Acute and Chronic Effects of Seizures on Cardiorespiratory Control in the SSKcnj16‐/‐Rat

Abstract

Epilepsy is a common neurological disorder in which 1/3rd of patients experiences repeated seizures, which puts them at greater risk for Sudden Unexpected Death in Epilepsy (SUDEP). The pathophysiological consequences of repeated seizures resulting in SUDEP, including the effects of repeated seizures on cardiorespiratory function, remain unclear. We previously established a rat model (SSKcnj16‐/‐rats) in which 10 days of repeated daily audiogenic generalized tonic‐clonic seizures (GTCSs) lead to ictal apnea, post‐ictal respiratory suppression, blunted chemoreflexes and high spontaneous mortality (PMID: 33232300). Here we tested the hypotheses that a single GTCS is sufficient to blunt ventilatory chemoreflexes and that repeated seizures lead to progressively greater post‐ictal heart rate (HR) suppression and/or increases in blood pressure (BP). In our pilot experiment, a male SSKcnj16‐/‐rat was implanted with a pressure telemeter and placed in a chronic monitoring plethysmograph to measure breathing and BP/HR continuously for 10 days. The rat was exposed to a 10 kHz sound (2 mins) to elicit a seizure once/day for 10 days. We found that audiogenic seizures led to ictal apneas of variable lengths (4‐25 sec) and ictal asystole (~1‐2 sec), followed by a 31% increase in BP and 30% decrease in HR on days 1‐4. On days 9‐10, there was a 45% increase in BP and 50% decrease in HR, suggesting a progressive effect on HR and BP with repeated seizures. Ongoing studies aim to determine if the ventilatory responses to hypoxia (12% O2) or hypercapnia (7% CO2) are affected 1 hr after recovery from a single GTCS. Naïve SSKcnj16‐/‐rats (n=4, female) were subjected to pre‐ and post‐seizure hypercapnic chemoreflex testing. Relative to room air breathing, minute ventilation (expressed as % of control) increased during hypercapnia before (262% ± 12%) and 1 hr post‐seizure (240% ± 21%). However, breathing frequency responses to hypercapnia 1 hr post‐seizure were reduced (126% ± 6%) compared to before (164% ± 14%), and tidal volume increased to a greater amount post‐seizure (192% ± 13%) compared to before (168% ± 7%), suggesting a significant shift away from a frequency‐mediated to a tidal volume‐mediated chemoreflex response in the post‐ictal period. Our preliminary data suggest that like breathing, repeated seizures may have a progressively negative and acute effect on BP and HR, and that solitary seizures are sufficient to fundamentally alter the hypercapnic ventilatory responses in this rat model, which may have high relevance to human SUDEP.