Mechanisms for myocardial beta-adrenergic receptor desensitization in heart failure.

نویسنده

  • H K Hammond
چکیده

C ongestive heart failure is associated with pronounced alterations in adrenergic nervous system function. Levels of myocardial norepinephrine are decreased, as first reported in 1963,1 a phenomenon later found to be associated with increased sympathetic nervous system activation and high levels of circulating plasma catecholamines2 in combination with abnormalities in neural reuptake of norepinephrine in the heart.3 In animal models of heart failure, the heart was found to be poorly responsive to nerve stimulation.4 In 1982, a plausible explanation for decreased adrenergic responsiveness of the heart was uncovered. In end-stage dilated heart failure in humans, myocardial p-adrenergic receptors (PAR) were found to be decreased in number, and hormonal activation of adenylate cyclase in myocardial homogenates from explanted hearts was decreased.5 PAR downregulation in heart failure appears to be relatively selective for the 831-receptor subtype, but even though the number of 132-adrenergic receptors in the heart is generally unchanged, functional coupling of j%-adrenergic receptors to adenylate cyclase is impaired.6 Although no definitive studies have been performed, the genesis of subtypeselective downregulation of PAR may be that myocardial 81-adrenergic receptors (more than myocardial 132-adrenergic receptors) are in close proximity to adrenergic nerve terminals7 and that the neurotransmitter norepinephrine has a greater affinity for p1than for P$-receptors. Thus, both on an anatomic and pharmacological basis, there may be a greater agonist-induced stimulus for downregulation of 81than }32-receptors. These observations provide a general understanding of why there might be subtype-selective jPAR downregulation but do little to offer a molecular mechanism by which such phenomena may occur.

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عنوان ژورنال:
  • Circulation

دوره 87 2  شماره 

صفحات  -

تاریخ انتشار 1993