Multifaceted Role of Sympathetic Influence in the Heart
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Authors
Fiore, Chase M
Issue Date
2025
Type
Dissertation
Language
en_US
Keywords
alpha adrenergic , cAMP , hERG , neuropeptide Y , sympathetic nervous system , ventricular myocyte
Alternative Title
Abstract
The autonomic nervous system continuously modulates cardiac output by balancing sympathetic and parasympathetic input to the heart. The parasympathetic nervous system (PNS) promotes cardiac slowing and stabilizes electrical activity, primarily through vagal input to the myocardium and conduction system. Generally acting in opposition to parasympathetic input, the sympathetic nervous system (SNS) orchestrates critical adaptations in cardiac function under physiological and pathological conditions. This dissertation investigates multiple facets of sympathetic modulation in ventricular myocytes, emphasizing the intricate and receptor-specific mechanisms through which neurohormonal signaling alters ion channel activity and myocardial excitability. First, we examine crosstalk between α1A-adrenergic receptors (α1AARs) and β-adrenergic signaling pathways in adult rat ventricular myocytes. Using FRET-based biosensors, we identify a novel “inside-out” signaling cascade originating from nuclear α1AARs that suppresses β-adrenergic receptor (βAR)-driven cyclic adenosine monophosphate (cAMP) production via a mitogen-activated protein kinase (MAPK) and G protein-coupled receptor kinase (GRK)/arrestin-dependent mechanism. These findings highlight a non-canonical mode of α1AAR function that blunts β-adrenergic signaling and may contribute to the cardioprotective effects observed with α1AAR activation in heart failure. Second, we demonstrate that neuropeptide Y (NPY), a sympathetic co-transmitter elevated after myocardial infarction (MI), exerts dual and receptor-specific modulation of the L-type calcium current (ICaL) in porcine ventricular myocytes. NPY alone enhances ICaL via Y1 receptor-mediated Gq signaling, whereas in the presence of norepinephrine (NE), it suppresses ICaL through Y2 receptor activation of Gi signaling. These effects become regionally dissociated following MI, with Y1-mediated potentiation lost altogether and Y2-mediated suppression persisting only in the infarct border zone, revealing a spatially restricted shift in autonomic signaling within the failing heart. Lastly, we explore the contribution of membrane environment to proarrhythmic drug interactions with hERG (KV11.1) channels. Depletion of membrane cholesterol via methyl-β-cyclodextrin (MβCD) differentially modulates the sensitivity of hERG current to pharmacological inhibitors, enhancing inhibition by ibutilide while attenuating effects of dofetilide and amiodarone. These results underscore the importance of lipid–channel interactions in modulating arrhythmogenic potential of ion channel blockers. Collectively, this work provides novel insight into sympathetic regulation of ventricular electrophysiology, elucidating both receptor-specific signaling pathways and biophysical determinants of channel function. By addressing cross-receptor interactions, regional heterogeneity, and membrane dynamics, these findings refine our understanding of autonomic influence on cardiac excitability in health and disease.