Vascular cytochrome P450 4A expression and 20-hydroxyeicosatetraenoic acid synthesis contribute to endothelial dysfunction in androgen-induced hypertension.
Epidemiological evidence suggests a role for sex-dependent mechanisms in the pathophysiology of hypertension. It has been shown that 5alpha-dihydrotestosterone (DHT) administration (56 mg/kg of body weight per day IP for 14 days) increases blood pressure, cytochrome P450 4A expression, and 20-hydroxyeicosatetraenoic acid synthesis in rats. We examined whether increased vascular 20-hydroxyeicosatetraenoic acid synthesis underlies endothelial dysfunction and hypertension in DHT-treated male Sprague-Dawley rats by using HET0016, a selective cytochrome P450 4A inhibitor. Coadministration of HET0016 (10 mg/kg per day IP for 14 days) to DHT-treated rats markedly reduced DHT-induced interlobar arterial production of 20-hydroxyeicosatetraenoic acid (14.3+/-1.5 versus 1.5+/-0.5 ng/mg of protein per hour; P<0.05), superoxide anion (246+/-47 versus 31+/-8 cpm/microg of protein), and the levels of gp91-phox, p47-phox, and 3-nitrosylated proteins. Moreover, the maximal relaxing response to acetylcholine in phenylephrine-preconstricted renal interlobar arteries from DHT-treated rats (42.8+/-4.8%) significantly (P<0.05) increased in the presence of HET0016 (81.5+/-10.8%). Importantly, the administration of HET0016 negated DHT-induced hypertension; systolic blood pressure was reduced from 146+/-2 mm Hg in DHT-treated rats to 130+/-1 mm Hg (P<0.05). The results strongly implicate vascular cytochrome P450 4A-derived 20-hydroxyeicosatetraenoic acid in the development of androgen-induced endothelial dysfunction and hypertension.
Singh
Harpreet
H
Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
Cheng
Jennifer
J
Deng
Huan
H
Kemp
Rowena
R
Ishizuka
Tsuneo
T
Nasjletti
Alberto
A
Schwartzman
Michal Laniado
ML
D000109:Acetylcholine / Q000494:pharmacology; D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D042926:Cytochrome P-450 CYP4A / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D013196:Dihydrotestosterone / Q000494:pharmacology; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D006893:Hydroxyeicosatetraenoic Acids / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D006973:Hypertension / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D012077:Renal Artery / Q000378:metabolism*; D013481:Superoxides / Q000037:antagonists & inhibitors; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D000578:Amidines; C000708209:HET0016; D006893:Hydroxyeicosatetraenoic Acids; D008562:Membrane Glycoproteins; D014665:Vasodilator Agents; D013196:Dihydrotestosterone; D013481:Superoxides; C055987:20-hydroxy-5,8,11,14-eicosatetraenoic acid; D042926:Cytochrome P-450 CYP4A; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C060505:neutrophil cytosolic factor 1; D000109:Acetylcholine