Effects of Intrarenal Infusion of 17-Octadecynoic Acid on Renal Antihypertensive Mechanisms in Anesthetized Rabbits

Abstract

To characterize the role of cytochrome P450 metabolism of fatty acids in the renal response to increased renal perfusion pressure, we tested the effects of renal arterial infusion of 17-octadecynoic acid (17-ODYA, 450 nmol/min) on renal and systemic hemodynamic, and renal excretory responses to step-wise increases in renal perfusion pressure (RPP) in anesthetized rabbits, using an extracorporeal circuit for renal autoperfusion. Inhibition of cytochrome P450-dependent fatty acid metabolism was estimated by comparing the metabolism of arachidonic acid in microsomes prepared from the kidneys of control and 17-ODYA-treated animals.Step-wise increases in RPP decreased mean arterial pressure, which previous studies have indicated is attributable to the release of a depressor hormone from the renal medulla. Elevations in RPP also increased renal blood flow and glomerular filtration rate, and the absolute and fractional excretions of urine and sodium. Intrarenal infusion of 17-ODYA reduced the metabolism of arachidonic acid to 20-hydroxyeicosatetraenoic acid by 41%, but it did not significantly influence the responses to increased renal perfusion pressure. We conclude that either the responses elicited by increased renal perfusion pressure in anesthetized rabbits do not depend on cytochrome P450-dependent fatty acid metabolism, or that cytochrome P450 activity must be inhibited by more than was achieved in the present study (41%), before functional effects on the response to increased renal perfusion pressure are observed. Am J Hypertens 1998;11:803-812

Cytochrome P450‐Dependent Metabolites Of Arachidonic Acid And Renal Function In The Rat

“…24 We also used miconazole, which inhibited the conversion of [ 14 C]-AA to epoxides by 54%, to evaluate the role of epoxides on renal responses to changes in RPP. However, DBDD did not affect the natriuresis and diuresis produced by elevation in RPP, an observation similar to that of Evans et al, 27 who demonstrated that inhibition of CYP450 enzymes with 17-ODYA had no effect on the pressure-natriuretic response in rabbits. 17 Under the same experimental conditions, miconazole was without effect.…”

“…17 Under the same experimental conditions, miconazole was without effect. However, DBDD did not affect the natriuresis and diuresis produced by elevation in RPP, an observation similar to that of Evans et al, 27 who demonstrated that inhibition of CYP450 enzymes with 17-ODYA had no effect on the pressure-natriuretic response in rabbits. 27 These observations rule out a role for 20-HETE in influencing the resultant natriuresis following increases in RPP in the rat or rabbit.…”

“…12,12-Dibromodecenoic acid eliminated autoregulation of RBF, an observation consistent with the role for 20-HETE as a mediator of renal autoregulation in the rat. 27 These observations rule out a role for 20-HETE in influencing the resultant natriuresis following increases in RPP in the rat or rabbit. However, DBDD did not affect the natriuresis and diuresis produced by elevation in RPP, an observation similar to that of Evans et al, 27 who demonstrated that inhibition of CYP450 enzymes with 17-ODYA had no effect on the pressure-natriuretic response in rabbits.…”

“…In the SHR, for example, in which there was a marked increase in the expression of the CYP450A2 gene 28 and 20-HETE production, 12 inhibition of CYP450-AA metabolism normalized blood pressure, 11 arguing for a role for 20-HETE in elevating renal vascular tone and resetting the pressure-natriuresis relationship. 27 Thus, it appears that following elevation of RPP, simultaneous release of the vasodilator medullipin may obscure the renal effect of 20-HETE. This was suggested to be due to reduced formation of sodium-retaining CYP450-AA metabolites.…”

Modulation of V1-receptor-mediated renal vasoconstriction by epoxyeicosatrienoic acids

“…Similarly, we previously found in anesthetized rabbits that renal arterial infusion of the nonselective CYP450 inhibitor 17-octadecynoic acid had no significant effects on RBF (13), and others have shown little effect of miconazole, a selective epoxygenase inhibitor, on RBF (31,32). Thus these data do not support a role for EETs in control of basal renal vascular tone.…”