Modulation of Endothelium-Dependent Hyperpolarization and Relaxation to Acetylcholine in Rat Mesenteric Artery by Cytochrome P450 Enzyme Activity

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Abstract
Acetylcholine (ACh) induced hyperpolarization and relaxation in rat mesenteric arteries contracted with norepinephrine, as indicated from studies with simultaneous microelectrode and tension recordings. We tested whether the hyperpolarization to ACh was modified by induction and depletion of cytochrome P450 enzymes. Enzyme induction by treating the animals with 3-methylcholanthrene and β-naphthoflavone for 3 days resulted in a significant increase in the endothelium-dependent hyperpolarization to a maximum of 22.7±1.0 mV from 13.9±0.4 mV in arteries from untreated animals. Enzyme depletion by treating the animals with CoCl2 for 2 days resulted in a significant reduction in the maximum hyperpolarization to 9.9±0.7 mV. When NO synthesis was inhibited by Nω-nitro-l-arginine, the relaxation was correlated to hyperpolarization. The Nω-nitro-l-arginine–resistant responses were significantly inhibited by clotrimazole. The relaxation to ACh was not altered by enzyme induction but was significantly reduced by enzyme depletion. In KCl-contracted arteries, modification of cytochrome P450 enzyme activity had no significant effect on the relaxation to ACh. Similarly, hyperpolarization and relaxation to pinacidil were not significantly affected. These results suggest that the hyperpolarization response to ACh is closely regulated by cytochrome P450–dependent enzymes.