Ketamine inhibits lung fluid clearance through reducing alveolar sodium transport

Abstract

Ketamine is a broadly used anaesthetic for analgosedation. Accumulating clinical evidence shows that ketamine causes pulmonary edema with unknown mechanisms. We measured the effects of ketamine on alveolar fluid clearance in human lung lobes ex vivo. Our results showed that intratracheal instillation of ketamine markedly decreased the reabsorption of 5% bovine serum albumin instillate. In the presence of amiloride (a specific ENaC blocker), fluid resolution was not further decreased, suggesting that ketamine could decrease amiloride-sensitive fraction of AFC associated with ENaC. Moreover, we measured the regulation of amiloride-sensitive currents by ketamine in A549 cells using whole-cell patch clamp mode. Our results suggested that ketamine decreased amiloride-sensitive Na+ currents (ENaC activity) in a dose-dependent fashion. These data demonstrate that reduction in lung ENaC activity and lung fluid clearance following administration of ketamine may be the crucial step of the pathogenesis of resultant pulmonary edema.

Figure 1

Effects of ketamine on alveolar fluid clearance in isolated human lungs. (a) Lungs were treated with 5% bovine serum albumin dissolved in physiologic saline solution in the absence of drugs (control), in the presence of amiloride (1 mM), ketamine (100 μM), and both (Keta + Amil). %AFC₆₀ represents the AFC percentage after 60 min. (b) Amiloride-sensitive (AS) AFC. Average AFC values are presented as the mean ± SEM, one-way ANOVA. *P < 0.05, **P < 0.01. n = 5-6.

Figure 2

Patch clamp recordings of amiloride-sensitive currents in A549 cells. (a) Representative recordings of amiloride-sensitive current traces in a cell before (control) and after delivery of different concentrations of ketamine (30 μM to 1 mM) to the bath. (b) Concentration-dependent inhibition of whole-cell currents by ketamine. For each cell, inward currents recorded at −100 mV were measured during perfusion with external solutions. Amiloride-sensitive (AS) currents were normalized to the current at −100 mV of control. IC₅₀ was calculated by best fitting the raw data points to the Hill equation. Inorm = 1/(1 + (ketamine/IC₅₀))^coe. (c) Amiloride-sensitive current density- (ASI_density-) voltage curves for average control currents (control), in the presence of different concentrations of ketamine (30 μM to 1 mM). Average values are presented as the mean ± SEM. One-way ANOVA. *P < 0.05, n = 7.