<b>Objective:</b> Chronic beta-adrenoceptor antagonist (β-blocker) treatment reduces the incidence of reversion to AF in patients, possibly via an adaptive myocardial response. However, the underlying electrophysiological mechanisms are presently unclear. We aimed to investigate electrophysiological changes in human atrial cells associated with chronic treatment with β-blockers and other cardiovascular-acting drugs. \ud \ud <b>Methods:</b> Myocytes were isolated enzymatically from the right atrial appendage of 40 consenting patients who were in sinus rhythm. The cellular action potential duration (APD), effective refractory period (ERP), L-type Ca<sup>2+</sup> current (<i>I</i><sub>CaL</sub>), transient (<i>I</i><sub>TO</sub>) and sustained (<i>I</i><sub>KSUS</sub>) outward K<sup>+</sup> currents, and input resistance (<i>R</i><sub>i</sub>) were recorded using the whole cell patch clamp. Drug treatments and clinical characteristics were compared with electrophysiological measurements using simple and multiple regression analyses. P<0.05 was taken as statistically significant. \ud \ud <b>Results:</b> In atrial cells from patients treated chronically with β-blockers, the APD<sub>90</sub> and ERP (75 beats/min stimulation) were significantly longer, at 213±11 and 233±11 ms, respectively (<i>n</i> = 15 patients), than in cells from non-β-blocked patients, at 176±12 and 184±12 ms (n = 11). These cells also displayed a significantly reduced action potential phase 1 velocity (22±3 vs. 34±3 V/s). Chronic β-blockade was also associated with a significant reduction in the heart rate (58±3 vs. 69±5 beats/min) and in the density of ITO (8.7±1.3 vs. 13.7±2.1 pA/pF), an increase in the Ri (214±24 vs. 132±14 MΩ), but no significant change in <i>I</i><sub>CaL</sub> or <i>I</i><sub>KSUS</sub>. The <i>I</i><sub>TO</sub> blocker 4-aminopyridine largely mimicked the changes in phase 1 and ERP associated with chronic β-blockade, in cells from non-β-blocked patients. Chronic treatment of patients with calcium channel blockers or angiotensin converting enzyme inhibitors (<i>n</i> = 11–13 patients) was not associated with any significant changes in atrial cell electrophysiology. \ud \ud <b>Conclusion:</b> The observed atrial cellular electrophysiological changes associated with chronic β-blockade are consistent with a long-term adaptive response, a type of ‘pharmacological remodelling’, and provide mechanistic evidence supportive of the anti-arrhythmic actions of β-blockade
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