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


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 un-balance 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 trypo-mastigotes 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 [3H]-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 in the acute Chagas disease that could impact the evolution and prognosis of the disease.

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Labrador-Hernández, M. , Jiménez, L. , Leon, G. , López, R. , Mendoza, W. , Bonfante-Rodriguez, C. , Torres-Peraza, J. and Bonfante-Cabarcas, R. (2014) A Decreased Expression and Functionality of Muscarinic Cholinergic Receptor in Acute Chagas Myocarditis. World Journal of Cardiovascular Diseases, 4, 305-315. doi: 10.4236/wjcd.2014.46040.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Guhl, F. and Lazdins-Helds, J.K. (2007) Grupo de trabajo científico. Reporte sobre la enfermedad de Chagas. OMS, Electronic Adress:
[2] Schmunis, G. (2007) Epidemiology of Chagas Disease in Non-Endemic Countries: The Role of International Migration. Memórias do Instituto Oswaldo Cruz, 102, 75-85.
[3] Jackson, Y., Gétaz, L., Wolff, H., Holst, M., Mauris, A., Tardin, A., Sztajzel, J., Besse,V., Loutan, L., Gaspoz, J.M., Jannin, J., Vinas, P.A., Luquetti, A. and Chappuis, F. (2010) Prevalence, Clinical Staging and Risk for Blood-Borne Transmission of Chagas Disease among Latin American Migrants in Geneva, Switzerland. PLOS Neglected Tropical Diseases, 4, e592.
[4] Piron, M., Vergés, M., Muñoz, J., Casamitjana, N., Sanz, S., Maymó, R.M., Hernández, J.M., Puig, L., Portús, M., Gascón, J. and Sauleda, S. (2008) Seroprevalence of Trypanosoma Cruzi Infection in At-Risk Blood Donors in Catalonia (Spain). Transfusion, 48, 1862-1868.
[5] Toso, M.A., Vial, U.F. and Galanti, N. (2011) Oral Transmission of Chagas’ Disease. Revista Medica de Chile, 139, 258-266.
[6] de Noya, B.A., Díaz-Bello, Z., Colmenares, C., Ruiz-Guevara, R., Mauriello, L., Zavala-Jaspe, R., Suarez, J.A., Abate, T., Naranjo, L., Paiva, M., Rivas, L., Castro, J., Márques, J., Mendoza, I., Acquatella, H., Torres, J. and Noya, O. (2010) Large Urban Outbreak of Orally Acquired Acute Chagas Disease at a School in Caracas, Venezuela. The Journal of Infectious Diseases, 201, 1308-1315.
[7] Benchimol-Barbosa, P.R. (2010) Trends on Acute Chagas’ Disease Transmitted by Oral Route in Brazil: Steady Increase in New Cases and a Concealed Residual Fluctuation. International Journal of Cardiology, 145, 494-496.
[8] Cutrim, F.S., Almeida, I.A., Eda, G.G. and Silva, A.R. (2010) Chagas’ Disease in the State of Maranhão, Brazil: Record of Acute Cases from 1994 to 2008. Revista da Sociedade Brasileira de Medicina Tropical, 43, 705-708.
[9] Pinto, A.Y., Valente, S.A., Vda, C.V., Ferreira Jr., A.G. and Coura, J.R. (2008) Acute phase of Chagas Disease in the Brazilian Amazon Region: Study of 233 Cases from Pará, Amapá and Maranhão Observed between 1988 and 2005. Revista da Sociedade Brasileira de Medicina Tropical, 41, 602-614.
[10] Nicholls, R.S., Cucunubá, Z.M., Knudson, A., Flórez, A.C., Montilla, M., Puerta, C.J. and Pavía, P.X. (2007) Acute Chagas Disease in Colombia: A Rarely Suspected Disease. Report of 10 Cases Presented during the 2002-2005 Period. Biomédica, 27, 8-17.
[11] Teixeira, A.R., Hecht, M.M., Guimaro, M.C., Sousa, A.O. and Nitz, N. (2011) Pathogenesis of Chagas’ Disease: Parasite Persistence and Autoimmunity. Clinical Microbiology Reviews, 24, 592-630.
[12] Dávila, D.F., Donis, J.H., Torres, A. and Ferrer, J.A. (2004) A Modified and Unifying Neurogenic Hypothesis Can Explain the Natural History of Chronic Chagas Heart Disease. International Journal of Cardiology, 96, 191-195.
[13] Da Cunha, A.B. (2003) Chagas’ Disease and the Involvement of the Autonomic Nervous System. Revista Portuguesa de Cardiologia, 22, 813-824.
[14] Peraza-Cruces, K., Gutiérrez-Guédez, L., Perozo, D.C., Lankford, C.R., Rodríguez-Bonfante, C. and Bonfante-Cabarcas, R. (2008) Trypanosoma Cruzi Infection Induces Up-Regulation of Cardiac Muscarinic Acetylcholine Receptors in Vivo and in Vitro. Brazilian Journal of Medical and Biological Research, 41, 796-803.
[15] Labrador-Hernández, M., Suárez-Graterol, O., Romero-Contreras, U., Rumenoff, L., Rodríguez-Bonfante, C. and Bonfante-Cabarcas, R. (2008) The Cholinergic System in Cyclophosphamide-Induced Chagas Dilated Myocardiopathy in Trypanosoma-Cruzi-Infected Rats: An Electrocardiographic Study. Investigación Clínica, 49, 207-224.
[16] Bonfante-Cabarcas, R., Hincapié, E.L., Hernández, E.J., Zambrano, R.F., Mancini, L.F., Mena, M.D. and Rodríguez-Bonfante, C. (2013) Electrophysiological and Pharmacological Evaluation of the Nicotinic Cholinergic System in Chagasic Rats. BMC Pharmacology and Toxicology, 14, 2.
[17] Pérez, C.C., Tobar, I.D., Jiménez, E., Castañeda, D., Rivero, M.B., Concepción, J.L., Chiurillo, M.A. and Bonfante-Cabarcas, R. (2006) Kinetic and Molecular Evidences That Human Cardiac Muscle Express Non-M2 Muscarinic Receptor Subtypes that Are Able to Interact Themselves. Pharmacological Research, 54, 345-355.
[18] Alvarado-Tapias, E., Miranda-Pacheco, R., Rodríguez-Bonfante, C.C., Velásquez, G., Loyo, J., Gil-Oviedo, M., Mogollón, N., Pérez-Aguilar, M.C., Recchimuzzi, G., Espinosa, R., Carrasco, H.J., Concepción, J.L. and Bonfante-Cabarcas, R.A. (2012) Electrocardiographic Repolarization Abnormalities Are Characteristic Signs of Acute Chagasic Cardiomyopathy. Investigación Clínica, 53, 378-394.
[19] Van Borren, M.M., Verkerk, A.O., Wilders, R., Hajji, N., Zegers, J.G., Bourier, J., Tan, H.L., Verheijck, E.E., Peters, S.L., Alewijnse, A.E. and Ravesloot, J.H. (2010) Effects of Muscarinic Receptor Stimulation on Ca2+ Transient, cAMP Production and Pacemaker Frequency of Rabbit Sinoatrial Node Cells. Basic Research in Cardiology, 105, 73-87.
[20] Tamargo, J., Caballero, R., Gómez, R., Valenzuela, C. and Delpón, E. (2004) Pharmacology of Cardiac Potassium Channels. Cardiovascular Research, 62, 9-33.
[21] Bucchi, A., Barbuti, A., Difrancesco, D. and Baruscotti, M. (2012) Funny Current and Cardiac Rhythm: Insights from HCN Knockout and Transgenic Mouse Models. Frontiers in Physiology, 3, 240.
[22] Scicchitano, P., Carbonara, S., Ricci, G., Mandurino, C., Locorotondo, M., Bulzis, G., Gesualdo, M., Zito, A., Carbonara, R., Dentamaro, I., Riccioni, G. and Ciccone, M.M. (2012) HCN Channels and Heart Rate. Molecules, 17, 4225-4235.
[23] DiFrancesco, D. and Tromba, C. (1988) Muscarinic Control of the Hyperpolarization-Activated Current (If) in Rabbit Sino-Atrial Node Myocytes. The Journal of Physiology, 405, 493-510.
[24] Fernández-Velasco, M., Goren, N., Benito, G., Blanco-Rivero, J., Boscá, L. and Delgado, C. (2003) Regional Distribution of Hyperpolarization-Activated Current (If) and Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel mRNA Expression in Ventricular Cells from Control and Hypertrophied Rat Hearts. The Journal of Physiology, 553, 395-405.
[25] Hofmann, F., Fabritz, L., Stieber, J., Schmitt, J., Kirchhof, P., Ludwig, A. and Herrmann, S. (2012) Ventricular HCN Channels Decrease the Repolarization Reserve in the Hypertrophic Heart. Cardiovascular Research, 95, 317-326.
[26] Mitchelson, F.J. (2012) The Pharmacology of McN-A-343. Pharmacology & Therapeutics, 135, 216-245.
[27] Valant, C., Gregory, K.J., Hall, N.E., Scammells, P.J., Lew, M.J., Sexton, P.M. and Christopoulos, A. (2008) A Novel Mechanism of G Protein-Coupled Receptor Functional Selectivity. Muscarinic Partial Agonist McN-A-343 as a Bitopic Orthosteric/Allosteric Ligand. The Journal of Biological Chemistry, 283, 29312-29321.
[28] Caulfield, M.P. and Birdsall, N.J. (1998) International Union of Pharmacology. XVII. Classification of Muscarinic Acetylcholine Receptors. Pharmacological Reviews, 50, 279-290.
[29] Marin-Neto, J.A., Cunha-Neto, E., Maciel, B.C. and Simões, M.V. (2007) Pathogenesis of Chronic Chagas Heart Disease. Circulation, 115, 1109-1123.
[30] Torres, A., Dávila, D.F., Gottberg, C.F., Donis, J.H., de Bellabarba, G.A. and Ramoni-Perazzi, P. (2000) Heart Rate Responses to a Muscarinic Agonist in Rats with Experimentally Induced Acute and Subacute Chagasic Myocarditis. Revista do Instituto de Medicina Tropical de São Paulo, 42, 219-224.
[31] Sabbah, H.N. (2011) Electrical Vagus Nerve Stimulation for the Treatment of Chronic Heart Failure. Cleveland Clinic Journal of Medicine, 78, S24-S29.
[32] Schwartz, P.J. (2011) Vagal Stimulation for Heart Diseases: From animals to Men—An Example of Translational Cardiology. Circulation Journal, 75, 20-27.
[33] Das, U.N. (2011) Vagal Nerve Stimulation in Prevention and Management of Coronary Heart Disease. World Journal of Cardiology, 3, 105-110.
[34] Wang, H., Yu, M., Ochani, M., Amella, C.A., Tanovic, M., Susarla, S., Li, J.H., Wang, H., Yang, H., Ulloa, L., Al-Abed, Y., Czura, C.J. and Tracey, K.J. (2003) Nicotinic Acetylcholine Receptor Alpha7 Subunit Is an Essential Regulator of Inflammation. Nature, 421, 384-388.

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