Fischmeister R, Méry P F
INSERM U-446, Faculté de Pharmacie, Université de Paris-Sud, Châtenay-Malabry, France.
C R Seances Soc Biol Fil. 1996;190(2-3):181-206.
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.
早期在全心的研究表明，环磷酸鸟苷（cGMP）可拮抗儿茶酚胺和环磷酸腺苷（cAMP）的正性肌力作用。由于L型钙通道电流（ICa）在心脏电活动和收缩活动的起始与发展中起主要作用，在过去十年里，cGMP途径对ICa的调节受到了广泛关注。对分离的心肌细胞中ICa进行膜片钳测量发现，至少有三种不同的cGMP效应器，它们在不同动物物种和心脏组织中可能以不同程度参与cGMP对ICa的调节。在蛙心室肌细胞中，cGMP通过刺激一种cGMP刺激的cAMP磷酸二酯酶（PDE2）来抑制ICa，而在大鼠心室肌细胞中，cGMP主要通过一种涉及激活cGMP依赖性蛋白激酶（cGMP-PK）的机制来抑制ICa。在豚鼠、蛙和人心肌细胞中，cGMP还可通过抑制一种cGMP抑制的cAMP磷酸二酯酶（PDE3）来刺激ICa。这种效应在人心房肌细胞中最为显著，并且在低浓度一氧化氮（NO）供体激活可溶性鸟苷酸环化酶活性时很容易出现。对纯化心肌细胞中内源性磷酸二酯酶和cGMP-PK的生化特性分析为这些cGMP对ICa的作用机制提供了进一步的证据。然而，多种药物对cGMP水平的调节并不总是与其对收缩性的影响一致。特别是，cGMP和NO途径在乙酰胆碱对心脏ICa和收缩性的调节中的参与仍存在疑问。
