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

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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 cyclase (AC) stimulation by catecholamines. Consequently, prevention of AC stimulation by beta-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 (Gi), mediated by muscarinic M2-, adenosine A1-, and perhaps alpha 2-adrenergic receptors. Activation of Gi during myocardial ischaemia could have some advantages, since Gi 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 tachyarrhythmias. 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 of ischaemic 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 Gi-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.