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dc.contributor.advisorSchwenke, Daryl
dc.contributor.advisorBrown, Colin
dc.contributor.authorRoy, Ranjan Kumer
dc.identifier.citationRoy, R. K. (2017). A novel central pathway for sympathetic activation in the early stages following an acute myocardial infarction (Thesis, Doctor of Philosophy). University of Otago. Retrieved from
dc.description.abstractAcute myocardial infarction (MI) initiates an adverse and sustained increase in cardiac sympathetic nerve activity (SNA), which begins as early as 30 min after the infarct, provoking arrhythmias and is a leading factor for the high mortality rate within the ensuing hours. The mechanism(s) responsible for the increase in cardiac SNA following MI remain to be fully elucidated, however, increased cardiac SNA likely culminates from interactions between various peripheral neural reflexes and the central integration of these signals, involving several hypothalamic and brainstem nuclei, in particular, the paraventricular nucleus (PVN), supraoptic nucleus (SON), subfornical organ (SFO), nucleus tractus solitarius (NTS), rostral ventrolateral medulla (RVLM), and area postrema (AP). The primary aim of this study was to determine the relative role of these brainstem and hypothalamic nuclei in triggering sympathetic activation in early stages of acute MI. Once the adverse increase in cardiac SNA is fully established, in chronic heart failure, it is essentially irreversible. However, in the early stages following acute MI, it appears possible to effectively prevent or reverse the initial increase in SNA. However, this “early period” is not well defined in the literature. Hence, the first objective of this study was to establish a precise time course of cardiac SNA in early stage of acute MI. The advanced technique of electrophysiology recording directly from the cardiac sympathetic nerve was used to record SNA continuously before and then for four hours following acute MI so as to establish a precise time profile for the increase in SNA following acute MI. The results showed that cardiac SNA began to increase within min following acute MI, reaching significance by 14 min post-MI (34 ± 8% increase in SNA) (n = 8, F (15, 180) = 5.20, P < 0.0001, two-way RM ANOVA). The second objective of this study was to ‘map’ the key brain nuclei responsible for sympathetic activation, in particular the PVN, SON, SFO, AP as well as the NTS, RVLM. Fos protein expression was used as a marker of neuronal activation. Interestingly, as early as 90 min post-MI, all nuclei of interest showed increased neuronal activation. In particular, the parvocellular division of PVN, which comprises pre-autonomic neurons that are heavily implicated in sympathetic activation, showed a higher degree of neuronal activation. e.g. neuronal activation within the parvocellular division of PVN for MI rats was 100% higher than that of sham rats (P = 0.0012, unpaired t-test). Given that the PVN comprises a diverse population of phenotypically different neurons, the third objective of this study was to identify the phenotype of the activated parvocellular neurons using double-label immunohistochemistry. Pre-autonomic parvocellular neurons express oxytocin, vasopressin, endorphin, dynorphin, somatostatin, enkephalin, corticotropin-releasing hormone and growth hormone-releasing hormone. The results revealed that there was increased activation of the parvocellular oxytocin neurons in MI rats (19 ± 2 cells / section, n = 8) than in sham rats (11 ± 2 cells / section, n = 8; P = 0.002, unpaired t-test). Only a sub-population of the parvocellular pre-autonomic oxytocin neurons project to the RVLM, and it is these neurons that have the potential to modulate SNA. Therefore, the fourth objective of this study was to determine whether those parvocellular PVN oxytocin neurons that are activated following MI do project to the RVLM. To do this a retrograde tracer was injected into the RVLM one week prior to the experimental induction of an MI. We then used double-label immunohistochemistry to show that, of all parvocellular PVN oxytocin neurons that project to the RVLM, ~30% are activated following MI (compared to ~0% for sham rats), suggesting that these activated oxytocin neurons likely contribute to the observed increase in SNA following acute MI. To test the final hypothesis that activated oxytocin neurons significantly contribute to sympathetic activation following MI, the technique of electrophysiology was once again used to record changes in cardiac SNA following MI. Importantly, one cohort of MI rats were injected with Retosiban (3 mg / ml), a potent oxytocin receptor antagonist, within 10 min of the acute MI. Remarkably, in those MI rats injected with Retosiban, the increase in cardiac SNA was completely prevented (n = 8, F (2, 15) = 12.37, P = 0.0007, two-way RM ANOVA) and, importantly, mortality rate was reduced from 40% to 11% (P < 0.05, Kaplan-Meier survival analysis). In conclusion, this study provides compelling evidence that PVN oxytocin neuronal activation play a crucial role in triggering an adverse increase in SNA in the early stages following acute MI. Importantly, the results from this study advocate oxytocin receptor blockers as a promising and novel therapeutic strategy for the immediate treatment of MI.
dc.publisherUniversity of Otago
dc.rightsAll items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjectSympathetic activation
dc.subjectmyocardail infarction
dc.subjectparvocellular oxytocin
dc.titleA novel central pathway for sympathetic activation in the early stages following an acute myocardial infarction
dc.language.rfc3066en of Physiology of Philosophy of Otago
otago.openaccessAbstract Only
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