Inhibition of Endothelial Nitric Oxide Synthase by Cytochrome P-450 Reductase Inhibitors

Abstract

Abstract

Nitric oxide synthase (NOS) shows similarities to cytochrome P-450 reductase. The two enzymes catalyze the oxidation of N-ω-hydroxy-L-arginine by NADPH and oxygen to nitric oxide (NO) and citrulline. Nitric oxide synthase activity is inhibited by L-arginine analogs like N-ω-nitro-L-arginine, which does not affect cytochrome P-450 reductase. Dihydroergotamine, miconazole, and troleandomycin are classical inhibitors of cytochrome. The present study shows the concentration-dependent inhibitory effect of these compounds and of L- but not D-N-ω-nitro-arginine on the activity of constitutive nitric oxide synthase from bovine aortic endothelial cells. Activity of nitric oxide synthase was estimated by measurement of conversion of [³H]arginine to [³H]citrulline. The tested cytochrome P-450 inhibitors are likely to interfere with heme of nitric oxide synthase. The data confirms a similarity as well as functional differences between the enzymes.