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Departments of 1 Medicine and 3 Biochemistry, Vanderbilt University Medical School, Nashville, Tennessee 37232; and 2 Department of Pharmacology, New York Medical College, Valhalla, New York 10595
Hypertension
is a leading cause of cardiovascular, cerebral, and renal disease
morbidity and mortality, and epidemiological evidence suggests a role
for sex-dependent mechanisms in the pathophysiology of hypertension. We
show here that treatment of rats with 5
-dihydrotestosterone increases the activity of the kidney arachidonate 
/-1 hydroxylase and the biosynthesis of 20-HETE (165 and 177% of control untreated male and female rats, respectively) and raises the systolic blood pressures of male and females rats by 46 and 57 mmHg, respectively. These androgen effects are associated with an upregulation in the
kidney levels of CYP 4A8 mRNA and a decrease in CYP 4A1 transcripts. Dissected renal microvessels, the target tissue for most of the prohypertensive actions of 20-HETE, show an androgen-dependent upregulation of vascular CYP 4A8 mRNA and a fourfold increase in
20-HETE synthase activity. We propose that androgens regulate renal
function and systemic blood pressure through a combination of
transcriptional and hemodynamic mechanisms that are ultimately responsible for the regulation of renovascular tone and function.
P-450 eicosanoids; androgens; CYP 4A8
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