Klabunde R E, Kimber N D, Kuk J E, Helgren M C, Förstermann U
Department of Pharmacology, Abbott Laboratories, Abbott Park, IL 60064.
Eur J Pharmacol. 1992 Nov 13;223(1):1-7. doi: 10.1016/0014-2999(92)90810-q.
NG-Methyl-L-arginine (NMA), an inhibitor of nitric oxide synthesis by vascular endothelium, depresses cardiac function and causes systemic vasoconstriction in vivo. The mechanism of cardiac depression is unclear. Since cGMP inhibits one isoform of myocardial phosphodiesterase (PDE), we hypothesized that a decrease in cGMP might increase PDE activity and lower myocardial cAMP levels, resulting in decreased contractility. Experiments were conducted in isolated, paced, Langendorff-perfused (constant flow) rat hearts under control or isoproterenol-stimulated conditions. In non-stimulated hearts, a 15 min infusion of 30 microM NMA had no effect on cAMP content or on left ventricular dP/dt; however, myocardial cGMP content was decreased. Infusion of 0.01 microM isoproterenol caused dP/dt to increase and caused coronary resistance to fall; myocardial cAMP levels increased while cGMP remained unchanged by isoproterenol. In this stimulated condition, infusion of 30 microM NMA decreased dP/dt and myocardial cGMP and cAMP concentrations. NMA caused coronary resistance to increase to similar maximal values in isoproterenol-stimulated and non-stimulated hearts. Although coronary flow was kept constant during NMA administration, NMA depressed cardiac contractility in isoproterenol-stimulated hearts, but not in non-stimulated hearts, and the depressed contractility in isoproterenol-treated hearts was associated with a decrease in myocardial content of cGMP and cAMP. Therefore, these results are consistent with the hypothesis that NMA may decrease myocardial contractility by decreasing cGMP which leads to increased PDE activity and decreased cAMP.
NG-甲基-L-精氨酸（NMA）是一种血管内皮一氧化氮合成的抑制剂，在体内可抑制心脏功能并引起全身血管收缩。心脏抑制的机制尚不清楚。由于环磷酸鸟苷（cGMP）可抑制心肌磷酸二酯酶（PDE）的一种同工型，我们推测cGMP的减少可能会增加PDE活性并降低心肌环磷酸腺苷（cAMP）水平，从而导致收缩力下降。实验在离体、起搏、Langendorff灌注（恒流）的大鼠心脏上进行，分为对照或异丙肾上腺素刺激条件。在未受刺激的心脏中，输注30微摩尔/升的NMA 15分钟对cAMP含量或左心室dP/dt无影响；然而，心肌cGMP含量降低。输注0.01微摩尔/升的异丙肾上腺素导致dP/dt增加并使冠状动脉阻力下降；心肌cAMP水平升高，而异丙肾上腺素使cGMP保持不变。在这种刺激条件下，输注30微摩尔/升的NMA可降低dP/dt以及心肌cGMP和cAMP浓度。在异丙肾上腺素刺激和未刺激的心脏中，NMA使冠状动脉阻力增加到相似的最大值。尽管在给予NMA期间冠状动脉血流保持恒定，但NMA在异丙肾上腺素刺激的心脏中抑制心脏收缩力，而在未受刺激的心脏中则不然，并且异丙肾上腺素处理的心脏中收缩力的降低与心肌cGMP和cAMP含量的减少有关。因此，这些结果与以下假设一致，即NMA可能通过降低cGMP来降低心肌收缩力，这会导致PDE活性增加和cAMP减少。
