Beta-adrenergic receptor-G protein-adenylyl cyclase signal transduction inthe failing heart

The beta-adrenergic receptor signal transduction pathway is critical for ra pid adjustments to increased cardiovascular demand (e.g., during exercise). In the face of chronic stimulation of this pathway, as occurs in the patho genesis of heart failure, beta-adrenergic receptor stimulation may become m aladaptive. Under these conditions, elevation of circulating catecholamines and depletion of cardiac tissue stores of norepinephrine occur in the fail ing heart, resulting in desensitization. Whether or not stimulation or inhi bition of the beta-adrenergic receptor signaling pathway is beneficial in h eart failure is controversial. One approach to address this question is to specifically overexpress a component of the beta-adrenergic receptor signal ing pathway in a transgenic mouse heart. We have characterized young and ol d adult mice with overexpressed cardiac G(s alpha), which couples the beta- adrenergic receptor to adenylyl cyclase. In younger animals, beta-adrenergi c receptor stimulation results in an augmented heart rate and cardiac contr actility. Over the life of the animal, however, a picture of cardiomyopathy develops. The result is a dilated heart with a large amount of fibrosis an d myocyte hypertrophy, degeneration atrophy, and apoptosis. Conversely, chr onic P-adrenergic receptor blockade prevents the development of cardiomyopa thy. These experiments support the point of view that chronic beta-adrenerg ic stimulation during the development of heart failure is deleterious and t hat protecting the heart with chronic beta-adrenergic receptor blockade is salutary, conceptually consistent with results of recent clinical trials ex amining the effects of beta-adrenergic receptor blockers in patients with h eart failure. (C)1999 by Excerpta Medica, Inc.