Involvement of Cytochrome P450 Metabolites in the Vascular Action of Angiotensin II on the Afferent Arterioles.
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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 <I>in vitro</I>, and the vasoconstrictor action of Ang II (10<SUP>−11</SUP>-10<SUP>−8</SUP> 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<SUP>−8</SUP> M, <I>n</I>=9, <I>p</I><0.0001). Pretreatment with miconazole, an inhibitor of CYP450 epoxygenase, at 10<SUP>−6</SUP> M decreased the basal diameter by 14±1% (<I>n</I>=6, <I>p</I><0.01) and augmented the vasoconstrictor action of Ang II (7±3% of control diameter at 10<SUP>−8</SUP> M, <I>p</I><0.001 <I>vs</I>. without miconazole). This augmentation was abolished by blocking the Ang II type 2 (AT<SUB>2</SUB>) receptor with PD 123319 at 10<SUP>−7</SUP> M. In contrast, pretreatment with 17-octadecynoic acid (17-ODYA, 10<SUP>−6</SUP> 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<SUP>−8</SUP> M, <I>p</I><0.01 <I>vs</I>. 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 <I>via</I> AT<SUB>2</SUB> receptors. (Hypertens Res 2001; 24: 551-557)
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