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1 Department of Pharmacology, , INSERM U644, IFRMP 23, Rouen University Hospital, Rouen, France
2 Department of Pharmacy, Rouen University Hospital, Rouen, France
* To whom correspondence should be addressed. E-mail: robinson.joannides{at}chu-rouen.fr.
Whether a cytochrome P450 (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 (echotracking) and blood flow (Doppler) were measured, after oral aspirin (500 mg), in 8 healthy volunteers during local infusion for 8 min of tetraethylammonium chloride (TEA: 9 µmol/min), as KCa channels inhibitor, fluconazole (0.4 µmol/min), as CYP inhibitor, alone and in combination with L-NMMA (8 µmol/min), as endothelial NO-synthase inhibitor. Endothelium-independent dilatation was assessed 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 effect 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, 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 KCa channels 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 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 to fluconazole suggests that different KCa channels-dependent hyperpolarizing mechanisms could exist in conduit arteries.
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