[Regulation of cardiac calcium current by cGMP/NO route].
Early studies in whole heart indicated that cGMP antagonized the positive inotropic effects of catecholamines and cAMP. Since the L-type Ca2+ channel current (ICa) plays a predominant role in the initiation and development of cardiac electrical and contractile activities, regulation of ICa by cGMP pathways has received much attention over the last ten years. Patch-clamp measurements of ICa in isolated cardiac myocytes reveal at least three different cGMP effectors that may participate to different degrees in different animal species and cardiac tissues in the regulation of ICa by cGMP. In frog ventricular myocytes, cGMP inhibits ICa by stimulation of a cGMP-stimulated cAMP phosphodiesterase (PDE2), whereas in rat ventricular myocytes, cGMP predominantly inhibits ICa via a mechanism involving activation of a cGMP-dependent protein kinase (cGMP-PK). In guinea pig, frog and human cardiomyocytes, cGMP can also stimulate ICa via an inhibition of a cGMP-inhibited cAMP phosphodiesterase (PDE3). This effect is most predominant in human atrial myocytes and appears readily during an activation of the soluble guanylate cyclase activity by low concentrations of nitric oxide (NO)-donors. Biochemical characterization of the endogenous phosphodiesterases and cGMP-PK in purified cardiac myocytes provide further evidence in support of these mechanisms of cGMP action on ICa. However, the regulation of cGMP levels by a variety of agents is not always consistent with their effects on contractility. In particular, the participation of cGMP and NO pathways in the regulation of cardiac ICa and contractility by acetylcholine is still questionable.
Fischmeister
R
R
INSERM U-446, Faculté de Pharmacie, Université de Paris-Sud, Châtenay-Malabry, France.
Méry
P F
PF
D000818:Animals; D015220:Calcium Channels / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism* / Q000502:physiology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D006321:Heart / Q000502:physiology; D006801:Humans; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism* / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D051381:Rats
D015220:Calcium Channels; D010726:Phosphodiesterase Inhibitors; D009569:Nitric Oxide; D017869:Cyclic GMP-Dependent Protein Kinases; D010727:Phosphoric Diester Hydrolases; D006152:Cyclic GMP