Myocardial β-Adrenergic receptor function during the development of pacing-induced heart failure

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 (H = 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 β-adrenergic receptors binding agonist with high affinity and adenylyl cyclase activity decreased (P < 0.0125) after 1 d of pacing. Total β-adrenergic receptor density was not changed at any time point, but β1-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 Giα2 isoform of the α subunit of the GTP-inhibitory protein rose after 3-4 wk of pacing. Thus, myocardial β-adrenergic signal transduction undergoes change shortly (1 d) after the initiation of pacing, before heart failure develops. The mechanism of β-adrenergic receptor dysfunction in pacing-induced heart failure is characterized initially by elevated plasma levels of catecholamines, uncoupling of β-adrenergic receptors, and a defect in the adenylyl cyclase catalytic unit. Selective down-regulation of β1-adrenergic receptors, increases in Giα2, and decreases in myocardial catecholamine levels occur as later events.