Muscarinic Receptor Subtypes Mediating Positive and Negative Inotropy in the Developing Chick Ventricle

Nouchi, Hideaki; Kaeriyama, Seri; Muramatsu, Akiko; Sato, M; Hirose, Kunihiko; Shimizu, Nagako; Tanaka, Hikaru; Shigenobu, Koki

doi:10.1254/jphs.fpj06013x

Cited by 13 publications

(9 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Inotropic responses after carbachol stimulation of M 2 receptors have also been reported in both guinea pig left ventricular papillary muscles (Korth and Kuhlkamp, 1987; Eglen et al. , 1988) and in developing chick ventricle (Nouchi et al. , 2007).…”

Section: Introductionmentioning

confidence: 82%

Activation of muscarinic receptors elicits inotropic responses in ventricular muscle from rats with heart failure through myosin light chain phosphorylation

Hussain¹,

Qvigstad²,

Birkeland³

et al. 2009

British J Pharmacology

View full text Add to dashboard Cite

Background and purpose: Muscarinic stimulation increases myofilament Ca2+ sensitivity with no apparent inotropic response in normal rat myocardium. Increased myofilament Ca 2+ sensitivity is a molecular mechanism promoting increased contractility in failing cardiac tissue. Thus, muscarinic receptor activation could elicit inotropic responses in ventricular myocardium from rats with heart failure, through increasing phosphorylation of myosin light chain (MLC). Experimental approach: Contractile force was measured in left ventricular papillary muscles from male Wistar rats, 6 weeks after left coronary artery ligation or sham surgery. Muscles were also frozen, and MLC-2 phosphorylation level was quantified. Key results: Carbachol (10 mmol·L -1 ) evoked a positive inotropic response only in muscles from rats with heart failure approximating 36% of that elicited by 1 mmol·L -1 isoproterenol (20 Ϯ 1.5% and 56 Ϯ 6.1% above basal respectively). Carbachol-evoked inotropic responses did not correlate with infarction size but did correlate with increased left ventricular end diastolic pressure, heart weight/body weight ratio and lung weight, primary indicators of the severity of heart failure. Only muscarinic receptor antagonists selective for M2 receptors antagonized carbachol-mediated inotropic effects with the expected potency. Carbachol-evoked inotropic responses and increase in phosphorylated MLC-2 were attenuated by MLC kinase (ML-9) and Rho-kinase inhibition (Y-27632), and inotropic responses were abolished by Pertussis toxin pretreatment. Conclusion and implications:In failing ventricular muscle, muscarinic receptor activation, most likely via M2 receptors, provides inotropic support by increasing MLC phosphorylation and consequently, myofilament Ca 2+ sensitivity. Enhancement of myofilament Ca 2+ sensitivity, representing a less energy-demanding mechanism of inotropic support may be particularly advantageous in failing hearts.

show abstract

Section: Introductionmentioning

confidence: 82%

Activation of muscarinic receptors elicits inotropic responses in ventricular muscle from rats with heart failure through myosin light chain phosphorylation

Hussain¹,

Qvigstad²,

Birkeland³

et al. 2009

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…It has been demonstrated that the M 1 receptor can stimulate L-type Ca 2ϩ currents in guinea pig ventricular cells (Gallo et al, 1993) and Ca 2ϩ release in rat ventricular cells (Sharma et al, 1996), causing positive inotropic effects. The M 1 receptor has also been implicated in mediating positive inotropic responses in isolated human (Du et al, 1995) and chicken myocardium (Nouchi et al, 2007). Conversely, Protas et al (1998) reported that the M 2 receptor, the same receptor subtype mediating inhibition of cardiac contractility, caused positive inotropic effects through activation of Na ϩ -Ca 2ϩ exchange and myofilament Ca 2ϩ sensitivity in guinea pigs.…”

Section: Discussionmentioning

confidence: 99%

M₃ Muscarinic Receptors Mediate Positive Inotropic Responses in Mouse Atria: A Study with Muscarinic Receptor Knockout Mice

Kitazawa¹,

Asakawa²,

Nakamura³

et al. 2009

J Pharmacol Exp Ther

View full text Add to dashboard Cite

The potential functional roles of M 3 muscarinic receptors in mouse atria were examined by pharmacological and molecular biological techniques, using wild-type mice, muscarinic M 2 or M 3 receptor single knockout (M 2 KO, M 3 KO), and M 2 and M 3 muscarinic receptor double knockout mice (M 2 /M 3 KO). Realtime quantitative reverse transcriptase-polymerase chain reaction analysis showed that the M 2 receptor mRNA was expressed predominantly in mouse atria but that the M 1 , M 3 , M 4 , and M 5 receptor subtypes were also expressed at low levels. Carbachol (10 nM-30 M) decreased the spontaneous beating frequency of right atria isolated from wild-type mice. Studies with subtype-preferring antagonists and atria from M 2 KO mice confirmed that this activity is mediated by the M 2 receptor subtype. In left atria from wild-type mice, carbachol decreased the amplitude of electrical field stimulation-evoked contractions (negative inotropic action), but this inhibition was transient and was followed by a gradual increase in contraction amplitude (positive inotropic response). In atria from M 3 KO mice, the transient negative inotropic action of carbachol changed to a sustained negative inotropic action. In contrast, in atria from M 2 KO mice, carbachol showed only positive inotropic activity. In atria from M 2 /M 3 double KO mice, carbachol was devoid of any inotropic activity. These observations, complemented by functional studies with subtype-preferring antagonists, convincingly demonstrate that atrial M 3 muscarinic receptors mediate positive inotropic effects in mouse atria. Physiologically, this activity may serve to dampen the inhibitory effects of M 2 receptor activation on atrial contractility.Muscarinic receptor stimulation by acetylcholine plays an important role in parasympathetic control of cardiac functions such as heart rate (chronotropic action), conduction velocity (dromotropic action), and contractility (inotropic action). Muscarinic receptors are prototypic members of the superfamily of G protein-coupled receptors, and molecular cloning studies have demonstrated the existence of five distinct mammalian muscarinic receptor subtypes (M 1 -M 5 ) (Caulfield and Birdsall, 1998). Based on their differential G protein-coupling properties, the five receptors can be subdivided into two major functional classes. The M 1 , M 3 , and M 5 receptors preferentially couple to G q/11 proteins, whereas the M 2 and M 4 receptors are selectively linked to G i/o proteins (Caulfield and Birdsall, 1998;Lanzafame et al., 2003). It is well documented that the heart predominantly expresses the M 2 receptor subtype (Brodde and Michel, 1999;Dhein et al., 2001). After activation of cardiac M 2 receptors, the activated ␣ subunit of G i proteins inhibits adenylate cyclase activity, resulting in a decrease of cytoplasmic cAMP, whereas the ␤␥ subunit of the G i proteins directly activates the inwardly rectifying muscarinic K ϩ channel (Yamada et al., 1998;Dhein et al., 2001). However, the M 2 receptor is not the only muscarinic ...

show abstract

“…Inotropic responses to muscarinic agonists in the heart have previously been reported in both normal human ventricular trabeculae [126], guinea pig papillary muscles [127,128], embryonic chick ventricle [129,130] and rat atria [128,131], but this is the first report of such in the rat ventricle. Additionally, in normal rat heart, carbachol has been found to increase Ca 2+ sensitivity with no apparent corresponding inotropic response [132,133].…”

Section: Agonist Effects In Contracting Cells and Muscle Stripsmentioning

confidence: 89%

Calculating reaction rate constants and estimating the efficacy of selective enzyme inhibitors

Eikemo

Skomedal

Levy

et al. 2008

Analytical Biochemistry

View full text Add to dashboard Cite

Muscarinic Receptor Subtypes Mediating Positive and Negative Inotropy in the Developing Chick Ventricle

Cited by 13 publications

References 27 publications

Activation of muscarinic receptors elicits inotropic responses in ventricular muscle from rats with heart failure through myosin light chain phosphorylation

Activation of muscarinic receptors elicits inotropic responses in ventricular muscle from rats with heart failure through myosin light chain phosphorylation

M₃ Muscarinic Receptors Mediate Positive Inotropic Responses in Mouse Atria: A Study with Muscarinic Receptor Knockout Mice

Calculating reaction rate constants and estimating the efficacy of selective enzyme inhibitors

Contact Info

Product

Resources

About

Muscarinic Receptor Subtypes Mediating Positive and Negative Inotropy in the Developing Chick Ventricle

Cited by 13 publications

References 27 publications

Activation of muscarinic receptors elicits inotropic responses in ventricular muscle from rats with heart failure through myosin light chain phosphorylation

Activation of muscarinic receptors elicits inotropic responses in ventricular muscle from rats with heart failure through myosin light chain phosphorylation

M3 Muscarinic Receptors Mediate Positive Inotropic Responses in Mouse Atria: A Study with Muscarinic Receptor Knockout Mice

Calculating reaction rate constants and estimating the efficacy of selective enzyme inhibitors

Contact Info

Product

Resources

About

M₃ Muscarinic Receptors Mediate Positive Inotropic Responses in Mouse Atria: A Study with Muscarinic Receptor Knockout Mice