Effect of molsidomine on basal Ca2+ current in rat cardiac cells

To determine the effect of molsidomine, a nitric oxide (NO) donor, on basal L-type Ca2+ current (ICa), the patch-clamp study was performed in single myocytes isolated from rat ventricles. External application of molsidomine (10 nM-100 microM) in the presence of internal Ca2+ (pCa = 6.85) inhibited basal ICa in a concentration-dependent manner. In the absence of internal Ca2+ (pCa = infinity), molsidomine concentration-dependently stimulated basal ICa. These opposite effects of molsidomine on ICa were not found when intracellular cGMP (1 mM) had been increased. Regardless of the presence or absence of internal Ca2+, milrinone application (20 microM) had a stimulatory effect on ICa in the absence of intracellular cGMP. In the continuing presence of milrinone, molsidomine (1-100 microM) at pCa infinity had no significant effect on the milrinone-enhanced ICa which was concentration-dependently inhibited by molsidomine (1-100 microM) at pCa 6.85. These results suggest that the inhibitory and stimulatory effects of molsidomine on basal ICa in the rat cardiac myocytes are related to an activation of the cGMP-dependent protein kinase (cGMP-PK) and an inhibition of the cGMP-inhibited cAMP-phosphodiesterase (PDE), respectively, and that these different actions appear to be mediated by the difference in intracellular Ca2+ levels.