The training-induced changes on automatism, conduction and myocardial refractoriness are not mediated by parasympathetic postganglionic neurons activity

The purpose of this study is to test the role that parasympathetic postganglionic neurons could play on the adaptive electrophysiological changes produced by physical training on intrinsic myocardial automatism, conduction and refractoriness. Trained rabbits were submitted to aphysical training protocol on treadmill during 6 weeks. The electrophysiological study was performed in an isolated heart preparation. The investigated myocardial properties were: (a) sinus automatism, (b) atrioventricular and ventriculoatrial conduction, (c) atrial, conduction system and ventricular refractoriness. The parameters to study the refractoriness were obtained by means of extrastimulus test at four diVerent pacing cycle lengths (10% shorter than spontaneous sinus cycle length, 250, 200 and 150 ms) and (d) mean dominant frequency (DF) of the induced ventricular Wbrillation (VF), using a spectral method. The electrophysiological protocol was performed before and during continuous atropine administration (1 ¿M), in order to block cholinergic receptors. Cholinergic receptor blockade did not modify either the increase in sinus cycle length, atrioventricular conduction and refractoriness (left ventricular and atrioventricular conduction system functional refractory periods) or the decrease of DF of VF. These Wndings reveal that the myocardial electrophysiological modiWcations produced by physical training are not mediated by intrinsic cardiac parasympathetic activity.The authors thank Carmen Rams, Ana Diaz, Pilar Navarro and Cesar Avellaneda for their excellent technical assistance. This work has been supported by grants from the Spanish Ministry of Education and Science (DEP2007-73234-C03-01) and Generalitat Valenciana (PROMETEO 2010/093). M Zarzoso was supported by a research scholarship from Generalitat Valenciana (BFPI/2008/003).Zarzoso Muñoz, M.; Such Miquel, L.; Parra Giraldo, G.; Brines Ferrando, L.; Such, L.; Chorro, F.; Guerrero, J.... (2012). The training-induced changes on automatism, conduction and myocardial refractoriness are not mediated by parasympathetic postganglionic neurons activity. European Journal of Applied Physiology. 112(6):2185-2193. https://doi.org/10.1007/s00421-011-2189-4S218521931126Armour JA, Hopkins DA (1990a) Activity of in vivo canine ventricular neurons. Am J Physiol Heart Circ Physiol 258:H326–H336. doi: 10.1152/ajpregu.00183.2004Armour JA, Hopkins DA (1990b) Activity of canine in situ left atrial ganglion neurons. Am J Physiol Heart Circ Physiol 259:H1207–H1215Armour JA (2004) Cardiac neuronal hierarchy in health and disease. 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Effect of chronic exercise on myocardial electrophysiological heterogeneity and stability. Role of intrinsic cholinergic neurons: A study in the isolated rabbit heart

[EN] A study has been made of the effect of chronic exercise on myocardial electrophysiological heterogeneity and stability, as well as of the role of cholinergic neurons in these changes. Determinations in hearts from untrained and trained rabbits on a treadmill were performed. The hearts were isolated and perfused. A pacing electrode and a recording multielectrode were located in the left ventricle. The parameters determined during induced VF, before and after atropine (1 mu M), were: fibrillatory cycle length (VV), ventricular functional refractory period (FRPVF), normalized energy (NE) of the fibrillatory signal and its coefficient of variation (CV), and electrical ventricular activation complexity, as an approach to myocardial heterogeneity and stability. The VV interval was longer in the trained group than in the control group both prior to atropine (78 +/- 10 vs. 68 +/- 10 ms) and after atropine (76 +/- 8 vs. 67 +/- 10 ms). Likewise, FRPVF was longer in the trained group than in the control group both prior to and after atropine (53 +/- 8 vs. 42 +/- 7 ms and 50 +/- 6 vs. 40 +/- 6 ms, respectively), and atropine did not modify FRPVF. The CV of FRPVF was lower in the trained group than in the control group prior to atropine (12.5 +/- 1.5% vs. 15.1 +/- 3.8%) and, decreased after atropine (15.1 +/- 3.8% vs. 12.2 +/- 2.4%) in the control group. The trained group showed higher NE values before (0.40 +/- 0.04 vs. 0.36 +/- 0.05) and after atropine (0.37 +/- 0.04 vs. 0.34 +/- 0.06; p = 0.08). Training decreased the CV of NE both before (23.3 +/- 2% vs. 25.2 +/- 4%; p = 0.08) and after parasympathetic blockade (22.6 +/- 1% vs. 26.1 +/- 5%). Cholinergic blockade did not modify these parameters within the control and trained groups. Activation complexity was lower in the trained than in the control animals before atropine (34 +/- 8 vs. 41 +/- 5), and increased after atropine in the control group (41 +/- 5 vs. 48 +/- 9, respectively). Thus, training decreases the intrinsic heterogeneity of the myocardium, increases electrophysiological stability, and prevents some modifications due to muscarinic block.This research was supported by the Spanish Ministry of Education and Science, (DEP2007-73234-C03-01 to AMA), http://www.mecd.gob.es/portada-mecd/; and the Generalitat Valenciana (PROMETEO 2010/093 to FJC, and FPI/2008/003 to MZ), http://www.gva.es/va/inicio/presentacion; jsessionid=ydprbDQZTsCTz85W1Such-Miquel, L.; Brines-Ferrando, L.; Alberola, A.; Zarzoso Muñoz, M.; Chorro Gasco, FJ.; Guerrero-Martínez, JF.; Parra-Giraldo, G.... (2018). Effect of chronic exercise on myocardial electrophysiological heterogeneity and stability. Role of intrinsic cholinergic neurons: A study in the isolated rabbit heart. 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Effects of S-Nitrosoglutathione on Electrophysiological Manifestations of Mechanoelectric Feedback

[EN] Electromechanical coupling studies have described the intervention of nitric oxide and S-nitrosylation processes in Ca2+ release induced by stretch, with heterogeneous findings. On the other hand, ion channel function activated by stretch is influenced by nitric oxide, and concentration-dependent biphasic effects upon several cellular functions have been described. The present study uses isolated and perfused rabbit hearts to investigate the changes in mechanoelectric feedback produced by two different concentrations of the nitric oxide carrier S-nitrosoglutathione. Epicardial multielectrodes were used to record myocardial activation at baseline and during and after left ventricular free wall stretch using an intraventricular device. Three experimental series were studied: (a) control (n=10); (b) S-nitrosoglutathione 10 mu M (n=11); and (c) S-nitrosoglutathione 50 mu M (n=11). The changes in ventricular fibrillation (VF) pattern induced by stretch were analyzed and compared. S-nitrosoglutathione 10 mu M did not modify VF at baseline, but attenuated acceleration of the arrhythmia (15.6 +/- 1.7 vs. 21.3 +/- 3.8Hz; p<0.0001) and reduction of percentile 5 of the activation intervals (42 +/- 3 vs. 38 +/- 4ms; p<0.05) induced by stretch. In contrast, at baseline using the 50 mu M concentration, percentile 5 was shortened (38 +/- 6 vs. 52 +/- 10ms; p<0.005) and the complexity index increased (1.77 +/- 0.18 vs. 1.27 +/- 0.13; p<0.0001). The greatest complexity indices (1.84 +/- 0.17; p<0.05) were obtained during stretch in this series. S-nitrosoglutathione 10 mu M attenuates the effects of mechanoelectric feedback, while at a concentration of 50 mu M the drug alters the baseline VF pattern and accentuates the increase in complexity of the arrhythmia induced by myocardial stretch.Carlos III Health Institute/FEDER funds (Spanish Ministry of Economy and Competitiveness): Grants FIS PI12/00407, PI15/01408, PIE15/00013, and RETIC “RIC” RD12/0042/0048. Generalitat Valenciana: Grant PROMETEO FASE II 2014/037.Such-Miquel, L.; Canto Serrano, ID.; Zarzoso Muñoz, M.; Brines-Ferrando, L.; Soler, C.; Parra-Giraldo, G.; Guill Ibáñez, A.... (2018). Effects of S-Nitrosoglutathione on Electrophysiological Manifestations of Mechanoelectric Feedback. Cardiovascular Toxicology. 18(6):520-529. https://doi.org/10.1007/s12012-018-9463-1S520529186Tamargo, J., Caballero, R., Gómez, R., & Delpón, E. (2010). Cardiac electrophysiological effects of nitric oxide. Cardiovascular Research, 87, 593–600.Gonzalez, D. R., Treuer, A., Sun, Q. A., Stamler, J. S., & Hare, J. M. (2009). S-nitrosylation of cardiac ion channels. Journal of Cardiovascular Pharmacology, 54, 188–195.Treuer, A. V., & Gonzalez, D. R. (2015). Nitric oxide synthases, S-nitrosylation and cardiovascular health: From molecular mechanisms to therapeutic opportunities. Molecular Medicine Reports, 11, 1555–1565.Beigi, F., Gonzalez, D. R., Minhas, K. M., Sun, Q. A., Foster, M. W., Khan, S. A., Treuer, A. V., Dulce, R. A., Harrison, R. W., Saraiva, R. M., Premer, C., Schulman, I. H., Stamler, J. S., & Hare, J. M. (2012). Dynamic denitrosylation via S-nitrosoglutathione reductase regulates cardiovascular function. Proceedings of the National Academy of Sciences of the United States of America, 109, 4314–4319.Broniowska, K. A., Diers, A. R., & Hogg, N. (2013). S-nitrosoglutathione. Biochimica et Biophysica Acta, 1830, 3173–3181.Zaman, K., Palmer, L. A., Doctor, A., Hunt, J. F., & Gaston, B. (2004). Concentration-dependent effects of endogenous S-nitrosoglutathione on gene regulation by specificity proteins Sp3 and Sp1. The Biochemical Journal, 380, 67–74.Janse, M. J., Coronel, R., Wilms-Schopman, F. J. G., & de Groot, J. R. (2003). Mechanical effects on arrhythmogenesis: From pipette to patient. Progress in Biophysics and Molecular Biology, 82, 187–195.Quinn, T. A., & Kohl, P. (2016). Rabbit models of cardiac mechano-electric and mechano-mechanical coupling. Progress in Biophysics and Molecular Biology, 121, 110–122.Vila-Petroff, M., Kim, S. H., Pepe, S., Dessy, C., Marbán, E., Balligand, J. L., & Sollott, S. J. (2001). Endogenous nitric oxide mechanisms mediate the stretch-dependency of Ca2+ release in cardiomyocytes. Nature Cell Biology, 3, 867–873.Leite-Moreira, A. M., Neves, J. S., Almeida-Coelho, J., Neiva-Sousa, M., & Leite-Moreira, A. F. (2016). On the study of the role of NO-mediated pathways in the myocardial response to acute stretch. Nitric Oxide: Biology and Chemistry, 53, 1–3.Peyronnet, R., Nerbonne, J. M., & Kohl, P. (2016). Cardiac mechano-gated ion channels and arrhythmias. Circulation Research 118, 311–329.Fischmeister, R., Castro, L., Abi-Gerges, A., Rochais, F., & Vandecasteele, G. (2005). Species- and tissue-dependent effects of NO and cyclic GMP on cardiac ion channels. Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology 142, 136–143.Kazanski, V. E., Kamkin, A. G., Makarenko, E. 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