Investigation of Miconazole as an Inhibitor of Endothelium-Derived Hyperpolarizing Factor

The vascular endothelium synthesizes at least three potent vasodilator substances: nitric oxide (NO), prostacyclin and an endothelium-derived hyperpolarizing factor (EDHF). EDHF release is stimulated by receptor-dependent agonists such as acetylcholine and bradykinin (BK), and leads to hyperpolarization of the underlying smooth muscle cells presumably by opening Ca(2+)-activated K(+) channels. Indirect pharmacologic evidence suggests that EDHF is a cytochrome P450-derived arachidonic acid metabolite, presumably an epoxide. Numerous inhibitors of EDHF have been defined in animal tissues. Of these, miconazole has proven to be safe when administered to humans as a topical and parenteral antifungal agent. At levels that are attained with routine clinical use, it has a rapid onset of action with high specificity of inhibition of EDHF in animal models. This study is designed to investigate the safety and efficacy of intra-arterial miconazole in inhibiting BK-mediated forearm vasodilation in normal volunteers.