Evidence for a basal release of a cytochrome-related endothelium-derived hyperpolarizing factor in the radial artery in humans

Abstract

Whether a cytochrome P-450 (CYP)-related endothelium-derived hyperpolarizing factor (EDHF), acting through calcium-activated potassium (KCa) channels, interacts with nitric oxide (NO) to regulate the basal diameter of human peripheral conduit arteries is unexplored in vivo. Radial artery diameter (echo tracking) and blood flow (Doppler) were measured, after oral aspirin (500 mg), in eight healthy volunteers during local infusion for 8 min of tetraethylammonium chloride (TEA; 9 μmol/min), as KCachannel inhibitor, and fluconazole (0.4 μmol/min), as CYP inhibitor, alone and in combination with NG-monomethyl-l-arginine (l-NMMA; 8 μmol/min), as endothelial NO synthase inhibitor. Endothelium-independent dilatation was assessed by using sodium nitroprusside (SNP). Radial diameter was unaffected by l-NMMA (0.4 ± 0.9%) and fluconazole (−1.6 ± 0.8%) but was decreased by TEA (−5.0 ± 1.0%), l-NMMA + fluconazole (−5.3 ± 0.5%), and l-NMMA + TEA (−9.9 ± 1.3%). These effects are still significant even when the concomitant decreases in blood flow induced by l-NMMA (−24 ± 4%), TEA (−21 ± 3%), l-NMMA + fluconazole (−26 ± 5%), and l-NMMA + TEA (−35 ± 4%) were taken as covariate into analysis. Conversely, fluconazole alone slightly but not significantly increased radial flow (13 ± 6%). l-NMMA alone or with TEA and with fluconazole enhanced radial artery dilatation to SNP, whereas TEA and fluconazole alone did not modify this response. These results confirm in humans the involvement of NO and KCachannels in the regulation of basal conduit artery diameter. Moreover, the synergistic effect of combined inhibition of NO synthesis and CYP on the decrease in radial diameter in the absence of such effect after l-NMMA and fluconazole alone unmasks the role of CYP in this regulation and shows the presence of an interaction between NO and a CYP-related EDHF to maintain peripheral conduit artery diameter in vivo. Furthermore, the higher vasoconstrictor effect of TEA compared with fluconazole suggests that different KCachannel-dependent hyperpolarizing mechanisms could exist in conduit arteries.