Kinetic and molecular evidences that human cardiac muscle express non-M2 muscarinic receptor subtypes that are able to interact themselves

Pérez, Carmen Carlota Nello; Bravo-Tobar, Iván Darío; Jiménez, Eliézer; Castañeda, Darwin; Rivero, María Belén; Concepción, Juan Luís; Chiurillo, Miguel Ángel; Bonfante-Cabarcas, Rafael

doi:10.1016/j.phrs.2006.07.001

Cited by 21 publications

(15 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This observation is consistent with the outcome of several previously published studies (Hardouin et al, 1998;Hellgren et al, 2000;Krejcí and Tucek, 2002;Wang et al, 2001;Pérez et al, 2006). Functional studies with right atria prepared from different muscarinic receptor knockout mice, complemented by studies with M 2 muscarinic receptor subtype-preferring antagonists, indicated that muscarinic agonist-induced reduction in heart rate is mediated by the M 2 receptor, in agreement with previous results (Caulfield and Birdsall, 1998;Stengel et al, 2000;Dhein et al, 2001).…”

Section: Discussionsupporting

confidence: 92%

“…However, the M 2 receptor is not the only muscarinic receptor subtype present in the heart (Wang et al, 2004). Pharmacological, biochemical, immunohistochemical, and molecular biological studies using whole heart tissues or isolated cardiomyocytes indicate that the heart, es-pecially cardiomyocytes, also expresses low levels of non-M 2 muscarinic receptors, including the M 1 and M 3 receptor subtypes (Gallo et al, 1993;Sharma et al, 1996;Hardouin et al, 1998;Hellgren et al, 2000;Wang et al, 2001Wang et al, , 2004Krejcí and Tucek, 2002;Pönicke et al, 2003;Willmy-Matthes et al, 2003;Pérez et al, 2006;Myslivecek et al, 2008).…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

Section: Discussionsupporting

confidence: 92%

mentioning

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

show abstract

“…The homogenate was filtered through four layers of cotton gauze and centrifuged at 50,000 g for 1 hour, at 4˚C. The supernatant was discharged and the pellet resuspended 1:10 w/v in ice-cold 4 mM EDTA, 0.1 mM PMSF, 25 [17]. Briefly, heart homogenates (500 µg of protein) were incubated with 2 nM [ 3 H]-QNB for 120 min in a final volume of 2.5 ml of 1 mM PMSF in PBS (pH 7.3 at 37˚C).…”

Section: [ 3 H]-qnb Binding Assaymentioning

confidence: 99%

A Decreased Expression and Functionality of Muscarinic Cholinergic Receptor in Acute Chagas Myocarditis

Labrador-Hernández¹,

Jimenez²,

León³

et al. 2014

WJCD

View full text Add to dashboard Cite

Background: Chagas disease is still a public health problem because of the remaining high prevalence, the expansion of the disease into developed countries and the re-emergences by oral transmission outbreaks. Chagas cardiomyopathy evolves as a consequence of an autonomic unbalance where the parasympathetic tone is undermined. Objective: To determine the functionality and expression of muscarinic cholinergic receptors in acute Chagas disease. Methodology: 62 male, 3-week-old Sprague Dawley rats were assayed; 32 were infected with Trypanosoma cruzi trypomastigotes and 30 were healthy controls. Electrocardiographic studies were conducted in the absence or presence of direct muscarinic (oxotremorine and McN-A-343) or indirect agonists (phenylephrine) or antagonist (pirenzepine). Muscarinic M1 and M2 receptor expression was determined by radioligand [ 3 H]-QNB binding assay and immunoblot. Results: Chagasic acute myocarditis was sustained by electrocardiographic signs and histopathological findings. Bradycardia induced by oxotremorine was significantly higher in healthy rats (HR) and the differences were enhanced by CsCl. In the absence of the agonist, CsCl induced a greater bradycardia in chagasic rats (ChR). In HR McN-A-343 induced tachycardia, however it induces bradycardia in the presence of a acetylcholinesterase inhibitor (neostigmine); no effects were observed in ChR. Pirenzepine induced a higher tachycardia in HR. Phenylephrine in the presence of pirenzepine induced a similar bradycardia in both groups, but recovery was faster in ChR. Muscarinic M1 and M2 receptor density was higher in HR. Conclusion: Muscarinic receptor expression and functionality are decreased * Corresponding author. M. Labrador-Hernández et al. 306in the acute Chagas disease that could impact the evolution and prognosis of the disease.

show abstract

“…33,34 In this study, we used a nonselective muscarinic antagonist for PET quantification; therefore, we cannot differentiate among different receptor subtypes.…”

Section: Technical Considerationsmentioning

confidence: 99%

Muscarinic Receptor Upregulation in Patients With Myocardial Infarction

Mazzadi

Pineau

Costes

et al. 2009

Circ: Cardiovascular Imaging

View full text Add to dashboard Cite

Background-Despite the major role attributed to myocardial vagal activity in left ventricular arrhythmogenesis in chronic myocardial infarction, the impact of infarction on left ventricular muscarinic receptor density remains unknown. Methods and Results-Left ventricular muscarinic receptor density was measured in vivo by positron emission tomography using the specific antagonist [ 11 C]methylquinuclidinyl benzilate ([ 11 C]MQNB) in 11 patients 43Ϯ20 days after myocardial infarction and 9 healthy volunteers. The extent of myocardial damage was quantified by delayed contrast-enhanced MRI. Three short-axis slices from each subject were analyzed in matched positron emission tomography and MRI images. A 2-injection positron emission tomography protocol was used; [11 C]MQNB timeactivity curves were obtained in 6 regions per slice and fitted to a 3-compartment ligand-receptor model. Four classes of myocardial regions were considered: normal (in volunteers); remote, supplied by healthy or Ͻ70% diameter reduction arteries and without MRI signs of damage; potentially damaged, supplied by infarct-related or Ͼ70% diameter reduction arteries and without signs of damage; and damaged, with damage. The muscarinic receptor density in remote (67Ϯ30 pmol/mL tissue; nϭ86) and potentially damaged (71Ϯ30 pmol/mL tissue; nϭ42) regions of patients was higher than in normal regions of volunteers (32Ϯ17 pmol/mL tissue; nϭ156; PϽ0.001). The muscarinic receptor density in damaged regions (42Ϯ21 pmol/mL tissue; nϭ58) was reduced compared with remote and potentially damaged regions (PϽ0.001) but was not significantly different from normal regions in volunteers (Pϭ0.093). Conclusions-Vagal

show abstract

Kinetic and molecular evidences that human cardiac muscle express non-M2 muscarinic receptor subtypes that are able to interact themselves

Cited by 21 publications

References 27 publications

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

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

A Decreased Expression and Functionality of Muscarinic Cholinergic Receptor in Acute Chagas Myocarditis

Muscarinic Receptor Upregulation in Patients With Myocardial Infarction

Contact Info

Product

Resources

About

Kinetic and molecular evidences that human cardiac muscle express non-M2 muscarinic receptor subtypes that are able to interact themselves

Cited by 21 publications

References 27 publications

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

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

A Decreased Expression and Functionality of Muscarinic Cholinergic Receptor in Acute Chagas Myocarditis

Muscarinic Receptor Upregulation in Patients With Myocardial Infarction

Contact Info

Product

Resources

About

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

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