NITRIC-OXIDE DONOR SIN-1 INHIBITS MAMMALIAN CARDIAC CALCIUM CURRENT THROUGH CGMP-DEPENDENT PROTEIN-KINASE

The effect of the nitric oxide (NO) donor SIN-1 (3-morpholino-sydnonimine) on the calcium current (I-Ca was examined in guinea pig ventricular myocytes. SIN-1 had little effect on basal I-Ca After moderate stimulation of I-Ca with 10 nM isoproterenol (ISO), 10 mu M SIN-1 caused either stimulation or inhibition of I-Ca; 100 mu M SIN-1 consistently caused inhibition. SIN-1 (1-100 mu M) inhibited Ic, equally following considerable enhancement of I-Ca by either 1 mu M ISO or 100 mu M 3-isobutyl-1-methylxanthine, a nonspecific phosphodiesterase (PDE) inhibitor. SIN-1 (100 mu M) also inhibited I-Ca equally following enhancement by either 10 mu M pipette adenosine 3',5'-cyclic monophosphate (cAMP) or hydrolysis-resistant 8-bromo-cAMP. Thus the inhibitory effect of SIN-1 appears independent of PDEs. Addition of LY-83583 (a blocker of guanylate cyclase) to the pipette or superfusion with KT-5823 [a blocker of the guanosine 3',5'-cyclic monophosphate (cGMP)-dependent protein kinase] suppressed the inhibitory effect of SIN-1. We conclude that NO is an important modulator of beta-adrenergic effects on I-Ca and that the mechanism of NO inhibition of I-Ca in mammalian cardiac cells involves the cGMP-dependent protein kinase.