β3-Adrenergic receptor antagonist improves exercise performance in pacing-induced heart failure

In heart failure (HF), the impaired left ventricular (LV) arterial coupling and diastolic dysfunction present at rest are exacerbated during exercise. We have previously shown that in HF at rest stimulation of beta(3)-adrenergic receptors by endogenous catecholamine depresses LV contraction and relaxation. beta(3)-Adrenergic receptors are activated at higher concentrations of catecholamine. Thus exercise may cause increased stimulation of cardiac beta(3)-adrenergic receptors and contribute to this abnormal response. We assessed the effect of L-748,337 (50 mu g/kg iv), a selective beta(3)-adrenergic receptor antagonist (beta(3)-ANT), on LV dynamics during exercise in 12 chronically instrumented dogs with pacing-induced HF. Compared with HF at rest, exercise increased LV end-systolic pressure (P-ES), minimum LV pressure (LVPmin), and the time constant of LV relaxation (tau) with an upward shift of early diastolic portion of LV pressure-volume loop. LV contractility decreased and arterial elastance (E-A) increased. LV arterial coupling (E-ES/E-A) (0.40 vs. 0.51) was impaired. Compared with exercise in HF preparation, exercise after beta(3)-ANT caused similar increases in heart rate and PES but significantly decreased tau (34.9 vs. 38.3 ms) and LVPmin with a downward shift of the early diastolic portion of LV pressure-volume loop and further augmented dV/dt(max). Both E-ES and E-ES/E-A (0.68 vs. 0.40) were increased. LV mechanical efficiency improved from 0.39 to 0.53. In conclusion, after HF, beta(3)-ANT improves LV diastolic filling; increases LV contractility, LV arterial coupling, and mechanical efficiency; and improves exercise performance.