M3 cholinoreceptors alter electrical activity of rat left atrium via suppression of L-type Ca2+ current without affecting K+ conductance

Abstract

Electrophysiological effects produced by selective activation of M3 cholinoreceptors were studied in isolated left atrium preparations from rat using the standard sharp glass microelectrode technique. The stimulation of M3 receptors was obtained by application of muscarinic agonist pilocarpine (10 M) in the presence of selective M2 antagonist methoctramine (10 M). Stimulation of M3 receptors induced marked reduction of action potential duration by 14.4 ± 2.4% and 16.1 ± 2.5% of control duration measured at 50 and 90% of repolarization, respectively. This effect was completely abolished by selective M3 blocker 4-DAMP (10 M). In isolated myocytes obtained from the rat left atrium, similar pharmacological stimulation of M3 receptors led to suppression of peak L-type calcium current by 13.9 ± 2.6% of control amplitude (measured at +10 mV), but failed to affect K currents I , I, and I . In the absence of M2 blocker methoctramine, pilocarpine (10 M) produced stronger attenuation of I and induced an increase in I. This additive inward rectifier current could be abolished by highly selective blocker of K3.1/3.4 channels tertiapin-Q (10 M) and therefore was identified as I . Thus, in the rat atrial myocardium activation of M3 receptors leads to shortening of action potentials via suppression of I, but does not enhance the major potassium currents involved in repolarization. Joint stimulation of M2 and M3 receptors produces stronger action potential shortening due to M2-mediated activation of I

Choline Attenuates Cardiac Fibrosis by Inhibiting p38MAPK Signaling Possibly by Acting on M3 Muscarinic Acetylcholine Receptor

“…It has been accepted that M 2 R is not the only functional subtype muscarinic and nicotinic acetylcholine receptors (mAChRs) in the heart (Saternos et al, 2018). Numerous studies have reported that M 3 R plays an important role in heart diseases (Filatova et al, 2017; Xue et al, 2017). However, these studies primarily focused on cardiomyocytes and no studies have reported the expression and function of M 3 R in cardiac fibroblasts, though it has been shown that M 3 R is expressed in certain types of non-cardiac fibroblasts.…”

Oryeongsan (Wulingsan) Ameliorates Impaired ANP Secretion of Atria from Spontaneously Hypertensive Rats

“…Present and previous studies show that expression of the M 2 mACh receptor and GIRK4 is negatively controlled by AT 1 receptor expression [6,21]. ACh-induced activation of K ACh channel could induce local hyperpolarization leading to a decrease of Ca 2+ entry through inhibition of L-type Ca 2+ channels located at the plasma membrane of atrial cardiomyoytes [31] (Fig. 8).…”

The role of M3 receptors in regulation of electrical activity deteriorates in the rat heart during ageing

“…To induce the selective activation of M3 cholinoreceptors we have used the protocol with muscarinic agonist pilocarpine validated by several earlier studies ( Abramochkin et al, 2012 ; Wang et al, 2012 ; Filatova et al, 2017 ), although more selective and high-affine antagonists of M2 and M3 receptors were used. Muscarinic agonist pilocarpine (10 -5 M) with slight selectivity to M1 and M3 receptors was applied to the experimental chamber alone or in the presence of highly selective M2 antagonist AQ-RA 741, 10 -7 M ( Doods et al, 1991 , 1994 ; Ivanova et al, 2019 ) after prior exposure of preparations to AQ-RA 741 alone.…”

“…25 μM β-escin was added to Cs + -based pipette solution as a perforating agent, only the freshly-prepared solution with β-escin was used throughout one experimental day, but not stored further. Perforated patch technique allowed to record I CaL with minimal rundown ( Fu et al, 2003 ; Filatova et al, 2017 ). The peak current density after 10 min of continuous recording was not less than 90% of control level.…”

“…shortens AP. In rats, M3 stimulation induces AP shortening as well, but via activation of phosphoinositol signaling pathway ( Abramochkin et al, 2008 ) and subsequent suppression of L-type calcium current I CaL ( Filatova et al, 2017 ). The increase in K + conductance in rat working cardiomyocytes is attributed exclusively to activation of M2 receptors ( Filatova et al, 2017 ).…”