Autonomic modulation of action potential and tension in guinea pig papillary muscles

Arreola, Jorge; Dirksen, Robert T.; Pérez‐Cornejo, Patricia; Piech, K. M.; Sheu, Shey‐Shing

doi:10.1016/0014-2999(94)90788-9

Cited by 6 publications

(3 citation statements)

References 22 publications

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“…Among five muscarinic receptor subtypes (Brodde and Michel, 1999), M1, M2, and M3 are present in the heart (Brodde and Michel, 1999;Fisher et al, 2004;Wang et al, 2007), with the M2 receptor having a dominant chronotropic effect (Fisher et al, 2004). The endogenous muscarinic receptor agonist acetylcholine (ACh) has been reported to shorten the QT interval on an electrocardiogram (ECG) (Patel et al, 2010), and stimulation of muscarinic receptors with carbachol (CCh) reduces the ventricular action potential duration (APD) in papillary muscles (Arreola et al, 1994). Recently, it was reported that M3 muscarinic receptor overexpression reduces the incidence of arrhythmias and mortality associated with myocardial ischemia/reperfusion in mice (Liu et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Muscarinic Receptor Activation Increases hERG Channel Expression through Phosphorylation of Ubiquitin Ligase Nedd4-2

Wang¹,

Hogan-Cann²,

Kang³

et al. 2014

Mol Pharmacol

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The human ether-à-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel, which is important for cardiac repolarization. Reduction of hERG current due to genetic mutations or drug interferences causes long QT syndrome, leading to cardiac arrhythmias and sudden death. To date, there is no effective therapeutic method to restore or enhance hERG channel function. Using cell biology and electrophysiological methods, we found that the muscarinic receptor agonist carbachol increased the expression and function of hERG, but not ether-à-go-go or K v 1.5 channels stably expressed in human embryonic kidney cells. The carbachol-mediated increase in hERG expression was abolished by the selective M3 antagonist 4-DAMP (1,1-dimethyl-4-diphenylacetoxypiperidinium iodide) but not by the M2 antagonistTreatment of cells with carbachol reduced the hERG-ubiquitin interaction and slowed the rate of hERG degradation. We previously showed that the E3 ubiquitin ligase Nedd4-2 mediates degradation of hERG channels. Here, we found that disrupting the Nedd4-2 binding domain in hERG completely eliminated the effect of carbachol on hERG channels. Carbachol treatment enhanced the phosphorylation level, but not the total level, of Nedd4-2. Blockade of the protein kinase C (PKC) pathway abolished the carbachol-induced enhancement of hERG channels. Our data suggest that muscarinic activation increases hERG channel expression by phosphorylating Nedd4-2 via the PKC pathway.

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Section: Introductionmentioning

confidence: 99%

Muscarinic Receptor Activation Increases hERG Channel Expression through Phosphorylation of Ubiquitin Ligase Nedd4-2

Wang¹,

Hogan-Cann²,

Kang³

et al. 2014

Mol Pharmacol

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“…Zhang et al (1998) showed that ACh decreased the contractile force of guinea‐pig atria in a dose‐dependent manner, whereas there was no effect on contractile function of the ventricular trabeculae. Stimulation of muscarinic ACh receptors with carbachol reduces the APD and has a positive inotropic effect in papillary muscles from both ventricles, with both effects being concentration dependent and atropine sensitive (Arreola et al 1994); ACh applied at 0.03–0.3 μ m to isolated guinea‐pig ventricular papillary muscle resulted in a significant shortening of APD and the contractile force showed no change or only a slight decrease, while ACh applied at 5 μ m reduced APD 50 and APD 90 whilst the contractile force was slightly increased (Yang et al 1989); in the presence of 10 μ m physostigmine (a cholinesterase inhibitor), ACh produced concentration‐dependent negative and positive inotropic effects in the presence and absence of the phosphodiesterase inhibitor IBMX (3‐isobutyl‐1‐methyl xanthine, 100 μ m ), with half‐maximal effective concentrations of 1.36 and 46 μ m , respectively (Korth et al 1987). The above‐mentioned studies did not compare the effects on the atria and the ventricles systemically, and the results are controversial.…”

Section: Discussionmentioning

confidence: 99%

“…The review article by Casadei (2001) provided evidence for a vagal/muscarinic regulation of left ventricular function in humans. In guinea‐pig ventricles, the available data on the direct negative effect of muscarinic agonists are not consistent (Korth & Kuhlkamp, 1987; Yang et al 1989; Arreola et al 1994; Zhang et al 1998). Moreover, the comparative effect of ACh on atrial and ventricular myocytes and the relationship between the force of contraction and the duration of the action potential are still unclear.…”

mentioning

confidence: 99%

Comparison of effects of acetylcholine on electromechanical characteristics in guinea‐pig atrium and ventricle

Zang

Chen²,

Yu³

et al. 2004

Experimental Physiology

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The direct negative effects of acetylcholine (ACh) on guinea-pig atria and ventricles were investigated using standard microelectrodes, a force transducer and a video edge-detection system. It was found that: (1) ACh (at 0.001-100 microm) decreased the force of contraction and shortened the action potential duration (APD) in both atria and ventricles in a concentration-dependent manner, and that the atria were more sensitive to ACh than the ventricles; and (2) the direct negative inotropic effect of ACh (1 microm) on an isolated cardiac cell was similar to that on the isolated myocardium. But this effect was not present in all isolated ventricular cells, while all the atrial cells responded to ACh. In conclusion, ACh had direct inhibitory effects on both atrial and ventricular tissue and myocytes, although the effects were greater in atria than in ventricles; and the negative inotropic effect of ACh was closely related to the shortening of the APD.

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Inositol-1,4,5-trisphosphate increases contractions but not L-type calcium current in guinea pig ventricular myocytes

Saeki¹

1999

Cardiovascular Research

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Increased myocyte shortening at low InsP3 concentrations accords with receptor-initiated sarcoplasmic reticulum Ca2+ release. The transient stimulation of contractions at low concentrations and the sustained reduction of contractions at high concentrations are not consistent with a role for InsP in the persistent increase of contractions by muscarinic agonist in ventricular muscle and myocytes. The failure of InsP3 to change ICa(L) when contractions were increased or decreased militates against the L-type calcium channel being an effector of InsP3.

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Autonomic modulation of action potential and tension in guinea pig papillary muscles

Cited by 6 publications

References 22 publications

Muscarinic Receptor Activation Increases hERG Channel Expression through Phosphorylation of Ubiquitin Ligase Nedd4-2

Muscarinic Receptor Activation Increases hERG Channel Expression through Phosphorylation of Ubiquitin Ligase Nedd4-2

Comparison of effects of acetylcholine on electromechanical characteristics in guinea‐pig atrium and ventricle

Inositol-1,4,5-trisphosphate increases contractions but not L-type calcium current in guinea pig ventricular myocytes

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