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 (ICa) was examined in guinea pig ventricular myocytes. SIN-1 had little effect on basal ICa. After moderate stimulation of ICa with 10 nM isoproterenol (ISO), 10 microM SIN-1 caused either stimulation or inhibition of ICa; 100 microM SIN-1 consistently caused inhibition. SIN-1 (1-100 microM) inhibited ICa equally following considerable enhancement of ICa by either 1 microM ISO or 100 microM 3-isobutyl-1-methylxanthine, a nonspecific phosphodiesterase (PDE) inhibitor. SIN-1 (100 microM) also inhibited ICa equally following enhancement by either 10 microM 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 ICa and that the mechanism of NO inhibition of ICa in mammalian cardiac cells involves the cGMP-dependent protein kinase.
Wahler
G M
GM
Department of Physiology and Biophysics, University of Illinois at Chicago 60612-7342.
Dollinger
S J
SJ
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000470:Alkaloids / Q000494:pharmacology; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors* / Q000502:physiology*; D002227:Carbazoles; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology*; D004553:Electric Conductivity; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D006321:Heart / Q000502:physiology*; D007211:Indoles; D007545:Isoproterenol / Q000494:pharmacology; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009206:Myocardium / Q000166:cytology; D009569:Nitric Oxide / Q000378:metabolism; D047428:Protein Kinase Inhibitors
D000470:Alkaloids; D000634:Aminoquinolines; D002227:Carbazoles; D007211:Indoles; D047428:Protein Kinase Inhibitors; C073601:KT 5823; D009569:Nitric Oxide; C002385:linsidomine; C041715:6-anilino-5,8-quinolinedione; D008981:Molsidomine; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D007545:Isoproterenol; D002118:Calcium; D015056:1-Methyl-3-isobutylxanthine