The β-adrenergic receptor-adenylate cyclase complex as a target for therapeutic intervention in heart failure.

In the human heart the β-adrenergic pathways are the primary means of increasing cardiac performance in response to acute or chronic stress. Control of β pathway function is achieved by changes in the receptors themselves, and to a lesser degree by adjustments in the inhibitory G protein (Gi). In heart failure myocardial β-receptor function is substantially reduced, but the β-receptor pathways are so powerful that they remain capable of Supporting inotropic function. Certain therapeutic interventions that improve exercise performance in heart failure can partially restore β-receptor pathway function to normal; these interventions include β-blocker therapy and treatment with angiotensin converting enzyme inhibitors. Other types of therapy, such as chronic administration of β-adrenergic agonists, may produce undesirable effects by increasing β-receptor subsensitivity; however, the effects of β-agonists on β-receptorfunction are somewhat unpredictable and certain β-agonists do not appear to produce much desensitization. Finally, the failing human heart is in effect partially denervated due to depletion of neuronal norepinephrine, and consequently in advanced heart failure β-agonists that possess an indirect component of action will be less effective than exclusively direct-acting agents. These observations indicate that the baseline status and the intervention-associated behaviour of the human myocardial β-adrenergic receptor systems need to be considered in developing therapeutic strategies in congestive heart failure. [ABSTRACT FROM PUBLISHER]