ß1, ß2, ß3 adrenoceptor subtypes differently modulate the pacemaker current in human ventricular myocytes.

ß1 ß2 and ß3 adrenoceptor (AR) subtypes are functionally present in the human ventricle. Recent evidence from both human and rat hearts suggests that subtypes are coupled to different metabolic pathways thus likely exerting diverse effects on target ion channels. However, the electrophysiologic effects of ßAR subtype's stimulation in human ventricular myocytes (HuVM) have been poorly characterized. The pacemaker channel f, which is modulated by catecholamines, is expressed in HuVM; thus we examined If control by ßAR subtypes in HuVM from explanted failing hearts. Patch-clamped HuVM were superfused with a modified Tyrode solution also containing (mM): KCl 25, BaCl2 2, MnCl2 2, 4-aminopyridine 0.5. If activation elicited by hyperpolarization (-60 to -140 mV), was fitted by a Boltzmann function to measure midpoint (VH) and maximum specific conductance (gmax). ß1AR stimulation with 1 µM noradrenaline (NA) caused a positive shift of VH (8.9±1.3 mV, n=5) significantly larger than that caused by ß2AR stimulation obtained with 1 µM isoprenaline plus the selective ß1 antagonist CGP 20712A (0.1 µM)(4.5±1.1 mV, n=4). The positive shift of VH induced by ß2AR was significantly increased (11.3±1.4 mV, n=5) by preincubation of HuVM with pertussis toxin (0.5 µg/ml) (p<0.05 vs. untreated cells), thus suggesting that also in HuVM, ß2AR are coupled to both stimulatory and inhibitory G proteins. ß1AR stimulation was practically unaffected by PTX-treatment (shift:10.5±1.8 mV, n=3). On the contrary, ß3AR stimulation with the selective agonist SR 58611A (1 µM) consistently caused a negative shift of If activation (-5 mV, n=4). None of ßAR subtypes modified gmax. Thus, ßAR subtypes modulate in a complementary fashion the pacemaker current If, which is thought to be an arrhythmogenic mechanism in the failing human heart.