There are five muscarinic receptor subtypes expressed in the human heart. The main subtype is the M2-muscarinic receptor. We hypothesized that overexpression of the M2-muscarinic receptor should augment any contractile effects that are M2-muscarinic receptor-mediated. Therefore, we generated a transgenic mouse with overexpression of the human M2-muscarinic receptor under the control of the heart-specific α-myosin heavy chain promoter (M2-TG). We performed contraction experiments with electrically stimulated (1 Hz) left atrial preparations (LA) and spontaneously beating right atrial preparations (RA) from adult M2-TG or from adult wild-type littermate mice (WT). We confirmed the expression of the human M2-muscarinic receptor in the mouse heart by reverse transcription polymerase chain reaction (RT-PCR) and radioligand binding experiments at cardiac membranes and tissue sections. We did not detect differences in hematoxylin/eosin staining or Masson/Goldner staining between M2-TG and WT. We noticed that carbachol (10 nM-10 µM cumulatively applied) alone or in the presence of 1 µM isoprenaline reduced the force of contraction (FOC) to a similar extent in LA from M2-TG and WT. The beating rate in RA was similarly decreased by carbachol alone or by carbachol in the presence of 1 µM isoprenaline in M2-TG and WT. Overall, the number of RA that displayed absolute arrhythmias was higher in atria from M2-TG compared to atria from WT. No arrhythmias were noted in LA from M2-TG or WT. Stimulation of human M2-muscarinic receptors induced absolute atrial arrhythmias more often in RA from M2-TG than in RA from WT. Overexpressed M2-muscarinic receptors were silent to the force and beating rate.

Department of Cardiac Surgery Medical Faculty Martin Luther University Halle Wittenberg Germany

Department of Pharmacology and Toxicology Faculty of Pharmacy Comenius University Odbojárov 10 SK 83232 Bratislava 3 Slovak Republic

Institute for Hematopathology Fangdieckstraße 75a D 22547 Hamburg Germany

Institute for Pharmacology and Toxicology Medical Faculty Martin Luther University Halle Wittenberg Germany

Institute of Pharmacy University of Regensburg Universitätsstraße 31 D 93053 Regensburg Germany

Institute of Physiology Charles University Albertov 5 CZ 128 00 Prague 2 Czech Republic

Scientific and Educational Resource Center for Molecular Morphology Peoples' Friendship University of Russia Miklukho Maklaya Street 6 RU 117198 Moscow Russia

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