Arterial stiffness is regulated by nitric oxide and endothelium-derived hyperpolarizing factor during changes in blood flow in humans.
Cytochrome-derived epoxyeicosatrienoic acids may be important endothelium-derived hyperpolarizing factors, opening calcium-activated potassium channels, but their involvement in the regulation of arterial stiffness during changes in blood flow in humans is unknown. In healthy volunteers, we measured arterial pressure, radial artery diameter, wall thickness, and flow (NIUS02) during hand skin heating in the presence of saline or inhibitors of NO synthase (N(G)-monomethyl-L-arginine), calcium-activated potassium channels (tetraethylammonium), and cytochrome epoxygenases (fluconazole). Arterial compliance and elastic modulus were calculated and fitted as functions of midwall stress to suppress the confounding influence of geometric changes. Under saline infusion, heating induced an upward shift of the compliance-midwall stress curve and a downward shift of the modulus-midwall stress curve demonstrating a decrease in arterial tone and stiffness when blood flow increases. These shifts were reduced by N(G)-monomethyl-L-arginine and abolished by the combinations of N(G)-monomethyl-L-arginine+tetraethylammonium and N(G)-monomethyl arginine+fluconazole. In parallel, in isolated mice coronary arteries, fluconazole and tetraethylammonium reduced the relaxations to acetylcholine. However, fluconazole did not affect the relaxations to the openers of calcium-activated potassium channels of small- and intermediate-conductance NS309 and of large-conductance NS1619 excluding a direct effect on these channels. Moreover, tetraethylammonium reduced the relaxations to NS1619 but not to NS309, suggesting that the endothelium-derived hyperpolarizing factor involved mainly acts on large-conductance calcium-activated potassium channels. These results show in humans that, during flow variations, arterial stiffness is regulated by the endothelium through the release of both NO and cytochrome-related endothelium-derived hyperpolarizing factor.
Bellien
Jeremy
J
Department of Pharmacology, Rouen University Hospital and Institut National de la Sante et de la Recherche Medicale U644, Rouen Medical School, Institut Federatif de Recherche Multidisciplinaire sur les Peptides 23, Institute for Biomedical Research, University of Rouen, Rouen, France.
Favre
Julie
J
Iacob
Michele
M
Gao
Ji
J
Thuillez
Christian
C
Richard
Vincent
V
Joannidès
Robinson
R
D000328:Adult; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001685:Biological Factors / Q000378:metabolism*; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004548:Elasticity / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D015725:Fluconazole / Q000008:administration & dosage; D006358:Hot Temperature; D006801:Humans; D006973:Hypertension / Q000378:metabolism* / Q000503:physiopathology*; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009569:Nitric Oxide / Q000378:metabolism*; D010091:Oximes / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000008:administration & dosage; D017534:Radial Artery / Q000187:drug effects / Q000502:physiology; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology*; D019789:Tetraethylammonium / Q000008:administration & dosage; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D055815:Young Adult; D019323:omega-N-Methylarginine / Q000008:administration & dosage*
C493327:6,7-dichloro-1H-indole-2,3-dione 3-oxime; D001562:Benzimidazoles; D001685:Biological Factors; D004791:Enzyme Inhibitors; D007211:Indoles; D010091:Oximes; D026902:Potassium Channel Blockers; C067410:endothelium-dependent hyperpolarization factor; C086491:NS 1619; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019789:Tetraethylammonium; D015725:Fluconazole