Fan T H, Liang C S, Kawashima S, Banerjee S P
Department of Medicine (Cardiology Unit) University of Rochester Medical Center, NY 14642.
Eur J Pharmacol. 1987 Aug 11;140(2):123-32. doi: 10.1016/0014-2999(87)90798-9.
The effects of congestive heart failure on the physiological and biochemical functions of the cardiac beta-adrenoceptor-coupled adenylate cyclase system were studied in dogs with right heart failure produced by progressive pulmonary artery constriction and tricuspid avulsion. The cardiac inotropic response to dobutamine was attenuated in congestive heart failure, as determined by the right and left ventricular dP/dt responses. Adrenergic beta-receptor density, measured by [3H]dihydroalprenolol binding, was reduced in membrane fractions of the failing right ventricle, but not in the left ventricle. The functional activity of the adenylate cyclase system was studied in vitro by measuring the net cyclic AMP production following additions of isoproterenol, 5'-guanylylimidodiphosphate (Gpp(NH)p), forskolin, or manganese chloride, which act either directly on the beta-adrenergic receptors or on one of the post-receptor components of the adenylate cyclase system. Congestive heart failure reduced the net production of cyclic AMP by isoproterenol, Gpp(NH)p, and forskolin in both the right and left ventricles, but did not alter the effect of manganese chloride. Thus, beta-receptor down-regulation is chamber-specific, occurring only in the hemodynamically stressed right ventricle. In contrast, the post-receptor defect of the adenylate cyclase system occurred in both ventricles of the heart failure dogs. This decreased activation of adenylate cyclase by beta-agonists may be responsible, at least in part, for the diminished cardiac inotropic response to catecholamines in congestive heart failure.
在通过渐进性肺动脉缩窄和三尖瓣撕脱术造成右心衰竭的犬类中，研究了充血性心力衰竭对心脏β-肾上腺素能受体偶联腺苷酸环化酶系统生理和生化功能的影响。通过右心室和左心室的dP/dt反应确定，充血性心力衰竭时心脏对多巴酚丁胺的变力反应减弱。用[3H]二氢阿普洛尔结合法测定，衰竭右心室膜部分的肾上腺素能β受体密度降低，但左心室未降低。通过测量加入异丙肾上腺素、5'-鸟苷酰亚胺二磷酸（Gpp(NH)p）、福斯可林或氯化锰后净环磷酸腺苷（cAMP）的产生，在体外研究腺苷酸环化酶系统的功能活性，这些物质要么直接作用于β-肾上腺素能受体，要么作用于腺苷酸环化酶系统的一种受体后成分。充血性心力衰竭降低了右心室和左心室中异丙肾上腺素、Gpp(NH)p和福斯可林诱导的cAMP净产生，但未改变氯化锰的作用。因此，β受体下调具有心室特异性，仅发生在血流动力学负荷过重的右心室。相反，腺苷酸环化酶系统的受体后缺陷发生在心力衰竭犬的两个心室中。β激动剂对腺苷酸环化酶的这种激活减少可能至少部分地导致了充血性心力衰竭时心脏对儿茶酚胺的变力反应减弱。
