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Losartan prevents stretch-induced electrical remodeling in cultured atrial neonatal myocytes

¹Laboratory of Muscle Research and Molecular Cardiology, Department of Internal Medicine III, University of Cologne, Cologne, and ²Medical Clinic II, Klinikum Weiden, Weiden, Germany

Submitted 27 May 2006 ; accepted in final form 5 February 2007

Atrial fibrillation (AF) is the most frequent arrhythmia found in clinical practice. In recent studies, a decrease in the development or recurrence of AF was found in hypertensive patients treated with angiotensin-converting enzyme inhibitors or angiotensin receptor-blocking agents. Hypertension is related to an increased wall tension in the atria, resulting in increased stretch of the individual myocyte, which is one of the major stimuli for the remodeling process. In the present study, we used a model of cultured atrial neonatal rat cardiomyocytes under conditions of stretch to provide insight into the mechanisms of the preventive effect of the angiotensin receptor-blocking agent losartan against AF on a molecular level. Stretch significantly increased protein-to-DNA ratio and atrial natriuretic factor mRNA expression, indicating hypertrophy. Expression of genes encoding for the inward rectifier K⁺ current (I_K1), Kir2.1, and Kir2.3, as well as the gene encoding for the ultrarapid delayed rectifier K⁺ current (I_Kur), Kv1.5, was significantly increased. In contrast, mRNA expression of Kv4.2 was significantly reduced in stretched myocytes. Alterations of gene expression correlated with the corresponding current densities: I_K1 and I_Kur densities were significantly increased in stretched myocytes, whereas transient outward K⁺ current (I_to) density was reduced. These alterations resulted in a significant abbreviation of the action potential duration. Losartan (1 µM) prevented stretch-induced increases in the protein-to-DNA ratio and atrial natriuretic peptide mRNA expression in stretched myocytes. Concomitantly, losartan attenuated stretch-induced alterations in I_K1, I_Kur, and I_to density and gene expression. This prevented the stretch-induced abbreviation of action potential duration. Prevention of stretch-induced electrical remodeling might contribute to the clinical effects of losartan against AF.

atrial fibrillation; mechanical stretch; hypertrophy; ion channels

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