Differential effect of cytochrome P-450 ω-hydroxylase inhibition on O₂-induced constriction of arterioles in SHR with early and established hypertension

Objective: To determine whether two structurally and mechanistically different inhibitors of cytochrome P-450 ω-hydroxylase would alter the enhanced vasoconstrictor response to elevated PO₂ in arterioles of spontaneously hypertensive rats (SHR). Cytochrome P-450 ω-hydroxylases, which catalyze the formation of the vasoconstrictor 20-hydroxyeicosatetraenoic acid from arachidonic acid, have been proposed to serve as microvascular O₂ sensors. Methods: Arteriolar diameters were measured in the in situ cremaster muscle of 4-to 6- and 12-to 16-week-old SHR and normotensive Wistar-Kyoto (WKY) controls during superfusion with physiological salt solution (PSS) equilibrated with 0% O₂ and 21% O₂ before and after P-450 enzyme inhibition. Results: The P-450 ω-hydroxylase inhibitors 17-octadecynoic acid (17-ODYA) and N-methylsulfonyl-12, 12-dibromododec-11-enamide (DDMS) significantly reduced O₂-induced constriction of arterioles of 12-to 16-week-old SHR and WKY and eliminated the difference in the response between the two groups. In contrast, both enzyme inhibitors attenuated the O₂-induced constriction of arterioles in the younger WKY, but not in the 4-to 6-week-old SHR. Conclusions: These results support the hypothesis that cytochrome P-450 4A may act as an O₂ sensor in the skeletal muscle microcirculation and suggest that 20-hydroxyeicosatetraenoic acid plays an important role in the enhanced response to elevated PO₂ in the SHR with established hypertension. Other mechanisms seem to contribute to the enhanced sensitivity of arterioles to elevated PO₂ in young SHR during the early development of hypertension.