Ketamine inhibits agonist-induced cAMP accumulation increase in human airway smooth muscle cells.
OBJECTIVE
Cyclic 3',5' adenosine monophosphate (cAMP) is a second messenger of the beta adrenergic receptor (betaAR). Ketamine causes an increase in the intracellular accumulation of cAMP in several non-human tissue preparations. A "species effect" may explain the differing results of ketamine on betaAR mediated responses, thus reports of a ketamine-induced increase in cAMP in other species may not be applicable to humans.


METHODS
The effect of ketamine (10(-3), 10(-4), or 10(-5) M) pretreatment (60 and 120 min) on isoproterenol [ISO, a beta adrenergic receptor (AR) agonist] or forskolin [FSK, an activator of adenylylcyclase (AC)]-induced intracellular accumulation of cAMP in a human airway smooth muscle (tracheal) cell line (HASM) was evaluated. In an in vitro HASM culture, cells with or without pretreatment were labeled with [3H]adenine to produce [3H]ATP, and following stimulation with ISO or FSK to convert the [3H]ATP to [3H]cAMP, the intracellular accumulation of [3H]cAMP was measured by sequential chromatography over Dowex and alumina columns.


RESULTS
Pretreatment of the HASM cells with ketamine (10(-3) and 10(-4) M) caused a reduction (P < 0.05, when compared to untreated cells) in ISO-induced cAMP accumulation, but did not effect cAMP accumulation following FSK stimulation. This effect of ketamine was greater at 120 min of pretreatment than at 60 min (10(-3) M ketamine only)(P < 0.05). No effect was found at either time period following pretreatment of the HASM cells with ketamine 10(-5) M.


CONCLUSIONS
These results demonstrate that pretreatment of the HASM cells with ketamine reduces ISO-induced cAMP accumulation. Since only ISO-induced cAMP was effected by ketamine, these data suggest that ketamine inhibits production of cAMP proximal to AC in the cAMP production pathway. These results also demonstrate that a mechanism other than that involving the betaAR and intracellular cAMP accumulation is responsible for the ketamine induced bronchodilation in humans.
Hill
G E
GE
Department of Anesthesiology, University of Texas Southwestern Medical Center at Dallas, 75235-9068, USA. gary.hill@email.swmed.edu
Anderson
J L
JL
Whitten
C W
CW
D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000778:Anesthetics, Dissociative / Q000494:pharmacology*; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000819:agonists* / Q000378:metabolism*; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D007649:Ketamine / Q000494:pharmacology*; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D014132:Trachea / Q000166:cytology / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D000778:Anesthetics, Dissociative; D005576:Colforsin; D007649:Ketamine; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D007545:Isoproterenol