The major renal eicosanoid products are PGE2 and PGI2, followed by PGF2α and TXA2. The kidney also synthesizes several hydroxyeicosatetraenoic acids, leukotrienes, cytochrome P450 products, and epoxides. Prostaglandins play important roles in maintaining blood pressure and regulating renal function, particularly in marginally functioning kidneys and volume-contracted states. Under these circumstances, renal cortical COX-2-derived PGE2 and PGI2 maintain renal blood flow and glomerular filtration rate through their local vasodilating effects. These prostaglandins also modulate systemic blood pressure through regulation of water and sodium excretion. Expression of medullary COX-2 and mPGES-1 is increased under conditions of high salt intake. COX-2-derived prostanoids increase medullary blood flow and inhibit tubular sodium reabsorption, while COX-1-derived products promote salt excretion in the collecting ducts. Increased water clearance probably results from an attenuation of the action of antidiuretic hormone (ADH) on adenylyl cyclase. Loss of these effects may underlie the systemic or salt-sensitive hypertension often associated with COX inhibition. A common misperception—often articulated in discussion of the cardiovascular toxicity of drugs such as rofecoxib—is that hypertension secondary to NSAID administration is somehow independent of the inhibition of prostaglandins. Loop diuretics, eg, furosemide, produce some of their effect by stimulating COX activity. In the normal kidney, this increases the synthesis of the vasodilator prostaglandins. Therefore, patient response to a loop diuretic is diminished if a COX inhibitor is administered concurrently (see Chapter 15).
There is an additional layer of complexity associated with the effects of renal prostaglandins. In contrast to the medullary enzyme, cortical COX-2 expression is increased by low salt intake, leading to increased renin release. This elevates glomerular filtration rate and contributes to enhanced sodium reabsorption and a rise in blood pressure. PGE2 is thought to stimulate renin release through activation of EP4 or EP2. PGI2 can also stimulate renin release and this may be relevant to maintenance of blood pressure in volume-contracted conditions and to the pathogenesis of renovascular hypertension. Inhibition of COX-2 may reduce blood pressure in these settings.
TXA2 causes intrarenal vasoconstriction (and perhaps an ADH-like effect), resulting in a decline in renal function. The normal kidney synthesizes only small amounts of TXA2. However, in renal conditions involving inflammatory cell infiltration (such as glomerulonephritis and renal transplant rejection), the inflammatory cells (monocyte-macrophages) release substantial amounts of TXA2. Theoretically, TXA2 synthase inhibitors or receptor antagonists should improve renal function in these patients, but no such drug is clinically available. Hypertension is associated with increased TXA2 and decreased PGE2 and PGI2 synthesis in some animal models, eg, the Goldblatt kidney model. It is not known whether these changes are primary contributing factors or secondary responses. PGF2α may elevate blood pressure by regulating renin release in the kidney. Although more research is necessary, FP antagonists have potential as novel antihypertensive drugs.
D. Reproductive Organs 1.