Ketamine inhibits sodium currents in identified cardiac parasympathetic neurons in nucleus ambiguus

Background: Ketamine increases both blood pressure and heart rate, effects commonly thought of as sympathoexcitatory. The authors investigated the possibility that ketamine increases heart rate by inhibiting the central cardiac parasympathetic mechanisms. Methods: We used a novel in vitro approach to study the effect of ketamine on the identified cardiac parasympathetic preganglionic neurons in rat brainstem slices. The cardiac parasympathetic neurons in the nucleus ambiguus were retrogradely prelabeled with the fluorescent tracer by placing rhodamine into the pericardial sac. Dye-labeled neurons were visually identified for patch clamp recording, and ketamine effects on isolated potassium (K ⁺) and sodium (Na ⁺) currents were studied. Results: Cardiac nucleus ambiguus neurons (n = 14) were inherently silent, but depolarization evoked sustained action potential trains with little delay or adaptation. Ketamine (10 μM) reduced this response but had no effect on the voltage threshold for action potentials (n = 14; P > 0.05). The current-voltage relations for the transient K ⁺ current and the delayed rectified K ⁺ current (n = 5) were unaltered by ketamine (10 μM-1 mM). Ketamine depressed the total Na ⁺ current dose-dependently (10 μM-1 mM). In addition, ketamine shifted the Na ⁺ current inactivation curves to more negative potentials, thus suggesting the enhancement of the Na ⁺ channel inactivation (P < 0.05; n = 7). In the presence of Cd ²⁺, ketamine (10 μM) continued to inhibit voltage-gated Na ⁺ currents, which recovered completely within 10 min. Conclusions: Ketamine inhibits Na ⁺ but not K ⁺ channel function in brainstem parasympathetic cardiac neurons, and such actions may mediate the decrease in parasympathetic cardiac activity and increase in heart rate that occurs with ketamine.