Effects of cytochrome P-450 inhibitors on endothelium-dependent relaxation in rabbit aorta.
Endothelium-dependent relaxation in rabbit aorta was inhibited by exposure to two cytochrome P-450 inhibitors, metyrapone and SKF-525A. Aortic rings were contracted to a stable plateau by addition of phenylephrine (10(-7) M). Relaxation was elicited by the cumulative addition of methacholine (3 X 10(-8) - 3 X 10(-6) M) or A23187 (10(-8) - 10(-6) M). Exposure to metyrapone (500 microM) or SKF-525A (10 micrograms/ml) was found to inhibit relaxation in response to concentrations of methacholine exceeding 10(-7) M. Maximal relaxation was inhibited 73% by metyrapone. Relaxation stimulated by concentrations of A23187 exceeding 10(-7) M was also found to be inhibited by both metyrapone and SKF-525A exposure. Maximum A23187-induced relaxation (55% of the phenylephrine contractile response) was inhibited 40% by metyrapone and 55% by SKF-525A. Arachidonic acid (10-100 microM) also elicited endothelium-dependent relaxation in rings pretreated with indomethacin (10 micrograms/ml) and contracted with phenylephrine. This relaxation response was abolished by exposure to metyrapone or SKF-525A. These results suggest that cytochrome P-450 may be involved in endothelium-dependent relaxation responses, perhaps by metabolizing arachidonic acid to active products.
D000818:Animals; D001011:Aorta / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D004727:Endothelium / Q000502:physiology; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D016210:Methacholine Chloride; D008688:Methacholine Compounds / Q000494:pharmacology; D008797:Metyrapone / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011335:Proadifen / Q000494:pharmacology; D011817:Rabbits
D065607:Cytochrome P-450 Enzyme Inhibitors; D007476:Ionophores; D008688:Methacholine Compounds; D016210:Methacholine Chloride; D011335:Proadifen; D002118:Calcium; D008797:Metyrapone