Cirrhosis, renal function and NSAIDs

Abstract

For several years it has been known that arachidonic acid (AA) metabolites (or the prostaglandin system, PG), which derive from the activation of membrane cyclooxygenase, play an important role in mediating renal function, renal salt and water excretion, renal plasma flow (RPF), glomerular filtration rate (GFR), and renin release. In fact, PGs are released by the glomeruli and by their afferent arterioles, thus influencing intraglomerular vascular tone (1,2). The PG system has been correlated with other autacoid systems, especially with the bradykinin-kinin system and leukotrienes, the latter being the result of the other branch of AA catabolism through activation of membrane lipoxygenase. PGs can also modify peripheral vascular resistance, and thus regulate systemic blood pressure, modulate immunological function and stimulate erythropoietin release. Intravenous infusion of prostaglandin E (PGE2), prostaglandin D2 (PGD2) and prostacyclin (PGI2) induce systemic vasodilation and decrease vascular resistance, while PGF2c~ and TxA2 infusion determine arteriolar vasoconstriction (3). The reciprocal influence of the PG system on major vasoactive systems (the sympathetic nervous system, SNS, and renin-angiotensin-aldosterone system, RAAS) also occurs when PG release is blocked with indomethacin, leading to an increased response to the infusion of arginin vasopressin or angiotensin II (4). Because of this prevalent vasodilating action, the infusion of PG2, PGD2 and PGI2 into the renal artery increases renal blood flow (5). Endoperoxides (PGG2, PGH2) (6), TxA2 (7) and leukotrienes C4 and D4 (8) induce, instead, a potent vasoconstriction of the renal arteries in experimental animals. During renal vasoconstriction, mainly induced by angiotensin II and norepinephrine, there is a rapid increase in the release of renal PGs (9,10). Other experiments, furthermore, show that the inhibition of PG release potentiates vascular vaoconstriction of the above mentioned substances (11 ). Moreover, PGs may have a direct effect on diuresis by acting on tubular reabsorption or indirectly, by influencing renal hemodynamics. Some studies demonstrate that PGI2 also inhibits sodium and water reabsorption in the thick ascending limbs of cortical tubules (12). Moreover, PGs can modulate vasopressin activity on water transport in the ductular cells. Cyclooxygenase inhibition induces an increase in urinary osmolality, and enhances renal sensitivity to vasopressin (13). The infusion of PGs and 9-deoxy16,16-dimethyl-9-methylene-PGE2, on the other hand, leads to an inhibition of the water retaining activity of vasopressin and an increase in free water clearance in animals (14).