INHIBITION BY SK-AND-F96365 OF NO-MEDIATED RELAXATION INDUCED BY CA2-ATPASE INHIBITORS IN RAT THORACIC AORTA()

1 We investigated the effect of SK&F96365, a putative inhibitor of rec eptor-operated Ca2+ entry, on the endothelium-dependent, NO-mediated r elaxation and cyclic GMP formation induced by Ca2+-ATPase ATPase inhib itors in rat thoracic aorta. 2 SK&F96365 inhibited cyclopiazonic acid or thapsigargin-induced relaxation and cyclic GMP formation mediated b y a constitutive NO synthase, which is known to be activated by the Ca 2+ that enters into the endothelial cells via plasma membrane Ca2+ cha nnels subsequent to depletion of stored Ca2+ by Ca2+-ATPase inhibitors . 3 SK&F96365 also inhibited relaxation and cyclic GMP formation induc ed by acetylcholine, without affecting those induced by nitroprusside and A23187. 4 Ni2+ attenuated relaxation and cyclic GMP formation indu ced by cyclopiazonic acid and acetylcholine. 5 In contrast, the voltag e-dependent Ca2+ channel blocker, nifedipine, did not affect the relax ation caused by Ca2+-ATPase inhibitors. 6 These results suggest that e ndothelium-dependent, NO-mediated relaxation of the arteries induced b y Ca2+-ATPase inhibitors is triggered by the Ca2+ that enters into end othelial cells via receptor-operated channels (SK&F96365-sensitive cha nnels) subsequent to depletion of stored Ca2+ as a result of inhibitio n of the Ca2+-ATPase (Ca2+ pump) of the stores.