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European Heart Journal 1991 12(Supplement F):76-82; doi:10.1093/eurheartj/12.suppl_F.76
Copyright © 1991 by the European Society of Cardiology.
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© 1991 The European Society of Cardiology

Specific M2-receptor activation: an alternative to treatment with beta-receptor blockers?

B. Rauch and F. Niroomand

Abt. Innere Medizin III, Medizinische Klinik, Universität Heidelberg, Bergheimerstr. 58, 6900 Heidelberg,Germany

Correspondence to: Dr Bernhard Rauch, Abt. Innere Median III, Mcdizinischc Klinik, Universitäit Heidelberg, Bergheimerstr. 58, 6900 Heidelberg, Germany

A major complication of acute myocardial ischaemia is the occurrence of malignant tachyarrhythmias, which may partly be due to a transient increase in cellular sensitivity to adenylyl cyclose (AC) stimulation by catecholamines. Consequently, prevention of AC stimulation by β-receptor blocking agents is effective in reducing the incidence of these arrhythmias. Activation of AC, however, can also be prevented by endogenous mechanisms through activation of inhibitory G-proteins (G1), mediated by muscarinic M2–, adenosine A1–, and perhaps alpha2–adrenergic receptors. Activation of G1 during myocardial ischaemia could have some advantages, since G1 not only mediates inhibition of AC but also promotes cellular hyperpolarization in atria and in the conduction system. In accordance with these considerations, there is growing evidence that activation of the cholinergic system may prevent ischaemia-induced tachy arrhythmias. However, the potential beneficial effect of cholinergic stimuli may be attenuated, as the muscarinic receptor-mediated inhibition of presynaptic exocytotic norepinephrine release is reduced during ischaemia. Furthermore, the response ofischaemic myocytes to cholinergic stimuli may be altered, as the function of inhibitory G-proteins mediated by muscarinic M2-receptors is reversibly impaired after short periods of ischaemia. This may lead to a reduction of the muscarinic receptor-mediated inhibition of AC and thereby contribute to ischaemia-induced arrhythmogenesis.

Prevention of ischaemia-induced alterations in G1-mediated signal transduction and/or (with certain limitations discussed below)selective activation of cardiac muscarinic M2-receptors could therefore be an alternative pharmacological treatment for acute myocardial ischaemia.

Key Words: Cardiac muscarinic receptors • myocardial ischemia • G-proteins • adenylyl cyclase • GTPase • arrhythmias


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