Losartan prevents stretch-induced electrical remodeling in cultured atrial neonatal myocytes.
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)), Kir 2.1, and Kir 2.3, as well as the gene encoding for the ultrarapid delayed rectifier K(+) current (I(Kur)), Kv 1.5, was significantly increased. In contrast, mRNA expression of Kv 4.2 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 microM) 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.
Saygili
Erol
E
Laboratory of Muscle Research and Molecular Cardiology, Department of Internal Medicine III, University of Cologne, Kerpenerstr. 62, 50924 Cologne, Germany.
Rana
Obaida R
OR
Saygili
Esra
E
Reuter
Hannes
H
Frank
Konrad
K
Schwinger
Robert H G
RH
Müller-Ehmsen
Jochen
J
Zobel
Carsten
C
D000200:Action Potentials / Q000187:drug effects; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000831:Animals, Newborn; D000959:Antihypertensive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000209:etiology / Q000517:prevention & control; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D049108:Cell Enlargement / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects*; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006973:Hypertension / Q000150:complications / Q000188:drug therapy; D007700:Kinetics; D051666:Kv1.5 Potassium Channel / Q000187:drug effects / Q000378:metabolism; D019808:Losartan / Q000494:pharmacology* / Q000627:therapeutic use; D040542:Mechanotransduction, Cellular / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D011188:Potassium / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects / Q000378:metabolism; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D051672:Shal Potassium Channels / Q000187:drug effects / Q000378:metabolism
D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; C490968:Kcnj4 protein, rat; C489461:Kir2.1 channel; D051666:Kv1.5 Potassium Channel; D024661:Potassium Channels, Inwardly Rectifying; D024642:Potassium Channels, Voltage-Gated; D012333:RNA, Messenger; D051672:Shal Potassium Channels; D009320:Atrial Natriuretic Factor; D019808:Losartan; D011188:Potassium