Cholinergic suppression of HR acceleration during intrinsic optogenetic activation of sympathetic cardiac neurons in perfused hearts
Document Type
Journal Article
Publication Date
10-24-2025
Journal
American journal of physiology. Heart and circulatory physiology
DOI
10.1152/ajpheart.00418.2025
Keywords
AV block; Acetylcholine; Autonomic Nervous System; Neurocardiac Electrophysiology; Optogenetics
Abstract
Cardiac autonomic pathways can be interrogated using optogenetics via selective expression of channelrhodopsin (ChR2) within intrinsic cardiac neurons. We tested the hypothesis that cholinergic activation via exogenous acetylcholine (ACh) would suppress the beta-adrenergic heart rate (HR) acceleration induced by tyrosine hydroxylase (TH) neuron stimulation. HR responses were measured for wild-type (WT) mice at increasing norepinephrine (NE) concentrations and for transgenic mice that expressed ChR2 in TH neurons while illuminating the right atrium using a 465nm microLED. Light pulse duty cycles (at 5Hz) increasing from 5-50% caused proportional increases in HR; however, HR was unstable at duty cycles >30%. At 20% duty cycle, HR increased 39.43±6.79%. HR increased for light pulse frequencies from 2.5-15Hz (30ms pulse width) but HR was unstable at 15Hz. HR increases for photostimulated TH hearts (TH) and WT hearts perfused with NE (1-800nM, WT+NE) had similar maxima but drastically different rise time constants (1.54±0.08 vs 18.04±3.87 sec, respectively). Increasing doses of ACh were added to the perfusate of WT+NE hearts and photostimulated TH hearts. High doses of ACh significantly diminished NE-induced and light-induced HR increases. Optogenetic activation of TH neurons caused rapid HR acceleration that was suppressed at higher ACh concentration than that required to suppress acceleration during NE perfusion. In WT+NE hearts this occurred at 400nM ACh and in TH hearts this did not occur until 1800nM ACh. AV block occurred more rapidly in TH hearts during photostimulation as ACh concentration increased, demonstrating a time-dependent element in the interaction of simultaneous cholinergic and adrenergic activation.
APA Citation
Russo, Rebekah; Moreno, Angel; Dwyer, Mary Kate; Skancke, Matthew; Trachiotis, Gregory; Mendelowitz, David; and Kay, Matthew W., "Cholinergic suppression of HR acceleration during intrinsic optogenetic activation of sympathetic cardiac neurons in perfused hearts" (2025). GW Authored Works. Paper 8234.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/8234
Department
Pharmacology and Physiology