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 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.

Levosimendan restores the positive force-frequency relation in heart failure

“…As summarized in Table 1, consistent with our past reports (7,38,41,52), chronic ventricular rapid pacing in a canine model produced progressive LV systolic and diastolic dysfunction. After 4 -5 wk of rapid pacing, the LV P ED was elevated (158%; HF: 29.9 Ϯ 5.1, normal: 11.6 Ϯ 3.3 mmHg).…”

“…To avoid the potential confounding effects of levosimendan-produced changes in loading conditions on conventional measures of LV contractile performance, we evaluated LV contractile performance in the pressure-volume (P-V) plane in conscious dogs with pacing-induced HF that mimics many of the functional and neurohormonal changes of clinical HF (5,7,29,33,38,41).…”

β3-adrenergic receptor activation increases human atrial tissue contractility and stimulates the L-type Ca2+ current

“…In human atrium and failing ventricle, several β 3 -AR agonists were found to be devoid of any cardiodepressant effect (26)(27)(28). These latter findings are of importance, since the amount of β 3 -AR proteins was shown to increase up to 3-fold in different models of heart failure (11,29,30).…”

“…Finally, the positive coupling of β 3 -ARs to I Ca,L in human atrium, with relatively modest consequences on force of contraction, might confer to these receptors a role in the control of beat frequency. During heart failure, the expression level of β 3 -ARs increases (11,29,30), and this might change their beneficial effect into a deleterious one, with a persistent negative inotropic effect enhancing myocardial depression. It remains to be determined whether the level of β 3 -ARs and their functional role are also modified in human atrial pathologies such as atrial dilation, arrhythmias, or fibrillation.…”

Angiotensin II Type 1 Receptor Blockade Prevents Alcoholic Cardiomyopathy

“…Hydraulic occluders were placed around the venae cavae by a technique that was described previously. 4,10 …”