Abstract
In a previous research, we described that vagal stimulation increases the infarct size by sympathetic co-activation. The aim of this study was to determine if hemodynamic changes secondary to the vagal stimulation are able to activate sympathetic compensatory neural reflexes, responsible for increasing the infarct size. A second goal was to determine if intermittent vagal stimulation avoids sympathetic activation and reduces infarct size by muscarinic activation of the Akt/glycogen synthase kinase 3 β (GSK-3β) pathway. Rabbits were subjected to 30 min of regional myocardial ischemia and 3 h of reperfusion without vagal stimulation, or the following protocols of right vagus nerve stimulation for 10 min before ischemia: (a) continuous vagal stimulation and (b) intermittent vagal stimulation (cycles of 10 s ON/50 s OFF). Continuous vagal stimulation increased the infarct size (70.7 ± 4.3 %), even after right vagal section (68.6 ± 4.1 %) compared with control group (52.0 ± 3.7 %, p < 0.05). Bilateral vagotomy, pacing, and esmolol abolished the deleterious effect, reaching an infarct size of 43.3 ± 5.1, 43.5 ± 2.1, and 46.0 ± 4.6 % (p < 0.05), respectively. Intermittent stimulation reduced the infarct size to 29.8 ± 3.0 % (p < 0.05 vs I/R). This effect was blocked with atropine (50.2 ± 3.6 %, p < 0.05). Continuous vagal stimulation induced bradycardia and increased the loading conditions and wall stretching of the atria. These changes provoked the co-activation reflex of the sympathetic nervous system, observed by the rise in plasmatic catecholamine levels, which increased the infarct size. Sympathetic co-activation was abolished by continuous vagal stimulation with constant heart rate or parasympathetic deafferentation. Intermittent vagal stimulation attenuated the sympathetic tone and reduced the infarct size by the muscarinic activation of the Akt pathway and GSK-3β inhibition. Continuous stimulation only phosphorylated Akt and GSK-3β when esmolol was administered.
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Acknowledgments
This work was supported by a research grant from National Agency for Scientific and Technological Promotion (ANPCyT, PICT 01071), the University of Buenos Aires (UBACyT M032), the National Council of Scientific and Technological Research (CONICET) (PIP0197/2011), and the Argentine Society of Cardiology.
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The procedures used in this study were approved by the Animal Care and Research Committee of the University of Buenos Aires (Protocol # 2004/11) and were in compliance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH publication, Eight edition; 2010).
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The authors declare that they have no conflict of interest.
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Bruno Buchholz and Martín Donato contributed equally to this work.
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Buchholz, B., Donato, M., Perez, V. et al. Changes in the loading conditions induced by vagal stimulation modify the myocardial infarct size through sympathetic-parasympathetic interactions. Pflugers Arch - Eur J Physiol 467, 1509–1522 (2015). https://doi.org/10.1007/s00424-014-1591-2
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DOI: https://doi.org/10.1007/s00424-014-1591-2