on June 4, 2007
Published online before print June 4, 2007, doi: 10.1161/HYPERTENSIONAHA.107.089599
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Submitted on February 19, 2007
From the Department of Pharmacology, New York Medical College, Valhalla. * To whom correspondence should be addressed. E-mail: michal_schwartzman{at}nymc.edu.
Abstract--Epidemiological evidence suggests a role for sex-dependent mechanisms in the pathophysiology of hypertension. It has been shown that 5
Revised on March 5, 2007
Vascular Cytochrome P450 4A Expression and 20-Hydroxyeicosatetraenoic Acid Synthesis Contribute to Endothelial Dysfunction in Androgen-Induced Hypertension
Harpreet Singh;
-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/µg 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.
Key words: hypertension • endothelial dysfunction • cytochrome P450 • NO • superoxide anion • 20-HETE
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