Elevated guanosine 3':5'-cyclic monophosphate mediates the depression of nitrovasodilator reactivity in endothelium-intact blood vessels

Abstract

The influence of endothelium-derived nitric oxide (EDNO) on relaxation induced by the nitrovasodilators, sodium nitroprusside and sodium nitrite was assessed in phenylephrine-stimulated hamster thoracic aortas, a preparation that displays significant basal release of EDNO. Removal of the endothelium or treatment with the NO synthase inhibitors, NG-nitro-L-arginine (L-NAG, 10-30 microM) or NG-methyl-L-arginine (L-NMMA; 100 microM) increased the potency and, except for sodium nitroprusside in endothelium-denuded segments, also increased the efficacy of the nitrovasodilators. Removal of the endothelium had no effect on relaxations induced by isoproterenol, an indication that these effects were specific for the nitrovasodilators. Removal of the endothelium, treatment of endothelium-intact preparations with L-NAG or L-NMMA, or exposure of these vessels to the guanylate cyclase inhibitor, methylene blue (10 microM) increased reactivity of the aortas to the guanosine 3':5'-cyclic monophosphate (cGMP) analogue, 8-Br cGMP. Measurement of cGMP revealed that endothelium-intact segments had a 6.5 fold higher level of cGMP than endothelium-denuded preparations and that sodium nitroprusside increased cGMP in both preparations by similar amounts in a concentration-dependent fashion. Exposure of endothelium-denuded or L-NAG-treated segments to sodium nitroprusside, to mimic the effects of basally released EDNO, depressed sodium nitrite and 8-Br cGMP reactivity in a manner similar to endothelium-intact segments. These data indicate that EDNO increases cGMP levels in vascular smooth muscle and that the elevated cGMP levels depress nitrovasodilator and 8-Br cGMP reactivities.