Pyridostigmine enhances atrial tachyarrhythmias in aging spontaneously hypertensive rats

Abstract

This study examined whether chronic administration of pyridostigmine, a reversible cholinesterase inhibitor, would exacerbate episodes of spontaneous atrial tachyarrhythmia (AT) in conscious, aging, spontaneously hypertensive rats (SHRs). Telemetric recordings of electrocardiogram (ECG, n = 5) and ECG/arterial pressure (n = 3) were performed in male 49-week old SHRs. After a 1-week period of continuous recording under baseline conditions, rats were implanted with osmotic minipumps that delivered pyridostigmine (15 mg/kg/day subcutaneously) for either 1 (n = 8) or 3 (n = 5) weeks. In the latter case, sympathovagal balance was assessed during the last infusion week by measuring heart rate (HR) changes in response to administration of cardiac autonomic blockers. An additional 1-week recording was performed after explantation of minipumps. Significant (P = 0.02) reductions in HR with no consistent changes in arterial pressure were observed. Frequency and duration of AT episodes were increased by pyridostigmine (0.01 ≤ P ≤ 0.07). This increase was sustained across the 3-week treatment period and reversible after cessation of treatment. Autonomic blockade revealed that intrinsic HR was above (P = 0.04) resting HR, pointing to a shift of sympathovagal balance towards vagal predominance. However, the respiratory-related component of HR variability (high-frequency power of RR interval) was lowered (P = 0.01) by pyridostigmine treatment, indicating reduced vagal modulation of HR. The results are consistent with a pathogenic role of the parasympathetic nervous system in the aging SHR model, and raise the possibility that sustained vagal activation may facilitate atrial arrhythmias.

Autonomic imbalance and atrial ectopic activity—a pathophysiological and clinical view

“…(Scridon et al, 2018) Increased sympathetic tone is a major pathophysiological feature of most of these conditions, although spontaneous unsustained AF has also been associated with sympathetic withdrawal and relative parasympathetic activity in aging, spontaneously hypertensive rats (Scridon et al, 2012). Moreover, in that model, sympathetic stimulation exhibited marked atrial antiarrhythmic effects, whereas parasympathetic stimulation induced a significant increase in atrial arrhythmic burden (Scridon et al, 2012;Sayin et al, 2015). Long-term vigorous endurance training has also been related to vagally-mediated AF (Figure 6).…”

“…Animal studies can generally provide much more robust mechanistic insights. More complex and more accurate methods can be used in preclinical studies and, unlike in clinical studies, selective and specific sympathetic and parasympathetic manipulation can be applied in experimental settings (Scridon et al, 2012;Sayin et al, 2015;Scridon et al, 2021). However, caution should be used when extrapolating animal data to human patients.…”