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Research Article Free access | 10.1172/JCI116312

Myocardial beta-adrenergic receptor function during the development of pacing-induced heart failure.

K Kiuchi, R P Shannon, K Komamura, D J Cohen, C Bianchi, C J Homcy, S F Vatner, and D E Vatner

Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115.

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Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115.

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Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115.

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Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115.

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Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115.

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Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115.

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Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115.

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Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115.

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Published March 1, 1993 - More info

Published in Volume 91, Issue 3 on March 1, 1993
J Clin Invest. 1993;91(3):907–914. https://doi.org/10.1172/JCI116312.
© 1993 The American Society for Clinical Investigation
Published March 1, 1993 - Version history
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Abstract

The development of pacing-induced heart failure was studied in chronically instrumented, conscious dogs paced at a rate of 240 beats/min for 1 d (n = 6), 1 wk (n = 6), and 3-4 wk (n = 7). Left ventricular (LV) dP/dt was decreased (P < 0.0125) at 1 d, LV end-diastolic pressure and heart rate were increased (P < 0.0125) at 1 wk, but clinical signs of heart failure were only observed after 3-4 wk of pacing. Plasma norepinephrine rose (P < 0.0125) after 1 d of pacing, whereas LV norepinephrine was reduced (P < 0.0125) only after 3-4 wk of pacing. Both the fraction of beta-adrenergic receptors binding agonist with high affinity and adenylyl cyclase activity decreased (P < 0.0125) after 1 d of pacing. Total beta-adrenergic receptor density was not changed at any time point, but beta 1-adrenergic receptor density was decreased (P < 0.0125) after 1 wk. The functional activity of the guanine nucleotide binding protein, Gs, was not reduced, but the Gi alpha 2 isoform of the alpha subunit of the GTP-inhibitory protein rose after 3-4 wk of pacing. Thus, myocardial beta-adrenergic signal transduction undergoes change shortly (1d) after the initiation of pacing, before heart failure develops. The mechanism of beta-adrenergic receptor dysfunction in pacing-induced heart failure is characterized initially by elevated plasma levels of catecholamines, uncoupling of beta-adrenergic receptors, and a defect in the adenylyl cyclase catalytic unit. Selective down-regulation of beta 1-adrenergic receptors, increases in Gi alpha 2, and decreases in myocardial catecholamine levels occur as later events.

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