Nitrite- and nitroxyl-induced relaxation in porcine coronary (micro-) arteries: underlying mechanisms and role as endothelium-derived hyperpolarizing factor(s).
To investigate the vasorelaxant efficacy of nitrite and nitroxyl (HNO) in porcine coronary (micro)arteries (PC(M)As), evaluating their role as endothelium-derived hyperpolarizing factors (EDHFs), preconstricted PCAs and PCMAs were exposed to UV light (a well-known inductor of nitrite; wave-length: 350-370nm), nitrite, the HNO donor Angeli's salt, or bradykinin. UV light-induced relaxation of PCAs increased identically after endothelium removal and endothelial nitric oxide (NO) synthase (eNOS) blockade. UV light-induced relaxation diminished during Na(+)-K(+)-ATPase inhibition and S-nitrosothiol-depletion, and disappeared during NO scavenging with hydroxocobalamin or soluble guanylyl cyclase (sGC) inhibition with ODQ. Nitrite-induced relaxation of PCAs required millimolar levels, i.e., >1000 times endogenous vascular nitrite. Angeli's salt relaxed PCMAs more potently than PCAs, and this was due to the fact that HNO directly activated sGC in PCMAs, whereas in PCAs this occurred following its conversion to NO only. sGC activation by NO/HNO resulted in Na(+)-K(+)-ATPase stimulation and K(v) channel activation. The HNO scavenger l-cysteine blocked bradykinin-induced relaxation in PCAs, and potentiated it in PCMAs. The latter did not occur in the presence of hydroxocobalamin, suggesting that it depended on l-cysteine-induced generation of vasorelaxant S-nitrosothiols. In all experimental setups, incubation with red wine extract mimicked the effects of ODQ. In conclusion, nitrite, via its conversion to NO and S-nitrosothiols, and HNO, either directly, or via its conversion to NO, mediate relaxant effects involving the sGC-cGMP pathway, Na(+)-K(+)-ATPase and/or K(v) channels. Red wine extract counteracts these beneficial effects. NO blocks nitrite activation, and HNO, but not nitrite, may act as EDHF in the coronary vascular bed.
Division of Pharmacology and Vascular Medicine, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.
Ilse P G
IP
Botden
Wendy W
WW
Batenburg
René
R
de Vries
Janneke G
JG
Langendonk
Eric J G
EJ
Sijbrands
A H Jan
AH
Danser
D000818:Animals; D001685:Biological Factors / Q000502:physiology; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D006152:Cyclic GMP / Q000502:physiology; D006162:Guanylate Cyclase / Q000502:physiology; D009573:Nitrites / Q000494:pharmacology*; D009589:Nitrogen Oxides / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D000254:Sodium-Potassium-Exchanging ATPase / Q000502:physiology; D000071756:Soluble Guanylyl Cyclase; D013552:Swine; D014466:Ultraviolet Rays; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D014920:Wine
D001685:Biological Factors; D009573:Nitrites; D009589:Nitrogen Oxides; D018160:Receptors, Cytoplasmic and Nuclear; C067410:endothelium-dependent hyperpolarization factor; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D000254:Sodium-Potassium-Exchanging ATPase; C039900:nitroxyl; D006152:Cyclic GMP