ABSTRACT-We investigated whether Ba2+ and Sr2+ can substitute for Ca' in stimulating the nitric oxide (NO) production and cause relaxation in vascular smooth muscle. Ba2+ and Sr2+, like Ca2+, relaxed K+ depolarized canine coronary arteries in the presence of diltiazem. The Ba2+-and Sr2+-induced relaxation was endothelium-dependent and was largely inhibited by NG-monomethyl-L-arginine (L-NMMA) and NGnitro-L-arginine (L-NNA), but not by indomethacin. These cations increased cyclic GMP levels in the coronary artery to a similar extent, and the increment was completely abolished by L-NMMA. The relaxation induced by each cation was attenuated in the presence of a combination of propranolol, phentolamine and atropine, and L-NNA markedly inhibited any remaining relaxation. This indicates that these cations produce endothelium-dependent relaxation through NO production as well as the relaxation mediated by neurotrasmitters. The present study suggests that Ba2+ and Sr2+ can substitute for Ca 2+ in the activation of the NO synthase pathway in the endothelium of canine coronary arteries.
Keywords:Barium, Strontium, Nitric oxide, Endothelium, Coronary arteryNitric oxide (NO) synthases have been shown to catalyze the conversion of L-arginine to NO radicals and Lcitrulline in the endothelium (1-3). An increase in intracellular Ca2+ is crucial for the activation of NO synthase in endothelial cells in the presence of calmodulin (4, 5). Ba2+ and Sr2+ have been shown to enter into cultured endothelial cells in response to bradykinin (6). However, no functional role of divalent cations in vascular endothelial cells has as yet been established in contrast to the situation in smooth muscle cells. Ca' and Sr2+ have been shown to cause an endothelium-dependent relaxation of canine coronary arteries contracted by prostaglandin (PG) F2a in the absence of Mgt+, but Ba2+ did not cause such a relaxation (7). On the other hand, Ba2+ and Sr2+ have been shown to substitute for Ca 2+ in the contraction of the rat tail artery (8). To our knowledge, no information has been published regarding any relaxant effect of Ba2+ produced through endothelial function.Our previous study has shown that Ca2+ produces an endothelium-dependent relaxation of K+-depolarized canine coronary arteries in the presence of Ca antagonists (9, 10). These antagonists were useful in distinguishing the contractile effect of Ca 21 on vascular smooth muscle from its relaxant effect through endothelial function. This is because Ca antagonists block L-type Ca2+ channels in smooth muscle, but do not affect the influx of Ca 2+ into endothelial cells (11). Under these conditions, an increase in Ca2+ in the endothelium should have induced production of NO from L-arginine and caused relaxation of the coronary arteries via an increase in cGMP levels. The present study aims to determine whether Ba2+ and Sr2+ can substitute for Ca 2+ in producing relaxation through activation of the NO synthase pathway in endothelial cells.In this study, we measured the tension of and cyclic GMP level...