Targeted M-Channel Activation in the Left Stellate Ganglion Protects Against Ischemia-Induced Ventricular Arrhythmias in Canines.

BACKGROUND

Acute myocardial ischemia (AMI)-triggered ventricular arrhythmias are closely linked to maladaptive sympathetic hyperactivity mediated via the left stellate ganglion (LSG). Although M-type potassium channels regulate neuronal excitability and hold therapeutic potential for neurological disorders, their role in intrinsic LSG neurons during ischemia remains unexplored. We investigated whether pharmacological M-channel activation in the LSG mitigates sympathetic overdrive and arrhythmogenesis in AMI.

METHODS AND

RESULTS

Twenty-four beagles underwent LSG microinjection of either vehicle (n=12) or retigabine (M-channel activator, 50 μM; n=12) 30 minutes before AMI induction. We assessed (1) neural parameters (LSG electrophysiology, plasma norepinephrine levels, and c-fos+/tyrosine hydroxylase+ neuron expression); (2) cardiac electrophysiological parameters (beat-to-beat repolarization variability, spatial dispersion of effective refractory period and action potential duration, ventricular fibrillation threshold, and spontaneous ventricular arrhythmias incidence); and (3) autonomic and hemodynamic measures (heart rate variability and blood pressure). Retigabine pretreatment significantly suppressed ischemia-induced LSG hyperactivity and reduced sympathetic activation markers compared with controls. Treated animals exhibited attenuated repolarization variability and reduced electrophysiological heterogeneity in ischemic myocardium. The retigabine group demonstrated a higher ventricular fibrillation threshold (26.67±2.61 versus 12.33±1.76 voltage (V), P=0.0008) and a lower incidence of ventricular arrhythmias during AMI, with only negligible effects on baseline cardiac repolarization duration or LSG function before ischemia induction.

CONCLUSIONS

Targeted activation of LSG M-channels with retigabine stabilizes ischemia-induced sympathetic hyperactivity, promotes cardiac autonomic balance, preserves repolarization homogeneity, and ultimately mitigates arrhythmic susceptibility. These findings highlight ganglionic M-channel modulation as a translatable strategy to suppress neurogenic arrhythmogenesis in AMI.