Recent studies have demonstrated that cytochrome P450-dependent metabolites of arachidonic acid (CYP450-AA) play important roles in the control of renal vascular resistance (RVR). In the present study, we examined the possible involvement of CYP450-AA in the vasoconstrictor action of angiotensin II (Ang II) on the afferent arterioles (Af-Arts), a vascular segment crucial to the control of RVR. Rabbit Af-Arts were microperfused at 60 mmHg in vitro, and the vasoconstrictor action of Ang II (10-11-10-8 M, added to both the bath and lumen) was examined with or without blocking the activity of CYP450 epoxygenase or hydroxylase. Ang II decreased the luminal diameter of Af-Arts in a dose-dependent manner (34±2% of control diameter at 10-8 M, n=9, p<0.0001). Pretreatment with miconazole, an inhibitor of CYP450 epoxygenase, at 10-6 M decreased the basal diameter by 14±1% (n=6, p<0.01) and augmented the vasoconstrictor action of Ang II (7±3% of control diameter at 10-8 M, p<0.001 vs. without miconazole). This augmentation was abolished by blocking the Ang II type 2 (AT2) receptor with PD 123319 at 10-7 M. In contrast, pretreatment with 17-octadecynoic acid (17-ODYA, 10-6 M), which inhibits both epoxygenase and hydroxylase activity, had no effect on the basal diameter but attenuated the vasoconstrictor action of Ang II (46±2% of control diameter at 10-8 M, p<0.01 vs. without 17-ODYA). Our results demonstrate that in the Af-Art, endogenous CYP450-AA are involved not only in the control of basal tone but also in the action of Ang II. Further, it appears that the CYP450 epoxygenase pathway attenuates Ang II action via AT2 receptors.
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