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This Article Full Text Full Text (PDF) All Versions of this Article: 290/4/H1347    most recent 01079.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (12) Citing Articles via Google Scholar Google Scholar Articles by Bellien, J. Articles by Thuillez, C. Search for Related Content PubMed PubMed Citation Articles by Bellien, J. Articles by Thuillez, C.

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

Departments of ¹Pharmacology (Institut National de la Santé et de la Recherche Médicale U644, Institut Fédératif de Recherche Multidisciplinaire sur les Peptides 23) and ²Pharmacy, Rouen University Hospital, Rouen, France

Submitted 12 October 2005 ; accepted in final form 30 November 2005

Whether a cytochrome P-450 (CYP)-related endothelium-derived hyperpolarizing factor (EDHF), acting through calcium-activated potassium (K_Ca) 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 K_Ca channel inhibitor, and fluconazole (0.4 µmol/min), as CYP inhibitor, alone and in combination with N^G-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 K_Ca 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 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 K_Ca channel-dependent hyperpolarizing mechanisms could exist in conduit arteries.

endothelium-derived factors; calcium-activated potassium channels; cytochrome P-450

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