, but no significant increase in systemic osmolality. Intravenous infusion of 0.3 M NaCl at 0.6 ml-kg-1-min-1 had no effect on drinking. Intracarotid infusion of 0.3 M sucrose in 0.15 M NaCl stimulated drinking to a similar extent as 0.3 M NaCl, whereas intracarotid 0.3 M urea in 0.15 M NaCl had no effect. Increasing the systemic plasma osmolality by infusing 1.04 M NaCl intravenously stimulated drinking, an effect which was abolished by removing the central osmotic stimulus with intracarotid infusions of water. These results are compatible with a central osmoreceptor theory of thirst.