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Tuesday 23 October 2007

The cytochrome p450 inhibitor ketoconazole potentiates 5-hydroxytryptamine-induced contraction in rat aorta.

By: Ogden KK, Falck JR, Watts SW.

J Pharmacol Exp Ther 2007 Nov;323(2):606-13

5-Hydroxytryptamine (5-HT; serotonin) is a potent vasoconstrictor and smooth muscle mitogen. Substances that produce similar responses also stimulate production of superoxide. We sought to determine whether 5-HT stimulates production of superoxide. 5-HT can be metabolized by cytochrome P450 to nitric oxide (NO), which scavenges superoxide. Thus, we hypothesized that inhibiting cytochrome P450 would potentiate 5-HT-induced contraction and reveal 5-HT-stimulated superoxide. In isolated tissue bath experiments using endotheliumintact rat aorta, the cytochrome P450 inhibitor ketoconazole (KTZ; 1-50 microM) caused a maximum 8-fold leftward shift in the 5-HT concentration-response curve that was not observed when aorta were stimulated with phenylephrine or KCl. 5-HT did not stimulate concentration-dependent increases in superoxide levels as measured by a lucigenin-enhanced chemiluminescent superoxide assay. KTZ (10 microM) did not reveal 5-HT-stimulated superoxide. The NO inhibitor N(omega)-nitro-L-arginine (L-NNA) (100 microM) with or without KTZ (10 microM) potentiated 5-HT-induced contraction independently of NADPH oxidase-derived superoxide but also did not reveal 5-HT-stimulated superoxide. Metabolism of 5-HT to NO depends on catalase, but the catalase inhibitor 3-amino-1,2,4-triazole (50 mM) attenuated 5-HT-induced contraction. Removal of endothelium did not alter the effects of KTZ on 5-HT-induced contraction, and, in endothelium-intact aorta, KTZ did not decrease acetylcholine-induced relaxation. Unlike KTZ, the cytochrome P450 inhibitors 1-aminobenzotriazole (0.5 mM) and clotrimazole (10 microM) did not potentiate 5-HT-induced contraction. Moreover, 14,15-epoxyeicosa-5(Z)-enoic acid (10 microM), an epoxyeicosatrienoic acid antagonist, caused a small rightward shift in the 5-HT concentration-response curve. These data suggest KTZ acts by a potentially novel mechanism to potentiate 5-HT-induced contraction.

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