Mechanism underlying the inhibitory interaction between the nitrovasodilator SIN-1 and the endothelium.
Experiments were designed to determine the influence of the endothelium on the relaxing potency of the nitrovasodilator SIN-1. Rings of coronary arteries were suspended for isometric-tension recording in organ chambers filled with modified Krebs-Ringer bicarbonate solution, aerated with 95% O2-5% CO2 and warmed to 37 degrees C. The experiments were performed in the presence of indomethacin and propranolol in order to inhibit cyclooxygenase and beta-adrenoceptors, respectively. In rings contracted with prostaglandin F2 alpha, SIN-1 caused concentration-dependent relaxations that were increased following endothelium removal. In rings denuded of endothelium, the relaxations evoked by SIN-1 were not affected by NG-monomethyl-L-arginine (L-NMMA, which inhibits the production of endothelium-derived relaxing factor), or by superoxide dismutase and catalase (scavengers of oxygen-derived free radicals), or by L-NMMA plus superoxide dismutase and catalase. In rings with endothelium, relaxations evoked by SIN-1 were increased significantly by L-NMMA or by superoxide dismutase and catalase, and were increased further by the combination of L-NMMA plus superoxide dismutase and catalase. The difference in potency of SIN-1 between arterial rings with and without endothelium was reduced by either L-NMMA or by superoxide dismutase and catalase, and was abolished by the combination of L-NMMA plus superoxide dismutase and catalase. Therefore, the inhibitory interaction between SIN-1 and the endothelium may result from an endothelium-dependent production of oxygen-derived free radicals that may inactivate the nitric oxide generated by SIN-1, and from an inhibitory interaction between SIN-1 and endothelium-derived relaxing factor, released under basal conditions.
Flavahan
N A
NA
Department of Physiology and Biophysics, Mayo Clinic, Rochester, Minnesota.
Vanhoutte
P M
PM
D000704:Analysis of Variance; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects*; D004285:Dogs; D005260:Female; D005609:Free Radicals; D066298:In Vitro Techniques; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology*
D005609:Free Radicals; D014665:Vasodilator Agents; D009569:Nitric Oxide; C002385:linsidomine; D008981:Molsidomine