Alveolar but not intravenous S-ketamine inhibits alveolar sodium transport and lung fluid clearance in rats

BACKGROUND: S-ketamine is frequently used for analgosedation, especially during sepsis and cardiovascular instability. Because S-ketamine blocks voltage-gated sodium (Na+) channels in neurons and skeletal muscle, it is conceivable that S-ketamine also blocks alveolar epithelial Na+ channels that are crucial for alveolar fluid clearance (AFC). We studied the effects of alveolar and IV S-ketamine on transalveolar Na+ transport and AFC, and investigated whether IV S-ketamine enters the alveolar space in response to endotoxemia-induced pulmonary inflammation. METHODS: Cultured rat alveolar type II (ATII) cells were exposed to S-ketamine and/or the Na+ channel blocker amiloride (100 microM) and transepithelial transport indicated by short circuit current (ISC) was measured in Ussing chambers. AFC was measured in fluid-instilled lungs of anesthetized rats with or without amiloride added to the instillate. S-ketamine was either added to the instillate or injected IV. To induce mild lung injury that might favor the appearance of IV S-ketamine at the alveolar surface, endotoxemia was induced by IV lipopolysaccharide (7.5 mg/kg). RESULTS: In ATII cells, S-ketamine (25 microg/mL) caused a decrease of ISC regardless of apical (-18.9%+/- 1.4%; P <0.001) or basolateral (-20.4% +/- 3.7%; P <0.001) application. In ATII cells pretreated with amiloride, addition of apical or basolateral S-ketamine did not decrease ISC. AFC was approximately 8% per 30 minutes in control rats. S-ketamine (5 microg/mL) in the instillate reduced AFC to 1.1% +/- 1.5% (P = 0.04) by decreasing amiloride-sensitive transepithelial Na+ transport. Intravenous S-ketamine (20 mg/kg) did not affect AFC (P = 0.31). In the presence of lipopolysaccharide-induced inflammation, the concentration of IV-injected S-ketamine in bronchoalveolar lavage fluid remained below the concentration that inhibited AFC. CONCLUSIONS: Although exposure of the rat alveolar epithelium to S-ketamine decreases amiloride-sensitive transalveolar Na+ transport and AFC, IV S-ketamine at clinically relevant bolus concentrations does not affect AFC, even in the presence of mild lung injury