Muscarinic Receptors in Cardioprotection and Vascular Tone Regulation

Abstract

Muscarinic acetylcholine receptors are metabotropic G-protein coupled receptors. Muscarinic receptors in the cardiovascular system play a central role in its regulation. Particularly M2 receptors slow down the heart rate by reducing the impulse conductivity through the atrioventricular node. In general, activation of muscarinic receptors has sedative effects on the cardiovascular system, including vasodilation, negative chronotropic and inotropic effects on the heart, and cardioprotective effects, including antifibrillatory effects. First, we review the signaling of individual subtypes of muscarinic receptors and their involvement in the physiology and pathology of the cardiovascular system. Then we review age and disease-related changes in signaling via muscarinic receptors in the cardiovascular system. Finally, we review molecular mechanisms involved in cardioprotection mediated by muscarinic receptors leading to negative chronotropic and inotropic and antifibrillatory effects on heart and vasodilation, like activation of acetylcholine-gated inward-rectifier K+-currents and endothelium-dependent and -independent vasodilation. We relate this knowledge with well-established cardioprotective treatments by vagal stimulation and muscarinic agonists. It is well known that estrogen exerts cardioprotective effects against atherosclerosis and ischemia-reperfusion injury. Recently, some sex hormones and neurosteroids have been shown to allosterically modulate muscarinic receptors. Thus, we outline possible treatment by steroid-based positive allosteric modulators of acetylcholine as a novel pharmacotherapeutic tactic. Keywords: Muscarinic receptors, Muscarinic agonists, Allosteric modulation, Cardiovascular system, Cardioprotection, Steroids.

Fig. 1

M₂ receptor signaling in supraventricular myocytes. In supraventricular myocytes, M₂ receptors positively modulate inwardly rectifying potassium channels by the βγ-subunits released from the G_i/o inhibitory G proteins resulting in hyperpolarization. Created with BioRender.com.

Fig. 2

M₂ receptor signaling in ventricular myocytes. In ventricular myocytes, M₂ receptors modulate the cAMP-dependent response to β-adrenergic receptor activation modulating activity of L-type Ca²⁺ and Na⁺/K⁺ pacemaker channels. Created with BioRender.com.

Fig. 3

Signaling of M₁, M₂ and M₃ receptors in the vascular system. In the vascular system, M₁, M₂ and M₃ receptors mediate vasodilation by release of NO from endotelium and cGMP-dependent removal of cytosolic calcium in smooth muscle cells, inhibiting the contractile apparatus and promoting vasodilation. Created with BioRender.com.

Fig. 4

Signaling of M₁ receptors in the heart. In the cardiomyocytes of the human heart M₁ receptors positively modulate inward-rectifier K⁺ channel contributing to shortening of duration of atrial action potential duration. Created with BioRender.com

Fig. 5

Signaling of M₃ receptors in the heart. Through stimulation of intracellular phosphoinositide hydrolysis, M₃ receptors improve cardiac contraction. By the activation of a delayed rectifying K⁺ current, M₃ receptors facilitate cardiac repolarization and exert negative chronotropic effects. Created with BioRender.com