The beta-adrenergic receptor-adenylate cyclase complex as a target for therapeutic intervention in heart failure.
In the human heart the beta-adrenergic pathways are the primary means of increasing cardiac performance in response to acute or chronic stress. Control of beta 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 beta-receptor function is substantially reduced, but the beta-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 beta-receptor pathway function to normal; these interventions include beta-blocker therapy and treatment with angiotensin converting enzyme inhibitors. Other types of therapy, such as chronic administration of beta-adrenergic agonists, may produce undesirable effects by increasing beta-receptor subsensitivity; however, the effects of beta-agonists on beta-receptor function are somewhat unpredictable and certain beta-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 beta-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 beta-adrenergic receptor systems need to be considered in developing therapeutic strategies in congestive heart failure.
Bristow
M R
MR
Cardiology Division, University of Utah Health Sciences Center, Salt Lake City 84132.
Port
J D
JD
Hershberger
R E
RE
Gilbert
E M
EM
Feldman
A M
AM
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000627:therapeutic use*; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D006333:Heart Failure / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*
D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; C029152:G-substrate; D009419:Nerve Tissue Proteins; D011943:Receptors, Adrenergic, beta; D000262:Adenylyl Cyclases