Role of Neurohumoral Abnormalities and -Adrenergic Reeptor Changes in Progression of Chronic Heart Failure

众所周知，在充血性心力衰竭时，刺激β-肾上腺素能受体的变力反应明显受到抑制。这种现象是由于β-肾上腺素能受体的下调和亚细胞信号转导系统的异常所致。然而，在衰竭前阶段，心脏β-肾上腺素能受体经常增加。这些观察结果可能支持这样的观点，即β-肾上腺素能受体的变化在心力衰竭的表现中起着重要作用。为了验证这一假说，我们研究了犬冠状动脉内微栓塞术(直径15或25m)所致急性心肌缺血恢复7天后心功能和β受体密度的变化。心肌去甲肾上腺素含量减少，β肾上腺素能受体数量增加，基础心功能恢复正常。然而，静脉注射Forsklin的变力反应明显受到抑制，而对异丙肾上腺素的反应明显正常。这些结果表明，在缺血性心肌病中，β-肾上腺素能受体的增加可能是对受损的β-受体亚细胞信号转导的补偿。为了验证这一观点，通过持续注射异丙肾上腺素，增加的β-肾上腺素能受体被强制下调。正如预期的那样，在β肾上腺素受体下调后，明显的心力衰竭变得明显。这些结果表明，β-肾上腺素能受体的改变在心力衰竭的代偿和表达中起主要作用。

It is well known that inotropic response of the beta-adrenoceptor stimulation is markedly depressed in congestive heart failure. This phenomenon is due to the down-regulation of beta-adrenergic receptors and abnormalities of the subcellular signal transduction system. However, in the pre-failure stage, cardiac beta-adrenoceptors are often increased. These observations may support the view that beta-adrenoceptor changes play an important role in manifestation of the heart failure. To test this hypothesis, we studied the changes in cardiac function and beta-adrenoceptor density in dogs 7 days after recovery from acute myocardial ischemia produced by intracoronary microembolization (15 or 25 m in diam). Myocardial norepinephrine content was depleted, but the number of betaadrenergic receptors was increased, and thus basal cardiac function was restored to normal. However, inotropic response to intravenous administration of forskolin was significantly depressed whereas the response to isoproterenol was apparently normal. These results indicate that an increase in beta-adrenergic receptors in ischemic cardiomyopathy may compensate the impaired subcellular signal transduction of beta-receptors. To verify this idea, increased beta-adrenergic receptors were imposed to be down-regulated by sustained infusion of isoproterenol. As expected, overt heart failure became manifest following the down-regulation of betaadrenoceptors. These results indicate that beta-adrenoceptor change plays a major role in compensation and expression of heart failure.