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CARDIOVASCULAR

The Cytochrome P450 Inhibitor Ketoconazole Potentiates 5-Hydroxytryptamine-Induced Contraction in Rat Aorta

Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan (K.K.O., S.W.W.); and Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas (J.R.F.)

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 µM) 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 µM) did not reveal 5-HT-stimulated superoxide. The NO inhibitor N-nitro-L-arginine (L-NNA) (100 µM) with or without KTZ (10 µM) 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 µM) did not potentiate 5-HT-induced contraction. Moreover, 14,15-epoxyeicosa-5(Z)-enoic acid (10 µM), 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.

Address correspondence to: Dr. Stephanie W. Watts, Department of Pharmacology and Toxicology, Michigan State University, B445 Life Sciences, East Lansing, MI 48824. E-mail: wattss{at}msu.edu

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