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Running Time: 136 minutes
Released: 09/2007
Studio Name: Diabolic Digital
Series: Milf Bone
Description: When you are craving a MILF to bone, grab one of the middle-aged babes and slam away! They're not young, they're not old, they're just right! They're in their sexual prime and you're not made to deal with a newbie or an amateur. A mother for every bite!
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Stars: Devon Lee, James Deen, Jenner
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Physical exercise, ß-adrenergic receptors, and vascular response
- Asher Cole
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1 REVIEW ARTICLE Physical exercise, ß-adrenergic receptors, and vascular response Exercício físico, receptores ß-adrenérgicos e resposta vascular Alexandre Sérgio Silva, Angelina Zanesco* Abstract Aerobic exercise promotes beneficial effects on the prevention and treatment of diseases such as arterial hypertension, atherosclerosis, venous insufficiency, and peripheral arterial disease. β-adrenergic receptors are present in a variety of cells. In the cardiovascular system, β-adrenergic receptors promote positive inotropic and chronotropic response and vasorelaxation. Although the effect of exercise training has been largely studied in the cardiac tissue, studies focused on the vascular tissue are rare and controversial. This review examines the data from studies using animal and human models to determine the effect of physical exercise on the relaxing response mediated by β-adrenergic receptors as well as the cellular mechanisms involved in this response. Studies have shown reduction, increase, or no effect of physical exercise on the relaxing response mediated by β-adrenergic receptors. Thus, the effects of exercise on the vascular β-adrenergic sensitivity should be more deeply investigated. Furthermore, the physiopathology of the vascular system is an open field for the discovery of new compounds and advances in the clinical practice. Keywords: β-adrenergic receptors, blood pressure, vascular smooth muscle, physical exercise. Resumo O exercício aeróbio promove efeitos benéficos na prevenção e tratamento de doenças como hipertensão arterial, aterosclerose, insuficiência venosa e doença arterial periférica. Os receptores β-adrenérgicos estão presentes em várias células. No sistema cardiovascular, promovem inotropismo e cronotropismo positivo cardíaco e relaxamento vascular. Embora os efeitos do exercício tenham sido investigados em receptores cardíacos, estudos focados nos vasos são escassos e controversos. Esta revisão abordará os efeitos do exercício físico sobre os receptores β-adrenérgicos vasculares em modelos animais e humanos e os mecanismos celulares envolvidos na resposta relaxante. Em geral, os estudos mostram resultantes conflitantes, onde observam diminuição, aumento ou nenhum efeito do exercício físico sobre a resposta relaxante. Assim, os efeitos do exercício na sensibilidade β-adrenérgica vascular merecem maior atenção, e os resultados mostram que a área de fisiopatologia vascular é um campo aberto para a descoberta de novos compostos e avanços na prática clínica. Palavras-chave: Receptores β-adrenérgicos, pressão arterial, músculo liso vascular, exercício físico. Introduction The last decades were marked by the increased prevalence of cardiovascular risk factors, such as sedentary lifestyle, obesity, and changes in lipid profile, thereby raising the incidence of chronic degenerative diseases, such as hypertension, type 2 diabetes mellitus, and atherosclerosis. 1 Some vascular diseases greatly compromise blood flow and oxygenation of different tissues, causing poor wound healing, infection, and pain, which may result in amputation mainly of the lower limbs, thus representing an important cause of death. 2 Venous insufficiency and peripheral arterial occlusive disease have a high prevalence in the population, especially among the elderly, affecting about 10-40%, and the etiopathogenesis of both conditions is closely associated with endothelial dysfunction. 2,3 Evidence shows that aerobic physical training promotes beneficial effects on the prevention and treatment of cardiovascular diseases and endocrine/metabolic disorders, such as hypertension, diabetes mellitus, dyslipidemia, and atherosclerosis. 4 One of the mechanisms by which physical exercise promotes these effects is associated with increased blood flow on the vessel wall, resulting in increased production and/or bioavailability of nitric oxide (NO) in vascular smooth muscle. 5,6 *Departamento de Educação Física, Instituto de Biociências, Universidade Estadual Paulista (UNESP), Rio Claro, SP, Brazil. No conflicts of interest declared concerning the publication of this article. Manuscript submitted Jan , accepted for publication Mar J Vasc Bras. 2010;9(2):47-56.
2 48 J Vasc Bras 2010, Vol. 9, Nº 2 Physical exercise and vascular response, Silva AS & Zanesco A Physical exercise promotes a direct impact on vascular function, with significant beneficial effects on the patient s quality of life. 4 Studies report that patients with peripheral arterial occlusive disease start to feel less pain and increase walking distance without claudication in response to physical exercise, significantly reducing mortality among these patients. 7-9 Although there are drugs that also improve walking ability without claudication, the results are still modest when compared to supervised exercise programs associated with smoking cessation. 10 In post-surgical varicose vein patients, physical exercise appears to be able to restore microvascular endothelial function to levels observed in age-matched healthy controls, even in the first minutes after exercise. 11 In addition to acting on endothelial cells, physical exercise reduces sympathetic activity and increases parasympathetic activity, leading to an improvement in vascular tone. 12 Physical exercise also contributes to morphological changes of the vessels, modulating the growth of vascular smooth muscle cells, the formation of endothelial cells, and apoptosis reduction and promoting angiogenesis. 6 There are reports of improvement in muscle oxidative activity in patients with peripheral arterial occlusive disease via decreased concentration of short-chain acylcarnitine, an intermediate of oxidative metabolism, 13 which contributes to increase the walking distance without claudication in patients with peripheral arterial occlusive disease performing exercise training. Adrenergic receptors are also implicated in vascular activity. Stimulation of α and β receptors in response to exposure to their agonists promotes constriction or relaxation of arteries and veins.no production by endothelial cells is partly mediated by activation of β-adrenergic receptors. 14 However, little is known about the role that β-adrenergic receptors play in blood vessels and the influence of physical exercise on these receptors in healthy individuals or patients with different pathological conditions, such as atherosclerosis, hypertension and diabetes mellitus. Therefore, this review approaches the involvement of β-adrenergic receptors in vasorelaxation, the effects of physical exercise on the relaxant response, and the molecular mechanisms involved. The study of β-adrenergic receptors offers an interesting field of study in the area of vascular physiology, which might open new perspectives in the prevention and/or treatment of vascular diseases of different etiologies. Vascular smooth muscle and endothelium Arterial vessels usually have three layers: the intima, which is in contact with blood elements and consists mainly of endothelial cells; the media, composed of smooth muscle cells; and the adventitia, composed of fibrous connective tissue, which is the outer coat of the artery. Smooth muscle cells are often spindle-shaped with larger diameters in the core region. The sarcoplasmic reticulum, less developed compared to reticula of other types of muscle cells, is closely associated with the plasma membrane, which explains its involvement in Ca 2+ signaling mechanisms and muscle contraction. The activation of this biochemical cascade of vascular smooth muscle contraction occurs through binding of contractile agents, such as norepinephrine, phenylephrine and endothelin, to specific membrane receptors present in the muscle cell. These receptors, in turn, activate a protein called G protein that stimulates phospholipase C, present in the cell membrane, which catalyzes the formation of second messengers from membrane phospholipids generating inositol-1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 binds to its receptors located in the sarcoplasmic reticulum, releasing to the cytosol Ca 2+ ions present within this organelle. The DAG molecule activates a protein called protein kinase C (PKC), which, in turn, phosphorylates proteins bound to L-type calcium channels, favoring the influx of extracellular Ca 2+ to the intracellular medium. These two messengers cause an elevation in Ca 2+ concentration, enabling actin-myosin interaction and producing contraction of vascular smooth muscle. 15 The relaxation of vascular smooth muscle is triggered by different agents produced by endothelial cells, including prostacyclin, endothelium-derived hyperpolarizing factor (EDHF), and NO. NO is considered the most potent vasodilator produced by the endothelium, and control of its production is directly related to various diseases, such as hypertension, atherosclerosis, and coronary artery disease. 16 Several mediators and neurotransmitters can promote the release of NO by endothelial cells, such as acetylcholine, bradykinin and norepinephrine, through activation of its specific receptors. More recently, hydrogen peroxide (H 2 O 2 ) and hydrogen sulfide (H 2 S) have been highlighted in vascular research as important mediators in the relaxant response of different vessels. 17,18 Thus, the discovery of these molecules in vascular function opens a relevant field on the therapeutic potential of thromboembolic disease. β-adrenergic receptors Adrenergic receptors were initially divided into two broad categories, α and β. Subsequently, they were subdivided into subtypes α 1, α 2, β 1, β 2, and β 3 by using subtype-selective antagonists and sequencing of amino acids that participate in
3 Physical exercise and vascular response, Silva AS & Zanesco A J Vasc Bras 2010, Vol. 9, Nº 2 49 their protein structures. α-adrenergic receptors are further subdivided into α 1A, α 1B, α 1D, α 2A, α 2B, and α 2C β-adrenergic receptors are present in different cells, acting on a variety of functions, including modulation of hormone release, metabolic control, and cardiovascular regulation. Stimulation of β-adrenergic receptors, in the islets of Langerhans, increases glucose in humans, thus β 2 - adrenergic agonists are used in the treatment of hypoglycemia. 22,23 In adipocytes, β 3 receptors have been shown to act on leptin release. 24 Moreover, the balance between lipogenesis and lipolysis is associated with stimulation of α- and β-adrenergic receptors, respectively. 25 Particularly in the cardiovascular system, β-adrenergic receptors promote positive cardiac chronotropic and inotropic response (increasing heart rate and contractile force, respectively) and vasodilation. These actions are triggered by the binding of catecholamines (epinephrine and norepinephrine, released from autonomic fibers) to different β-adrenergic receptor subtypes present in cardiac muscle cells and blood vessels. Currently, at least three β-adrenergic receptor subtypes are recognized: β 1, β 2, and β 3. β 1 and β 2 receptors were the first to be classified based on the use of subtype-selective agonists and antagonists. 26 β 3 -adrenergic receptors were first described in adipocytes, 27 and their presence was subsequently demonstrated in cardiac tissue, mediating chronotropism, 28 and also in blood vessels, promoting vasodilation. 14 The classification of β-adrenergic receptors was possible through the synthesis of selective agonists, such as BRL and CL ,30 The existence of a fourth β-adrenergic receptor, called β 4, which would mediate muscle glucose uptake and cardiac chronotropism and inotropism in humans and rats, was proposed by various authors However, other studies report that β 1 receptors may present an altered conformational state, in which they lose affinity for their specific ligands and start to have affinity for other agonists that activate β 3 and also β 4 receptors, such as the agonist CGP Thus, the existence of β 4 -adrenergic receptor remains unclear. The affinity and efficacy of β-adrenergic drugs may also vary depending on the conformational state of receptors and their mechanisms for coupling to proteins and second messengers present within the cells that constitute the tissue. 39,40 The density of β-adrenergic receptors also varies greatly among different cells and tissues and according to the species studied Vascular β-adrenergic receptors Early studies investigating vascular beds have shown the existence of two β-adrenergic receptor subtypes, β 1 and β 2, in different arteries and veins. It was observed that the vasodilator response was mediated predominantly by β 2 - adrenergic receptors compared with β 1 -receptor subtypes, with an order of potency of epinephrine > norepinephrine > phenylephrine, although this classification of potency does not apply to all vascular beds. 5 Some studies show that β 1 -adrenergic receptors also promote vasodilation, 48,49 whereas other studies show that β 3 -receptor subtypes participate in the vasodilator response of arteries of various species, such as human coronary arteries, 14,50 rat aorta, 51 and canine pulmonary arteries In rat aorta, it was demonstrated that some relaxant responses appear to be mediated by a population of atypical receptors (presumably β 4 ), through the use of conventional agonists/antagonists that stimulate β 1 -, β 2 -, and β 3 -receptor subtypes On the other hand, other studies failed to confirm the participation of β 3 -adrenergic receptors and of this atypical receptor (β 4 ) in this preparation. 58,59 In rat mesenteric arteries, β 4 -adrenergic receptor also seems to be present, 60 but these data were not confirmed in a subsequent study in these arteries. 48 Studies involving femoral and brachial arteries are scarce compared to more central and larger arteries, such as the aorta and mesenteric artery. In one of these few studies, the presence of β 1 - and β 2 -adrenergic receptors was observed through the use of selective agonists/antagonists in porcine femoral artery. 61 On the other hand, in rabbit femoral arteries, only β 2 -receptor subtypes were shown to mediate the vasodilator response. 62 Mechanism of action of β-adrenergic receptors The multiple intracellular signaling pathways in response to the activation of β-adrenergic receptors in blood vessels modify according to the β-adrenoceptor subtype that is mediating relaxant responses and to the vascular bed studied. 61 Although the activation of cyclic adenosine monophosphate (camp) is the classic pathway for the vasodilator response to β-adrenergic stimulation, dependent and independent mechanisms of formation of this second messenger contribute to the relaxant response induced by the activation of these receptors. 63,64 For details, see Figure 1. Signaling pathway: camp-protein kinase A Adrenoceptors belong to a superfamily of membrane receptors closely related and coupled to G proteins. All these proteins share a common peptide structure, in which the amino-terminal portion (N), extracellularly, is connected to the carboxyl-terminal chain (C)
4 50 J Vasc Bras 2010, Vol. 9, Nº 2 Physical exercise and vascular response, Silva AS & Zanesco A intracellularly by seven transmembrane domains. The relative size of N- and C-terminal chains and of the third intracellular loop varies considerably from receptor to receptor. 65,66 The third intracellular loop of β-adrenoceptors is the site for coupling of these receptors to G protein. G proteins are heterotrimers, consisting of one hydrophilic α-subunit and two hydrophobic subunits, β and γ. In the absence of agonists, when G protein is inactive, a molecule of guanosine diphosphate (GDP) is bound to the α-subunit, forming a complex associated with β- and γ-subunits. In the presence of agonists, the activated receptor interacts with G protein and induces the conversion of GDP into guanosine triphosphate (GTP) in the α-subunit. After binding to GTP, the α-subunit dissociates from βγ-subunits and becomes active. The α-subunit remains free until GTP hydrolysis and formation of GDP occurs, leading to its reassociation with βγ-subunits. The α-subunit of Gs protein, when activated, leads to stimulation of adenylyl cyclase, which leads to the formation of camp second messenger from ATP breakdown. camp activates protein kinase A that will promote reduction in intracellular Ca 2+ concentration in vascular smooth muscle cells, with consequent vasodilation. 66,67 For details, see Figure 1. Signaling pathway by activation of calciumdependent potassium channels Maintenance of relaxant activity of the aorta in response to isoprenaline, even in the presence of SQ 22,536 (an adenylyl cyclase inhibitor), supports the existence of camp-independent mechanism in certain vessels. 51 In addition, relaxation is abolished in the presence of iberiotoxin, a K + channel blocker, suggesting the involvement of large-conductance Ca 2+ -activated K + channels (MaxiK). These data are consistent with a previous study that demonstrated the importance of K + channels in the relaxant response of the basilar artery of the guinea pig. 68 Additionally, relaxation was shown to be dependent on MaxiK channels only for responses mediated by β 1 - and β 2 -adrenergic receptors, whereas, for β 3 receptors, K v channels do not appear to be involved. 51 The mechanism by which activation of β-adrenergic receptors promotes relaxation is carried out through the activation and opening of K + channels, allowing their extracellular release, which, in turn, causes reduction in membrane potential, leading to cell hyperpolarization. This results in the closure of voltage-dependent Ca 2+ channels. Ca 2+ channel closure by membrane hyperpolarization causes a reduction in the Ca 2+ -calmodulin complex and in the phosphorylation of the myosin light chain, leading to relaxation. 10 For details, see Figure 1. Signaling pathway: nitric oxide-cgmp Classic pathway of G-protein activation of β-adrenergic receptors, activation of adenylyl cyclase, and formation of camp, which, in turn, activates protein kinase A (panel B). Two other pathways include activation of a variety of proteins that activate enos and result in NO formation (panel A) and opening of potassium channels, promoting membrane hyperpolarization, which, in turn, promotes the closure of voltage-dependent calcium channels (panel C). Both the classic pathway, camp formation, and voltage-dependent calcium channel activating pathway occur in vascular smooth muscle, whereas NO formation occurs in the endothelium. BAR = β-adrenergic receptors; enos = endothelial nitric oxide synthase; NO = nitric oxide; α, β, and γ = G protein subunits; KC = potassium channels; CC = voltagedependent calcium channels. Figure 1 Mechanisms by which β-adrenergic receptors promote vasorelaxation. Another signaling pathway of β-adrenergic receptormediated, camp-independent relaxation is the endothelial pathway. Vasodilator response by stimulation of β-adrenergic receptors has been shown to be partially 69,70 or completely 14 inhibited by endothelium removal or in the presence of NO synthase inhibitors, such as L-NAME. Furthermore, inhibition of soluble guanylate cyclase in vessels without endothelium eliminates the vasodilator response, whereas addition of sodium nitroprusside restores vasorelaxation. Thus, these studies show that NO produced by endothelial cells is involved in β-adrenoceptor-induced relaxation. The mechanisms by which β-adrenergic receptors promote NO release seem to involve several signaling pathways, such as mitogen-activated protein kinase (MEK), p42/p44 mitogen-activated protein kinase (MAPK) or ERK1/2, and phosphatidylinositol 3-kinase (PI3K), both in humans and laboratory animals The activation of these enzymes by β-adrenergic receptors leads to activation of endothelial NO synthase (enos) present in endothelial cells, which,
5 Physical exercise and vascular response, Silva AS & Zanesco A J Vasc Bras 2010, Vol. 9, Nº 2 51 in turn, will promote oxidation of a terminal nitrogen of the guanidine group of L-arginine, forming equimolar amounts of NO and L-citrulline. Once formed, NO diffuses rapidly from endothelial to smooth muscle cells, where it interacts with the heme group of soluble guanylate cyclase, stimulating its catalytic activity and leading to the formation of cyclic guanosine monophosphate (cgmp), which, in turn, reduces intracellular Ca 2+ levels. For details, see Figure 1. The mechanisms by which NO/cGMP pathway induces vasodilation include inhibition of IP3 generation, increased sequestration of cytosolic Ca 2+, dephosphorylation of the myosin light chain, inhibition of Ca 2+ influx, protein kinase activation, stimulation of membrane Ca 2+ -ATPase, and opening of K + channels. 74 Phosphodiesterases and vascular disease The importance of camp and cgmp as mediators of various cellular functions, including regulation of vascular tone, proliferation of smooth muscle cells, and inhibition of platelet adhesion and aggregation, has given rise to several studies for the development and synthesis of various compounds in order to increase or control intracellular levels as a treatment for several diseases, such as erectile dysfunction, cardiac and vascular diseases. 5 Intracellular camp and cgmp levels are controlled by enzymes called phosphodiesterases, which catalyze hydrolysis of these mediators, leading to the formation of 5 camp and 5 cgmp, respectively. There are at least 11 isoforms of phosphodiesterase, including phosphodiesterases type 3 and 5, which are highly selective for degradation of camp and cgmp, respectively. 75 The compound cilostazol, a selective inhibitor of phosphodiesterase 3, has been widely used in clinical practice for the treatment of intermittent claudication in peripheral arterial occlusive disease, promoting increased intracellular camp levels. The administration of cilostazol promotes potent vasodilation and inhibition of platelet aggregation, improving pain and walking ability. 2,10 Furthermore, β-adrenergic receptor activation leads to activation of two important second messengers, camp and cgmp, whose therapeutic target is the focus of major drug companies, highlighting the importance of investigating the role that these receptors play in vascular disease. Recently, German researchers have synthesized the compounds BAY and BAY , direct soluble guanylate cyclase activators, which have proven to be potent vasodilators with great therapeutic potential for vascular diseases such as thrombosis and peripheral arterial occlusive disease. 76 Thus, drug therapy for vascular diseases still requires further advances, and its association with non-pharmacological therapy, such as physical exercise, deserves attention within the area of angiology, since physical exercise promotes important changes in the vascular system, especially in the endothelium. Physical exercise and endothelial activation Physical exercise is characterized by skeletal muscle contraction, and during exercise performance significant cardiovascular alterations occur, such as: increased blood flow into the muscles in activity, reduction in peripheral vascular resistance proportional to the increase in cardiac output, and, consequently, increased systolic blood pressure. To adjust all cardiovascular alterations that physical exercise causes, there are mechanisms for neural and humoral regulation. Humoral factors that will cause reduction in peripheral vascular resistance and, consequently, in blood pressure are primarily dependent on the endothelium. 16 Increased pulsatile blood flow and pressure that blood exerts on the vascular wall produce the so-called shear stress, which acts on the intima of vessels where endothelial cells are found. Shear stress is a powerful stimulus for the generation of the vasodilator agent NO in the vascular system. Associated with this phenomenon, physical exercise is an important stimulus to increase blood flow and, consequently, promotes increased NO production that triggers beneficial effects, such as vasorelaxation and inhibition of platelet aggregation, preventing diseases such as hypertension and atherosclerosis. 6 NO plays a protective role in the atherosclerosis process by two signaling pathways. First, NO prevents the formation of oxidized LDL-cholesterol molecules, through its antioxidant action (which is concentration-dependent), decreasing the formation of reactive species of oxygen, which are fundamental for the process of oxidation of LDL-cholesterol molecules; second, by its inhibitory action on platelet adhesion and aggregation, preventing thrombus formation and subsequent partial or total ischemia of the tissues involved. 6 Studies evaluating hypercholesterolemic animals showed increased expression of the antioxidant enzyme superoxide dismutase (SOD) and better relaxant sensitivity through vascular β-adrenoceptor-activated NO/cGMP pathway in chronic response to exercise. 77,78 The mechanisms by which shear stress promotes increased NO production involves the activation of different membrane proteins called mechanosensitive channels. These mechanoreceptors may be Gs proteins, ion channels, caveolin, and integrins, which capture tension changes on
6 52 J Vasc Bras 2010, Vol. 9, Nº 2 Physical exercise and vascular response, Silva AS & Zanesco A the cell wall and convert mechanical stimuli into chemical stimuli for enos activation. 16 The pathways involved in this process are related to the activation of PKC, csrc, and Akt/PI3K, which phosphorylate enos activating it. 79 Shear stress-induced NO production occurs regardless of Ca 2+ presence, since Akt protein reduces enos sensitivity to this ion. The ability of endothelial cells to perceive and respond to changes in blood flow is an essential factor in the regulation of vascular tone and involves the activation of cell growth factors, promoting the remodeling of the arterial wall and maintenance of endothelial integrity. 6 Thus, one of the beneficial effects of regular physical activity is closely related to its ability to stimulate NO synthase by endothelial cells and, consequently, to control blood pressure. Increased NO production also promotes antithrombotic effects, preventing thromboembolic diseases and atherosclerosis, a phenomenon that is due to inhibition of platelet aggregation by NO. 5,6 Effects of physical activity on vascular β-adrenergic sensitivity The effects of exercise on vasomotor function have been extensively studied using both vasoconstrictors, such as norepinephrine and phenylephrine, 80,81 and vasodilator agents, such as acetylcholine and bradykinin Norepinephrine induces vasoconstriction by activating α-adrenergic receptors present within vascular smooth muscle cells, whereas acetylcholine promotes vasodilation by activating muscarinic receptors present within endothelial cells. On the other hand, information about the effects of exercise on β-adrenoceptor-mediated vasodilator responses is much more scarce, and these few conflicting data show reduced, increased or no effect of physical exercise on the relaxant response. Most existing studies associate relaxant responses of β-adrenergic receptors with the aging process or cardiovascular diseases The first studies analyzing the involvement of vascular β-adrenergic receptors in response to physical training date from the late 1970s and have investigated vascular reactivity in response to chronic use of β-blockers in exercise-trained and sedentary rats. 94 It was observed that trained animals without β-blockade showed higher skin temperature when exposed to 5 C room temperature, in addition to increased vasodilator response to isoprenaline, as judged from the increase in body temperature during a training period. The author suggested increased sensitivity of β 2 -adrenoceptors or decreased sensitivity of α-adrenoceptors as an explanation for these phenomena.subsequent studies used blood flow and coronary vascular resistance to access the effects of β-adrenoceptor blockade. It was demonstrated that the β 2 -adrenergic receptor selective antagonist ICI significantly decreased coronary blood flow velocity and increased late diastolic coronary resistance in dogs during a running session. 95 These data showed the important participation of β-adrenergic response in the relaxant response of coronary arteries during exercise.a later study confirmed these results and even showed that coronary resistance and diameter appeared to be also affected by α-adrenergic receptor activity, since the application of phentolamine (a non-selective α-adrenoceptor antagonist) with propranolol (a non-selective β-adrenoceptor antagonist) reduced the vasoconstrictor effect of β-adrenoceptor blockade during exercise. 96 More recently, studies have been conducted with older animals showing that exercise improved sensitivity of β-adrenergic receptors when the vasodilator response mediated by these receptors had been previously reduced by the aging process. 97 Thus, the results showed that a 6-week training program of 5 days/week swimming exercise improved vasodilator response to the non-selective β-adrenoceptor agonist isoproterenol, in coronary arteries, compared with the sedentary group. Another study, conducted with old and young rats, showed that a 10- to 12-week treadmill program of 5 days/week running exercise, with 60-minute sessions, improved vasodilator response to isoproterenol in gastrocnemius muscle vessels from old rats, but not in young animals. 98 Collectively, these studies show the beneficial effects of physical exercise on vascular sensitivity in the aging process. However, β-adrenoceptor responsiveness to exercise is not homogeneous, depending on several factors, such as the region of vascular bed to be studied (regions of different diameters in the same artery may respond differently to physical exercise). 99 Another important variable is the type of artery studied; resistance vessels (forearm) or conductance vessels (brachial artery) showed different responses in relation to blood flow both to endotheliumdependent agonist (acetylcholine) and to endotheliumindependent sodium nitroprusside. 96 Likewise, there may be differences in responses according to the animal studied. Thus, studies related to relaxant responses mediated by β-adrenergic receptors need to be better designed regarding the classification of receptors mediating vasodilator responses in different vessels, the role of physical exercise in this response, and the possible beneficial effects that these receptors may play in the prevention and treatment of vascular diseases.
7 Physical exercise and vascular response, Silva AS & Zanesco A J Vasc Bras 2010, Vol. 9, Nº 2 53 Conclusions The effects of exercise on the vasodilator response mediated by β-adrenergic receptors are conflicting.overall, previous studies show improvement in vascular reactivity to β-adrenoceptor agonists in response to exercise in old animals, but studies involving vascular diseases are scarce and less conclusive. For a better understanding of the effects of physical exercise on vascular β-adrenergic sensitivity, signaling pathways, such as camp, cgmp, and ion channels, should be considered and investigated, since factors such as oxidant activity and functional status of the endothelium are involved in the activation of these receptors. Collectively, the existing data show that the area of vascular pathophysiology is an open field for the discovery of new compounds and advances in clinical practice. References 1. Schramm JMA, Oliveira AF, Leite IC, et al. 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10 56 J Vasc Bras 2010, Vol. 9, Nº 2 Physical exercise and vascular response, Silva AS & Zanesco A in aged rat carotid arteries. Am J Physiol Heart Circ Physiol. 2003;285:H Donato AJ, Lesniewski LA, Delp MD. Ageing and exercise training alter adrenergic vasomotor responses of rat skeletal muscle arterioles. J Physiol. 2007;579: Drieu la Rochelle C, Berdeaux A, Richard V, Giudicelli JF. Coronary effects of a combined beta adrenoceptor blocking and calcium antagonist therapy in running dogs. J Cardiovasc Pharmacol. 1991;18: Correspondence: Angelina Zanesco Av. 24A, 1515, Jardim Bela Vista CEP Rio Claro, SP, Brazil Tel.: (19) Fax: (19) Author contributions Conception and design: AZ Analysis and interpretation: AZ and ASS Data collection: ASS Writing the article: AZ and ASS Critical revision of the article: AZ and ASS Final approval of the article*: AZ and ASS Statistical analysis: Overall responsibility: AZ and ASS Obtained funding: FAPESP *All authors have read and approved of the final version of the article submitted to J Vasc Bras.
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subset: commoncrawl


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Dog Walkers in Iuka, MS
Book a dog walker to give your dog a 30-minute walk around your neighborhood.
Krystal's Boarding!!!
Florence, AL, 35633
Dog Boarding, House Sitting, Drop-In Visits, Doggy Day Care, Dog Walking
About: Hi there!!! I am Krystal! I have been around dogs my entire life, but I have an amazing Australian Shepherd, a little over a year ago, and boy is h... (more)
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Rover also offers dog walking in:
|Allsboro, AL
|Burnsville, MS
|Doskie, MS
|Eastport, MS
|Holcut, MS
|Margerum, AL
|Oldham, MS
|Paden, MS
|Short, MS
|Waterloo, AL
We've been there: rushing home during every lunch break to take the dog for a quick walk around the block. Good news: You can easily find and book Iuka dog walking services on Rover. Whether you need a one-time dog walker or someone to take your dog for a stroll every day, we've got you covered. Exercise for your dog and peace of mind for you are just a few clicks away. Every walk is covered by premium pet insurance, at no extra cost to you. You can even ask your dog walker to send you a photo update. Whether you already have a favorite pet sitter on Rover or you're new to the site, we'd love to connect you with a dog walker in Iuka the next time you're unavailable. We're confident you and your dog will love it.
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text: Chassis# 9110121901 Engine# 6106811 Gearbox# 104657 Paint Code: 2424 Burgundy A 1970 Porsche 911T Karmann Coupe. All matching numbers, comes with a COA.2.2 Liter with Webbers. Burgundy with a black interior. The car just came out of a long term ownership. It was in indoor storage for many years. According to the COA, the car has many desirable options, such as: • US equipment • Lock for lid/release cable • Trim strips on rims • Antenna left w/loudspeaker & noise suppression • Comfort equipment The rear fenders are slightly flared with fiberglass. Floors are original but rusted out on many places. Large capacity fuel tank. The interior is all apart but does come with the car. Missing the front and rear glass. Has the desirable 15 inch Fuchs. The original engine with Webbers turns over by hand. An excellent opportunity to own and restore a longhood coupe. The values are steadily increasing on these early Porsches. Any questions welcome. Please message or call Frank Sajjad at 2166452100. (We can help to make arrangements for worldwide shipping.) Shipping cost to Rotterdam or Felixstowe, UK is $1,500


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Spiced Ginseng Iced Tea
Slideshow: Nonalcoholic Drinks
- Active:
- Total Time:
- Servings: makes about 2 quarts
- 8 cups cold water
- 8 cardamom pods, crushed
- 6 whole cloves
- 2 cinnamon sticks
- 1 star anise pod
- 8 ginseng tea bags
- 1/4 cup plus 1 tablespoon honey
- Ice cubes
How to make this recipe
In a large saucepan, combine the cold water with the cardamom pods, cloves, cinnamon sticks and star anise and bring to a boil. Remove from the heat and add the tea bags. Let steep for 5 minutes. Remove the tea bags and stir in the honey until it is dissolved. Strain the tea into a pitcher and let cool to room temperature, then refrigerate until chilled. Serve in tall glasses over ice.
Make Ahead
The iced tea can be refrigerated in a covered pitcher for up to 2 days.
Contributed By Melissa Rubel Jacobson Published June 2005


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Perplex Singh – The "Senior" Junior
But it was after he entered those hallowed gates, that he realised this would be a completely different world, than what he was used to. Late nights, Google, Ctrl+C, Ctrl+V, Presentations, Parties.. Everything was a far cry from his rustic background.
Confused by the goings on all around him, he often comes to Arbit for guidance, but after hearing Arbit's jargonistic mumblings, goes back even more bewildered than before.
Amused by the constant confusion inside his mind, all his friends call him Perplex'Singh !!
Click here to view all Comics featuring Perplex


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SOS Distress Light - Electronic Flare
The SOS Distress Light is the first and ONLY LED Visual Distress Signal Device that meets U.S. Coast Guard requirements to completely replace traditional pyrotechnic flares. Unlike traditional flares, this electronic flare never expires which solves the challenge of flare disposal.
This floating electronic flare can be hand-held, tethered, or hoisted aloft. It runs up to 60 hours, unlike traditional flares which last minutes or less.
- Complies with all U.S. Coast Guard requirements for "Night Visual Distress Signals" as found in the Code of Federal Regulations: 46 CFR 161.013
- Flashes ONLY the SOS light sequence
- When combined with a daytime distress signal flag (included in package), meets ALL USCG Federal Requirements for DAY and NIGHT use in lieu of traditional flares
- Floats with lens-up to optimize both the all-around horizontal and vertical light beams
- No expiration or disposal issues
- Family and boat SAFE – no flame!
- SIMPLE twist-on operation
- Visible up to 10 nautical miles
- Battery-operated (3 C-cell Alkaline)
- Made in U.S.A.
- Patent Numbers: 9,171,436 and D720,247
- Includes Distress Flag
What makes the SOS Distress Light truly exceptional:
- It is the ONLY alternative to traditional flares
- It meets ALL U.S. Coast Guard requirements
- It NEVER expires, which solves the challenge of flare disposal
- No hazardous shipping or storage risks
- Weems & Plath


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"Fat Man" is the code name for the atomic bomb that was detonated over Nagasaki, Japan, by the United States on August 9, 1945, at 11:02 AM (JST). It was the second of the only two nuclear weapons to be used in warfare and was the third man-made nuclear explosion. The name also refers more generically to the early nuclear weapon designs of U.S. weapons based on the "Fat Man" model. It was an implosion-type weapon with a plutonium core. [1]
Type Nuclear weapon Place of origin United States Specifications Weight 10,200 lbs (4,630 kg) Length 10.6 Feet (3.25m) Diameter 5 Feet (1.52m) Blast yield 21 kilotons
Fat Man was possibly named after Winston Churchill [2], though Robert Serber said in his memoirs that as the "Fat Man" bomb was round and fat, he named it after Sydney Greenstreet's character of "Kasper Gutman" in The Maltese Falcon. The design of "Fat Man" nuclear assembly was substantially the same as "the gadget" detonated at the Trinity test in July 1945.
"Fat Man" was detonated at an altitude of about 1,800 feet (550 m) over the city, and was dropped from a B-29 bomber Bockscar, piloted by Major Charles Sweeney of the 393d Bombardment Squadron, Heavy. The bomb had a yield of about 21 kilotons of TNT, or 8.78×1013 joules = 88 TJ (terajoules).[3] Because of Nagasaki's hilly terrain, the damage was somewhat less extensive than that in relatively flat Hiroshima. An estimated 39,000 people were killed outright by the bombing at Nagasaki, and about 25,000 were injured.[4] Thousands more would die later from related blast and burn injuries, and hundreds more from radiation illnesses from exposure to the bomb's initial radiations. The aerial bombing raid on Nagasaki had the third highest fatality rate[5] in World War II after the nuclear strike on Hiroshima[6][7][8][9] and the March 9/10 1945 fire bombing raid on Tokyo[10].


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Added on 01-Apr-2005
Hi All,Here is the info for the QUEEN MANIAQueen ManiaSaturday 09 April9:10pm - 10:10pmITV1 LondonZoe Ball presents a celebration of the music of Queen to coincide with the 30th anniversary of the release of Bohemian Rhapsody. With performances from Melanie C, G4, Lesley Garrett, Heather Small, Tony Christie, Toyah Wilcox, Myleene Klass and Russell Watson, and a special version of I Want To Break Free by stars of Coronation Street. Plus classic archive footage of Queen, and celebrities talking about the band. Queen Mania: The Show Must Go On (Behind The Scenes)Saturday 09 April10:10pm - 11:15pmITV2The celebration of rock giants Queen continues, as the band celebrates 30 years since the release of Bohemian Rhapsody. Featuring classic archive footage, and interviews with famous fans about the music, concerts and videos that made the band a phenomenon. Those sharing their memories include Melanie C, Lesley Garrett, Heather Small, Toyah Willcox, Myleene Klass, Russell Watson, Tricia Penrose, Paul Ross and Rowland Rivron.Pretty cool stuff I think!can't wait to see it.
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Hereford Cathedral, Herefordshire Genealogy
Parish History
The city comprises the parishes of All Saints, containing 3091;St. Martin, 1069; St. John the Baptist, 1303; St. Nicholas, 1182; St. Owen, 1755; and St. Peter, 2521 inhabitants. The chapel of All Saints' was consolidated with that of St. Martin's. The Cathedral church of St Mary's and St Ethelbert is an ancient structure, partly in the Norman style, with a tower strengthened with buttresses, and surmounted by a lofty spire; the aisles are separated from the nave by circular columns and pointed arches, and there are a fine altar-piece, and some stalls supposed to have been appropriated to the brethren of St. Anthony. The building was lately enlarged, and 400 free sittings provided; and a very handsome organ was erected in 1826. St. Martin's church, which was situated on the south bank of the river, near the bridge, was destroyed during the parliamentary war. The present church was consecrated in October 1845; the interior is well arranged, and fitted up with open seats. The living of St. John the Baptist's is a discharged vicarage, valued in the king's books at £7. 12. 1.; net income, £150; patrons and appropriators, the Dean and Chapter of Hereford. The west nave of the cathedral was appropriated as a church for this parish till the accidental fall of its tower, in 1786. At present the north transept is used for the purpose. The living of St. Nicholas is a discharged rectory, valued in the king's books at £10, and in the patronage of the Crown: the tithes have been commuted for £185, of which £128 are payable to the rector. The church, previous to the Dissolution, had two chantries in honour of the Virgin. The living of St. Owen's is a rectory, united to the vicarage of St. Peter's, the former valued in the king's books at £4. 10. 10., and the latter at £10. 0. 2.; net income, £366; patrons, the Trustees of the late Rev. Henry Gipps; appropriators, the Dean and Chapter. The vicarial tithes of St. Owen's have been commuted for £75. The church, which was situated without the walls of the city, was destroyed during the parliamentary war. On its site, a neat school-house, which is also used as a chapel of ease, was recently erected. The church ofSt. Peter, founded in 1070, is in the Norman style, with a tower surmounted by a neat spire, and was repaired and partly rebuilt in 1793. There are places of worship for the Society of Friends, Independents, the Countess of Huntingdon's Connexion, Wesleyans, and Roman Catholics.[1]
Civil Registration
Birth, marriages and deaths were kept by the government, from July 1837 to the present day. The civil registration article tells more about these records. There are several Internet sites with name lists or indexes. A popular site is FreeBMD.
Church records
Census records from 1841 to 1911 are available online. For access, see England Census Records and Indexes Online. Census records from 1841 to 1891 are also available on film through a Family History Center or at the Family History Library.
Census records
Poor Law Unions
Probate records
Records of wills, administrations, inventories, indexes, etc. were filed by the court with jurisdiction over this parish. Go to Herefordshire Probate Records to find the name of the court having primary jurisdiction. Scroll down in the article to the section Court Jurisdictions by Parish.
Maps and Gazetteers
Maps are a visual look at the locations in England. Gazetteers contain brief summaries about a place.
Web sites
Contributor: add any relevant sites that aren't mentioned above.
- ↑ Lewis, Samuel A., A Topographical Dictionary of England (1848), pp. 482-491. Adapted. Date accessed: 14 February 2013.


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2011 NFL Draft: Back-to-back big games raise profile of OT Carimi
The No. 1-ranked team in the nation fell for the third straight week during a wild Saturday of college football. Week 8 also saw a pair of highly regarded prospects sliding down draft boards while an underrated left tackle is moving in the opposite direction.