20‐HETE contributes to hypertension in postmenopausal rats.

Abstract

20‐HETE, a major metabolite of cytochrome P450 (CYP)‐4A, is a potent vasoconstrictor of renal arterioles, and has been shown to mediate hypertension in several animal models. The present study tested the hypothesis that 20‐HETE is involved in mediating hypertension in an animal model of postmenopausal hypertension, the old female spontaneously hypertensive rat (OF‐SHR). A CYP4A inhibitor of 20‐HETE production, 1‐aminobenzotriazole (ABT; 50 mg/kg per day i.p.), or vehicle, was administered to OF‐SHR, aged 16 mos, and young female SHR (YF‐SHR), aged 3 mos, (n=3–4 per group). Mean arterial pressure (MAP) was measured by radiotelemetry. ABT decreased MAP in OF‐SHR (164±5 vs. 151±6 mm Hg, p<0.05), whereas it had no effect in YF‐SHR (138±3 vs.136±1 mm Hg). CYP4A (isoform 2) mRNA expression was measured by real‐time RT‐PCR in kidney cortex and medulla of OF‐SHR and YF‐SHR. CYP4A2 mRNA expression was significantly upregulated in kidney cortex of OF‐SHR compared to YF‐SHR. In other studies administration of a specific 20‐HETE inhibitor, HET0016, also significantly decreased MAP in OF‐SHR. In summary, administration of the CYP4A inhibitor and a specific 20‐HETE inhibitor markedly attenuated hypertension in postmenopausal rats. Increases in renal vascular 20‐HETE constitute a new pathway that may be involved in mediating postmenopausal hypertension. (Supported by HL 51971).