Regional β-adrenergic regulation of action potential duration and arrhythmias in the pig right ventricle

Abstract

The right ventricular outflow tract (RVOT) is the main origin of idiopathic ventricular tachycardia (VT). Although these arrhythmias appear to be cAMP-dependent, the actual mechanisms leading to VT remain uncertain. Here we studied β-adrenergic regulation of action potential duration (APD) in the healthy pig right ventricle (RV). To determine regional β-adrenergic regulation of APD and arrhythmias in the RVOT. The RV of 4 pig hearts were isolated and perfused via both the coronary arteries. Epicardial 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 of β-adrenergic receptors was determined respectively by RT-PCR and Western-Blot. The expression of β1-adrenergic receptor (β1-AR) was lower in the RVOT at the mRNA level ( P < 0.05) but remained unchanged at the protein level compared to the RVFW while β2-adrenergic receptor (β2-AR) expression remained similar in both regions. At lower concentrations (0.6–10 nM), isoprenaline (ISO) led to a prolongation of APD80 in the RVOT and the RVFW. Higher ISO concentrations (500 nM–1 μM) led to a larger APD80 shortening in the RVOT than in the RVFW and triggered VT episodes that originated from the RVOT or the anterior RV. β2-AR blockade (ICI 118,551 100 nM) accelerated while β1-AR blocker Metoprolol (4 μM) slowed or abolished VT. Similar ISO concentrations triggered bursts of Ca2+ transients in RVOT myocytes that stopped upon ISO washout while these events remained rare in RVFW myocytes. β-adrenergic stimulation differentially regulates APD80 in the RVOT and RVFW. Although β1-AR expression was similar in the 2 regions, ISO preferentially shortened APD and triggered arrhythmia in the RVOT. These results suggest the presence of a high sensitivity of RVOT electrophysiology to β-adrenergic stimulation.