Regional modulation of action potential duration and arrhythmias by ß1- and ß2-adrenergic receptor stimulation in the porcine right ventricle

Abstract

The right ventricular outflow tract (RVOT) is the main origin of idiopathic ventricular tachycardia (IVTs). Sympathetic stimulation is involved in IVTs but mechanisms underlying this preferential origin remain unknown. To determine the role of ß1- and ß2-adrenergic receptors (ß1-AR, ß2-AR) in the regional modulation of right ventricular (RV) electrophysiological properties and arrhythmias. Porcine RVs were isolated and perfused via both right and left coronary arteries. Epicardial (EPI) electrical activity was optically mapped (di-4-ANEPPS 20 μM) and APD measured at 80% repolarization (APD80) in the RVOT and posterior RV free wall region (RVFW). Regional mRNA and protein expression for ß1-AR and ß2-AR was determined respectively by RT-PCR and Western-Blot. Combined ß1- and ß2-AR stimulation (50 nM isoprenaline, ISO) shortened APD80 EPI with a larger effect in the RVFW than the RVOT. Interestingly, isolated ß2-AR stimulation (10–25 μM salbutamol, SALBU with 4 μM metoprolol, METO) only decreased APD80 significantly in the RVOT EPI ( P < 0.05). ß2-AR stimulation did not affect APD80 in the RVOT endocardium leading to a larger transmural APD gradient in this region ( P < 0.01). ß1-AR expression was lower in the RVOT than in the RVFW EPI at the mRNA and protein levels. Conversely, ß2-AR protein expression was greater in the RVOT EPI ( P < 0.05). ISO (1.8 nM–1 μM) led to a significant increase in spontaneous arrhythmias while isolated ß2-AR did not (SALBU 10–50 μM). At higher concentrations (500nM-1 μM) ISO triggered VT episodes that originated from the RVOT or the anterior RV. ß2-AR blockade (ICI 118,551 100 nM) accelerated while ß1-AR blocker METO (4 μM) slowed or abolished VT. Conlcusion These results suggest a ß2-AR specific regulation of RVOT electrophysiology but its role in the triggering of arrhythmias in this region requires further studies.