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Effect of Androgen treatment on renal vascular CYP 4A expression, 20‐HETE synthesis and blood pressure.

Epidemiological evidence suggests a role for sex‐dependent mechanisms in the pathophysiology of hypertension. Cytochrome P450 (CYP) 4A‐derived aracidonic acid ω‐hydroxylation to 20‐hydroxyeicosatetraenoic acid (20‐HETE) has been implicated in the regulation of blood pressure. We investigated the consequences of 5α‐dihydrotestosterone (DHT) treatment on renal vascular CYP 4A expression, 20‐HETE synthesis and blood pressure in male and female Sprague Dawley rats. DHT (70mg/Kg.b.w/day for 2weeks) increased systolic blood pressure in male rats (from 127± 2.5 to 148± 3.5 mm of Hg, p< 0.005) and in female rats (from 128± 2.2 to 143± 3.4 mm of Hg, p < 0.05). Relative to data in vehicle‐treated rats, interlobar arteries from DHT‐ treated rats produced increased levels of 20‐HETE in male rats (12.26± 1.18 vs 16.8 ± 1.34 pmol/mg protein, p<0.05) and in female rats (24.72 ±1.85 vs 32.76 ± 2.08 pmol/mg protein, p <0.01); there was no significant difference in the production of 18‐ and 19‐HETE in any of the groups. DHT treatment increased vascular CYP 4A‐immunoreactive protein levels and CYP 4A8 mRNA measured by real time PCR (1.24 ± 0.15 X 106 vs 0.24 ±0.22 X 106 copy number in DHT‐ vs vehicle‐treated rats; p<0.05). No changes in the CYP 4A1, CYP 4A2 and CYP4A3 mRNAs were detected. Collectively, these findings demonstrate that DHT is associated with upregulation of CYP 4A expression, specifically CYP 4A8, and increased production of vascular 20‐HETE, which may impair endothelial function, promote constrictor mechanisms and contribute to the development of androgen‐dependent hypertension. NIH grant HL34300