Effects of converting enzyme inhibitors on renal P-450 metabolism of arachidonic acid.

Abstract

The effects of blockade of the renin-angiotensin system on the renal metabolism of arachidonic acid (AA) were examined. Male Sprague-Dawley rats were treated with vehicle, captopril (25 mg x kg(-1) x day(-1)), enalapril (10 mg x kg(-1) x day(-1)), or candesartan (1 mg x kg(-1) x day(-1)) for 1 wk. The production of 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) by renal cortical microsomes increased in rats treated with captopril by 59 and 24% and by 90 and 58% in rats treated with enalapril. Captopril and enalapril increased 20-HETE production in the outer medulla by 100 and 143%, respectively. In contrast, blockade of ANG II type 1 receptors with candesartan had no effect on the renal metabolism of AA. Captopril and enalapril increased cytochrome P-450 (CYP450) reductase protein levels in the renal cortex and outer medulla and the expression of CYP450 4A protein in the outer medulla. The effects of captopril on the renal metabolism of AA were prevented by the bradykinin-receptor antagonist, HOE-140, or the nitric oxide (NO) synthase inhibitor, N(G)-nitro-L-arginine methyl ester. These results suggest that angiotensin-converting enzyme inhibitors may increase the formation of 20-HETE and EETs secondary to increases in the intrarenal levels of kinins and NO.