The contribution of cytochrome P450 products to the regulation of vascular tone in humans

The endothelium releases a number of vasoactive substances including nitric oxide, prostacyclin, and an as yet uncharacterized endothelium-derived hyperpolarizing factor (EDHF). The purpose of the project was to test the hypothesis that a cytochrome P450-derived product acts as an EDHF in vivo in human skeletal muscle resistance vessels. Forearm vasodilatation to intra-arterial acetylcholine and bradykinin was measured in healthy male and female subjects before and during coinfusion of the cytochrome P450 inhibitor miconazole. Studies were also done in the presence of L-NMMA and aspirin to inhibit nitric oxide synthase and cyclooxygenase, respectively.; Miconazole infused alone had no effect on resting blood flow. In the presence of L-NMMA and aspirin, miconazole significantly attenuated endothelium-dependent dilatation, but had no effect on responses to nitroprusside or adenosine, endothelium-independent dilator agents. Doubling the dose of L-NMMA did not alter this effect of miconazole, suggesting that its effects were not due to nitric oxide inhibition. Further, miconazole did not inhibit endothelium-dependent responses when ouabain was used to block hyperpolarization. These are the first in vivo data in humans demonstrating that cytochrome P450-derived products contribute to endothelium-dependent dilatation. The lack of a miconazole effect in the presence of ouabain suggests that P450 products act as an EDHF in human resistance arterioles.; Finally, the hypothesis that aging increases the cytochrome P450-dependent component of endothelium-dependent dilatation was tested. Vasodilatation to acetylcholine and bradykinin was measured in male and female subjects (greater than 50 years of age) before and during coinfusion of the cytochrome P450 inhibitor miconazole. In the older population, previously demonstrated to have reduced nitric oxide activity, a greater portion of endothelium-dependent dilatation was inhibited by miconazole. These are the first in vivo human data to demonstrate an increased contribution of a cytochrome P450-dependent component to endothelium-dependent dilatation in conditions of chronic nitric oxide deficiency.