Effects of 17-octadecynoic acid, a suicide-substrate inhibitor of cytochrome P450 fatty acid omega-hydroxylase, on renal function in rats.
This study evaluated the ability of 17-octadecynoic acid (17-ODYA) to inhibit the metabolism of arachidonic acid by cytochrome P450 in renal cortical microsomes of rats, and characterized the effects of intrarenal infusion of this substance on renal hemodynamics and the excretion of water and electrolytes. 17-ODYA was a potent inhibitor (IC50 < 100 nM) of the formation of 20-hydroxyeicosatetraenoic acid, epoxyeicosatrienoic acids and dihydroxyeicosatrienoic acids by rat renal cortical microsomes incubated with arachidonic acid. Infusion of 17-ODYA (16.5 nmol/min; n = 8) directly into the renal cortical interstitium of rats produced a diuresis and a natriuresis which were associated with an increase in renal papillary blood flow in the absence of changes in renal blood flow, cortical blood flow or glomerular filtration rate. 17-ODYA inhibited the omega-hydroxylation of arachidonic acid by microsomes prepared from the infused kidney by 61.3 +/- 9.2% (n = 7) relative to that observed in the contralateral kidney, whereas infusion of vehicle (n = 6) or palmitate (n = 4) had no effect on renal metabolism of arachidonic acid by cytochrome P450. Infusion of 17-ODYA (33 nmol/min) into the renal artery of rats also increased urine flow and sodium excretion, whereas renal blood flow and glomerular filtration rate were not significantly altered. Papillary blood flow increased 36% during infusion of 17-ODYA into the renal artery, and renal interstitial hydrostatic pressure increased from 8.7 +/- 1.1 to 13.8 +/- 1.5 mm Hg. These results suggest that endogenous cytochrome P450 metabolites of arachidonic acid influence renal medullary hemodynamics and the excretion of water and electrolytes.
Zou
A P
AP
Department of Physiology, Medical College of Wisconsin, Milwaukee.
Ma
Y H
YH
Sui
Z H
ZH
Ortiz de Montellano
P R
PR
Clark
J E
JE
Masters
B S
BS
Roman
R J
RJ
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D042926:Cytochrome P-450 CYP4A; D065607:Cytochrome P-450 Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D007261:Infusions, Intra-Arterial; D007672:Kidney Cortex / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D012077:Renal Artery
D065607:Cytochrome P-450 Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D016718:Arachidonic Acid; C047008:17-octadecynoic acid; D006899:Mixed Function Oxygenases; D042926:Cytochrome P-450 CYP4A