Effects of different dosages esketamine on cardiac conduction and heterogeneity of Cx43: the epicardial mapping in guinea pigs

BACKGROUND: Esketamine is favored in clinical settings. Relative to other anesthetics it preserves protective airway reflexes, maintains spontaneous respiration, stabilizes hemodynamics, and alleviates neuropathic pain. This study sought to evaluate the cardiac safety of esketamine at 3 sub-anesthetic gradient concentrations. METHODS: We examined the cardiac electrophysiological effects of esketamine with infusion rates of 0.125, 0.25, and 0.5 mg·kg(−1)·h(−1). Short-term studies were performed in ventricular myocytes using patch-clamp techniques and optically mapped Langendorff-perfused guinea-pig hearts. Long-term studies were performed using Langendorff-perfused guinea-pig hearts and electrically mapping the receipt of the infusion for 3 hours. RESULTS: Esketamine changed the action potential (AP) morphology of cardiomyocytes. Notably, it increased the resting membrane potential (RMP), attenuated the amplitude of action potential (APA), reduced the maximum upstroke velocity (Vmax), and shortened the action potential duration (APD) at 30% to 70%, which led to relatively prolonged monophasic action potentials (MAP) triangulation in G(0.25) and G(0.5). All the effects were partially eluted. Optical mapping demonstrated almost equal and heterogeneous conduction. G(0.125) resulted in an increased heart rate (HR) accompanied by a shortened APD. No detectable arrhythmia was observed at the cycle lengths (CLs) used. Long-term electrical mapping demonstrated the dose-dependent deceleration of the Vmax and APA, but only prolonged the AP parameters in G(0.5). Left-ventricular isochronal conduction maps revealed the conduction heterogeneities at G(0.5), and conduction velocity (CV) was increased in G(0.125) and G(0.25.) None of these effects were reversed on drug washout. Electrocardiogram (ECG) traces revealed an accelerated HR with the associated curtailment of QT intervals in G(0.125); HRs were decreased in G(0.25 )and G(0.5); the PR intervals and QRS duration differed between G(0.125) and G(0.25), G(0.5), which elicited electrical alternans. Connexin43 (Cx43) expression were significantly decreased in G(0.125), G(0.25) and G(0.5). CONCLUSIONS: These data provide a basic electrophysiology for esketamine. Specifically, we found that (I) various methods of esketamine infusion had different effects on cardiac conduction at different dosages; (II) the heterogeneous expression of Cx43 is associated with spatially dispersed conduction; and (III) potential cardiac risks should be considered for high-risk patients receiving continuous esketamine infusions of high dosages.