Key result
In dogs with pacing-induced heart failure, the specific beta3-adrenoreceptor antagonist L-748,337 increased LV contractile performance by 34% (from 3.8 to 5.1 mmHg/ml, P<0.05).
Why the study?
Does L-748,337 improve left ventricular and cardiomyocyte dysfunction in dogs with pacing-induced heart failure?
Does L-748,337 improve left ventricular and cardiomyocyte dysfunction in dogs with pacing-induced heart failure?
Answers are grounded in this paper and cite their sources.
Endogenous beta3-adrenoreceptor activation contributes to the depression of LV contraction and relaxation in heart failure, and its blockade improves cardiac performance in a canine model.
The objective of the present study was to test the hypothesis that endogenous beta(3)-adrenoreceptor (AR) activation contributes to left ventricular (LV) and cardiomyocyte dysfunction in heart failure (CHF). Stimulation of the beta(3)-AR inhibits cardiac contraction. In the failing myocardium, beta(3)-ARs are upregulated, suggesting that stimulation of beta(3)-ARs may contribute to depressed cardiac performance in CHF. We assessed the functional significance of endogenous beta(3)-AR activation in 10 conscious dogs before and after pacing-induced CHF. Under normal conditions, L-748,337, a specific beta(3)-AR antagonist, produced a mild increase in LV contractile performance assessed by the slope (E(es)) 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 (tau; 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 E(es) (34%, 3.8 +/- 0.7 vs. 5.1 +/- 0.8 mmHg/ml, P < 0.05) and a greater decrease in tau (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 microm/s, P < 0.05). The L-748,337-induced myocyte response was associated with improved intracellular Ca(2+) 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 beta(3)-AR by endogenous catecholamine contributes to the depression of LV contraction and relaxation in CHF.
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Morimoto et al. (2004) studied Heart failure (n=10). L-748,337 (specific beta3-AR antagonist) vs. Baseline (before L-748,337 administration) was evaluated on LV contractile performance assessed by the slope (E(es)) of the LV pressure-volume relation after CHF (34% increase, p=<0.05). In dogs with pacing-induced heart failure, the specific beta3-adrenoreceptor antagonist L-748,337 increased LV contractile performance by 34% (from 3.8 to 5.1 mmHg/ml, P<0.05).
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