Anti-adrenergic effects of endothelin on human atrial action potentials are potentially anti-arrhythmic

Abstract

Endothelin-1 (ET-1) is elevated in patients with atrial fibrillation (AF) and heart failure. We investigated effects of ET-1 on human atrial cellular electrophysiological measurements expected to influence the genesis and maintenance of AF. Action potential characteristics and L-type Ca<sup>2+</sup> current (I<sub>CaL</sub>) were recorded by whole cell patch clamp, in atrial isolated myocytes obtained from patients in sinus rhythm. Isoproterenol (ISO) at 0.05 μM prolonged the action potential duration at 50% repolarisation (APD<sub>50</sub>: 54 ± 10 vs. 28 ± 5 ms; <i>P</i> < 0.05, <i>N</i> = 15 cells, 10 patients), but neither late repolarisation nor cellular effective refractory period (ERP) were affected. ET-1 (10 nM) reversed the effect of ISO on APD<sub>50</sub>, and had no basal effect (in the absence of ISO) on repolarisation or ERP. During repetitive stimulation, ISO (0.05 μM) produced arrhythmic depolarisations (<i>P</i> < 0.05). Each was abolished by ET-1 at 10 nM (<i>P</i> < 0.05). ISO (0.05 μM) increased peak I<sub>CaL</sub> from –5.5 ± 0.4 to –14.6 ± 0.9 pA/pF (P < 0.05; N = 79 cells, 34 patients). ET-1 (10 nM) reversed this effect by 98 ± 10% (P < 0.05), with no effect on basal I<sub>CaL</sub>. Chronic treatment of patients with a β-blocker did not significantly alter basal APD50 or I<sub>CaL</sub>, the increase in APD50 or I<sub>CaL</sub> by 0.05 μM ISO, nor the subsequent reversal of this effect on APD50 by 10 nM ET-1. The marked anti-adrenergic effects of ET-1 on human atrial cellular action potential plateau, arrhythmic depolarisations and I<sub>CaL</sub>, without affecting ERP and independently of β-blocker treatment, may be expected to contribute a potentially anti-arrhythmic influence in the atria of patients with AF and heart failure