CYP450 4A inhibition attenuates O2 induced arteriolar constriction in chronic but not acute Goldblatt hypertension.

We explored the role of 20-hydroxy-5Z, 8Z, 11Z, 14Z-eicosatetraenoic acid (20-HETE) in oxygen-induced vasoconstriction in a normal renin form of hypertension [the 1 kidney-1 clip Goldblatt hypertensive rat (1K1C)] and a high renin form of hypertension [the 2 kidney-1 clip Goldblatt hypertensive rat (2K1C)]. A silver clip was placed around the left renal artery of adult Sprague-Dawley males. The right kidney was removed in the 1K1C group and left intact in the 2K1C group. Arteriolar responses to elevation of O(2) concentration in the superfusion solution from 0% O(2) to 21% O(2) were determined in the in situ cremaster muscle before and after inhibition of cytochrome P450 4A omega-hydroxylase (CYP450 4A) with N-methyl-sulfonyl-12, 12-dibromododec-11-enamide (DDMS). Arteriolar constriction to elevated PO(2) was enhanced in the chronic 1K1C but not the acute 1K1C or 2K1C. DDMS eliminated O(2)-induced arteriolar constriction in the 9-week 1K1C, but had no effect in the 2-week 1K1C, and only partially inhibited O(2)-induced constriction of arterioles in the 4-week 2K1C rat. These findings indicate that although the CYP4A/20-HETE system contributes to arteriolar constriction in response to elevated PO(2) in the established stage of 1K1C renovascular hypertension, physiological alterations in other mechanisms are the primary determinants of O(2)-induced constriction of arterioles in the early and developing stages of 1K1C and 2K1C hypertension.