Peptidergic modulation of guinea pig intrinsic cardiac neurons

Ithaca College, Ithaca NY

Investigators

Abstract

? DESCRIPTION (provided by applicant): Chronic heart disease induces functional and phenotypic changes within cardiac tissues and the neuronal systems that control the heart. An imbalance in autonomic neuronal control that results in reduced parasympathetic activity coupled with increased and heterogeneous sympathetic activity increases the risk of cardiac arrhythmias and sudden death. The intrinsic cardiac nervous system (ICN), the final common pathway for parasympathetic autonomic control to the heart, integrates information from multiple inputs and can produce short-loop reflex control of cardiac function on a beat-to-beat basis. While multiple studies have focused on cardiac stress-induced changes in sympathetic neuronal control, much less attention has been paid to the critical role of information processing within peripheral parasympathetic autonomic ganglia and how they remodel/adapt to imposed stress. It is our hypothesis that cardiac stress-induced adaptations within the intrinsic cardiac nervous system represent efforts to maintain parasympathetic efferent output via functional and phenotypic alterations in select intrinsic cardiac neuronal populations. These adaptations within the ICN could counteract, in part, the maladaptive effects of excessive and heterogeneous sympathetic excitation associated with progressive cardiac disease. Increased sympathetic efferent activity can alter cardiac function through increased release of norepinephrine and neuropeptide Y (NPY) from sympathetic efferent fibers, along with sympathetic-induced increases in the production of the peptide hormone angiotensin II (AngII) and its metabolite, Ang(1-7). To specifically address the importance of altered peptide levels on the development of cardiac pathology, this proposal will evaluate how the intrinsic cardiac nervous system responds to elevated levels of AngII and NPY following myocardial infarction (MI) in the guinea pig. Using a whole mount preparation of the guinea pig cardiac plexus, we will evaluate the physiological responses of individual intrinsic cardiac neurons to AngII and NPY in tissues from control and MI animals. Our primary specific aims are (1) to determine the role of Angiotensin II receptors (AT1R, AT2R, MasR) in the modulation of ICN output with MI and (2) to determine the effects of increased release of NPY on the ICN following MI. We will use a multidisciplinary approach, which includes sharp electrode voltage recordings from individual neurons in the whole mount preparation, whole cell voltage clamp recordings from neurons within the intact network, immunohistochemistry, and biochemical measurements of protein and mRNA expression levels. Combined, the results from these studies will aid in determining the mechanisms by which these peptides can modulate neuronal function. This information can be used to develop better pharmacotherapies to treat chronic heart disease.