alpha- and beta-Adrenoceptor modulation of the electrophysiological properties of ventricular myocytes from human failing hearts.

Human ventricular myocytes (HuVM) enzymatically isolated from hearts explanted for terminal heart failure show a prolonged action potential duration (APD) and the presence of the pacemaker current, If. Both these alterations are considered arrhythmogenic. To elucidate the proarrhythmic role of catecholamines, we studied the effect of -adrenoceptor (AR) and -adrenoceptor (AR) stimulation on APD and If recorded from HuVM. Calcium-tolerant myocytes were isolated by an enzymatic procedure from the explanted hearts of patients with terminal ischemic or dilated cardiomyopathy by perfusing a portion of the left ventricular wall through a branch of a coronary artery. Patch-clamped cells were superfused with normal or modified Tyrode's solution containing (mM): KCI (25), BaCl2 (2), MnC12 (2), 4-aminopyridine (0.5), CdCl2 (0.2). Action potentials showing a diastolic depolarization (DD) were consistently recorded. Isoproterenol (ISO, 1 M) significantly increased the slope of DD (1.3±0.4 vs 0.2±0.1 mV/s) and prolonged APD (1.6±0.2 vs 1.0±0.1 s) (n=8, p<0.02). Addition of adenosine (ADO, 0.1 M) reversed the effect of ISO on APD (1.0±0.1 s) and DD (0.3±0.1 mV/s) (n=6, p<0.05 vs ISO). The effect of AR stimulation on DD steepness was paralleled by that on If. In the presence of ISO, the activation curve of If was shifted toward less negative potentials by 11.6±3 mV; adding ADO caused a shift in the opposite direction (-8.9 ±1.3 mV vs ISO alone), AR stimulation with phenylephrine (30 M) plus propranolol (1 M) prolonged APD (1.3±0.3 vs 0.9±0.2 s, n=6, p=0.07) but did not affect either DD (0.5±0.3 vs 0.4±0.3 mV/s, n=6) or If (-77±4 vs -76±5 mV, n=4). Thus, AR stimulation by catecholamines may exacerbate electrophysiologic alterations in the failing human heart and favor the appearance of arrhythmias.