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

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 nitri...

Full description

Saved in:
Bibliographic Details
Published in:The Journal of pharmacology and experimental therapeutics 2007-11, Vol.323 (2), p.606-613
Main Authors: Ogden, Kevin K, Falck, John R, Watts, Stephanie W
Format: Article
Language:English
Subjects:
Animals
Aorta, Thoracic - drug effects
Aorta, Thoracic - physiology
Catalase - physiology
Cytochrome P-450 Enzyme Inhibitors
Drug Synergism
Enzyme Inhibitors - pharmacology
Ketoconazole - pharmacology
Male
Nitric Oxide - metabolism
Nitric Oxide Synthase - physiology
Nitroarginine - pharmacology
Rats
Rats, Sprague-Dawley
Receptor, Serotonin, 5-HT2A - physiology
Serotonin - metabolism
Serotonin - pharmacology
Superoxides - metabolism
Vasoconstriction - drug effects
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 ω -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.
ISSN:0022-3565
1521-0103
DOI:10.1124/jpet.107.128454