Functional M3 cholinoreceptors are present in pacemaker and working myocardium of murine heart

Abstract

The presence of M3 cholinoreceptors and their role in mediation of action potential waveform modulation were determined by immunolabeling of receptor proteins and standard microelectrode technique, respectively. The sinoatrial node (SAN), which was determined as a connexin 43 negative area within the intercaval region, the surrounding atrial tissue, and the working ventricular myocardium exhibited labeling of both M3 and M2 receptors. However, the density of M3 and M2 labeling was about twofold higher in the SAN compared to working myocardium. The stimulation of M3 receptors was obtained by application of nonselective M1 and M3 muscarinic agonist pilocarpine (10(-5) M) in the presence of selective M2 blocker methoctramine (10(-7) M). Stimulation of M3 receptors provoked marked shortening of action potential duration in atrial and ventricular working myocardium. In the SAN, M3 stimulation leads to a significant reduction of sinus rhythm rate accompanied with slowing of diastolic depolarization and increase of action potential upstroke velocity. All electrophysiological effects of selective M3 stimulation were suppressed by specific blocker of M3 receptors 4-DAMP (10(-8) M). We conclude that M3 cholinoreceptors are present in pacemaker and working myocardium of murine heart, where they mediate negative cholinergic effects: slowing of sinus rhythm and shortening of action potentials.

Electrophysiological, Vasoactive, and Gastromodulatory Effects of Stevia in Healthy Wistar Rats

“…Stevia reduced the action potential duration, which potentially reduces the likelihood of arrhythmias and may also be linked to the selective activation of cardiac M 2 muscarinic receptor-mediated blockade of intracellular calcium currents. A recent study showed that pilocarpine (a selective muscarinic receptor agonist) caused a marked reduction in APD 50 and APD 90 on mice atrial myocardium and ventricular preparations [40]. Our finding corroborates this report as stevia was found to activate M 2 muscarinic receptors on healthy gastrointestinal tissues.…”

Effects of Acetylcholine and Noradrenalin on Action Potentials of Isolated Rabbit Sinoatrial and Atrial Myocytes

“…It should be kept in mind that noradrenalin not only stimulates the G s -coupled β 1 –β 3 adrenoceptors but also the G q -coupled α 1 and G i -coupled α 2 adrenoceptors, and that acetylcholine not only stimulates the G i -coupled M 2 -receptor but also the other muscarinic receptors, including the G q -coupled M 3 -receptor, which is functionally present in the murine sinoatrial node (Abramochkin et al, 2012). Adding to this complexity, it has also become clear that GPCR signaling is not a simple linear pathway of receptor, G protein, and effector.…”

Cardiovascular effects of antimuscarinic agents and beta3-adrenergic receptor agonist for the treatment of overactive bladder

“…Their activation may influence both the pace-making activity of the SA and AV nodes and the regulation of cardiac muscle contractile activity by shortening action potential duration [13,14]. Abramochkin et al [15] have demonstrated, in the murine heart, that M3 stimulation of the SA node reduces pacemaker activity, consequently, causing HR decrease. Anyway, these effects are very modest when compared with M2response but may play a role in pathological condition such as heart failure, ischemia or atrial fibrillation owing to an increased number of this receptor subtype and to a decrease in M2 receptors; thus, the role of these receptors is therefore not insignificant [16].…”