057 The role of cytochrome p450 metabolites as an endothelium-derived hyperpolarising factor in the regulation of vascular tone in vivo in the forearm vasculature of healthy and diabetic individuals

Abstract

Background Epoxyeicosatrienoic acids are arachidonic-acid-derived products of cytochrome P450 (CYP450) epoxygenases. Endothelium-derived hyperpolarizing factor (EDHF) stimulates calcium dependent potassium channels by CYP450 metabolites that can be inhibited with fluconazole (FLU). The role of EDHF in impaired endothelial function remains undefined. We hypothesised a differential contribution of EDHF in diabetics (DM) compared to healthy subjects. Methods In 16 healthy and 14 DM subjects, we measured forearm blood flow (FBF) with venous occlusion strain gauge plethysmography at rest and after endothelium-dependent and -independent vasodilation with acetylcholine (7.5, 15, 30 μg/min) or bradykinin (100, 200, 400 ng/min) and sodium nitroprusside (1.6 and 3.2 μg/min), respectively. Measurements were repeated after NO blockade with LNG monomethyl arginine (L-NMMA, 8 μmol/min), CYP450 blockade with fluconazole (0.4–1.6 μmol/min) and combined NO and CYP450 blockade. Results L-NMMA reduced resting FBF by −1.75 mls/min (p Conclusions NO is the major contributor to resting vasodilator tone in healthy subjects, whereas both NO and hyperpolarisation via CYP450 metabolites contribute to resting tone in DM. However, in the absence of NO in healthy subjects CYP450 metabolites were observed to have an important contribution suggesting an upregulation of EDHF activity via CYP450 metabolites when there is a decreased NO bioavailability. CYP450 metabolites do not contribute to pharmacologically stimulated vasodilation in either DM or healthy subjects, but whether other EDHFs play a role needs to be studied.