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.
Berger
Marc M
MM
Department of Anesthesiology, University Hospital Heidelberg, Heidelberg, Germany.
Pitzer
Bernhard
B
Zügel
Stefanie
S
Wieland
Catharina W
CW
Vlaar
Alexander P
AP
Schultz
Marcus J
MJ
Dahan
Albert
A
Bärtsch
Peter
P
Hollmann
Markus W
MW
Mairbäurl
Heimo
H
D000778:Anesthetics, Dissociative / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001273:Atmosphere Exposure Chambers; D001826:Body Fluids / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002469:Cell Separation; D002478:Cells, Cultured; D019446:Endotoxemia / Q000097:blood; D007275:Injections, Intravenous; D007649:Ketamine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism*
D000778:Anesthetics, Dissociative; D008070:Lipopolysaccharides; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D007649:Ketamine; D012964:Sodium; C033419:norketamine