Endogenous β3-adrenoreceptor activation contributes to left ventricular and cardiomyocyte dysfunction in heart failure

Abstract

The objective of the present study was to test the hypothesis that endogenous β3-adrenoreceptor (AR) activation contributes to left ventricular (LV) and cardiomyocyte dysfunction in heart failure (CHF). Stimulation of the β3-AR inhibits cardiac contraction. In the failing myocardium, β3-ARs are upregulated, suggesting that stimulation of β3-ARs may contribute to depressed cardiac performance in CHF. We assessed the functional significance of endogenous β3-AR activation in 10 conscious dogs before and after pacing-induced CHF. Under normal conditions, L-748,337, a specific β3-AR antagonist, produced a mild increase in LV contractile performance assessed by the slope ( Ees) of the LV pressure-volume relation (18%, 6.2 ± 0.9 vs. 7.3 ± 1.2 mmHg/ml, P < 0.05) and the improved LV relaxation time constant (τ; 28.4 ± 1.9 vs. 26.8 ± 1.0 ms, P < 0.05). After CHF, the plasma norepinephrine concentration increased eightfold, and L-748,337 produced a larger increase in Ees (34%, 3.8 ± 0.7 vs. 5.1 ± 0.8 mmHg/ml, P < 0.05) and a greater decrease in τ (46.4 ± 4.2 vs. 41.0 ± 3.9 ms, P < 0.05). Similar responses were observed in isolated myocytes harvested from LV biopsies before and after CHF. In the normal myocyte, L-748,337 did not cause significant changes in contraction or relengthening. In contrast, in CHF myocytes, L-748,337 produced significant increases in contraction (5.8 ± 0.9 vs. 6.8 ± 0.9%, P < 0.05) and relengthening (33.5 ± 4.2 vs. 39.7 ± 4.0 μm/s, P < 0.05). The L-748,337-induced myocyte response was associated with improved intracellular Ca2+ concentration regulation. In CHF myocytes, nadolol caused a decrease in contraction and relengthening, and adding isoproterenol to nadolol caused a further depression of myocyte function. Stimulation of β3-AR by endogenous catecholamine contributes to the depression of LV contraction and relaxation in CHF.