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(Circulation. 1996;93:763-771.)
© 1996 American Heart Association, Inc.

Articles

Chronic Treatment With Carbachol Sensitizes the Myocardium to cAMP-Induced Arrhythmia

Thomas Eschenhagen, MD; Ulrike Mende, MD; Matthias Diederich, MD; Boris Hertle, MD; Christian Memmesheimer, MD; Andreas Pohl, MD; Wilhelm Schmitz, MD; Hasso Scholz, MD; Markus Steinfath, MD; Michael Böhm, MD; Martin C. Michel, MD; Otto-Erich Brodde, PhD; Achim Raap, MD

From Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Hamburg (T.E., U.M., M.D., B.H., C.M., A.P., W.S., H.S., M.S.); Klinik III für Innere Medizin, Universität zu Köln (M.B.); Biochemisches Forschungslabor, Medizinische Klinik und Poliklinik, Universitätsklinikum Essen (M.C.M., O.-E.B.); and Beiersdorf-Lilly GmbH, Hamburg (A.R.), Germany.

Background The present study investigated biochemical and functional consequences of chronic activation of the inhibitory G_i-coupled adenylyl cyclase pathway in the heart.

Methods and Results Rats (220 to 260 g) were treated with 4-day infusions of the M-cholinoceptor agonist carbachol (9.6 mg/kg per day) or vehicle. An additional group that received the ß-adrenoceptor agonist isoprenaline (2.4 mg/kg per day) served as control. The main finding was that chronic infusion of carbachol led to a marked increase in isoprenaline- or forskolin-induced arrhythmia in electrically driven papillary muscles (in vitro). Compared with control, the potency of isoprenaline and forskolin to induce arrhythmia in cardiac preparations from carbachol-treated rats was increased 36- and 2.2-fold and the efficacy was increased 7.3- and 2.3-fold, respectively. The potency of carbachol to antagonize the isoprenaline- and forskolin-induced arrhythmia was decreased 30-fold. These changes were accompanied by a decrease in left ventricular M-cholinoceptor density by 15% (P<.05) and a decrease in pertussis toxin–sensitive G proteins (G_i) by 26% (P<.05) without a decrease in the corresponding mRNAs. ß-Adrenoceptor density and basal and stimulated adenylyl cyclase activity remained unchanged. In contrast, isoprenaline infusion induced a decrease in arrhythmogenic potency of forskolin (P=NS), which was accompanied by a decrease in ß-adrenoceptor density, an increase in G_i protein and mRNA levels, and a decrease in basal and stimulated adenylyl cyclase activity.

Conclusions Chronic parasympathetic activation sensitizes the myocardium to cAMP-induced arrhythmia. These changes may be due to quantitative alterations in functional G_i.

Key Words: acetylcholine • signal transduction • receptors, adrenergic, beta • arrhythmia

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