Abstract
Purpose
Cyclic 3′,5′ adenosine monophosphate (cAMP) is a second messenger of the beta adrenergic receptor (BAR). 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 BAR 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 10−5M.
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 BAR and intracellular cAMP accumulation is responsible for the ketamine induced bronchodilation in humans.
Résumé
Objectif
L’adénosine monophosphate-3′, 5′ cyclique (AMPc) est un second messager du récepteur bêta-adrénergique (RBA). La kétamine augmente l’accumulation intracellulaire d’AMPc dans certaines préparations de tissus non humains. Un «effet lié à l’espèce» peut expliquer les différentes réactions de la kétamine sur les réponses à médiation RBA. L’augmentation d’AMPc induite par la kétamine pourrait donc ne pas s’appliquer aux humains.
Méthode
On a évalué l’effet du prétraitement (60 ou 120 min) de kétamine ( 10−3, 10−4, ou 10−5 M) sur l’accumulation intracellulaire d’AMPc induite par l’isoprotérénol [ISO, un agohiste des récepteurs bêta-adrénergiques (RBA)] ou par la forskoline [FSK, un activateur de l’adényl-cyclase (AC)] dans une lignée cellulaire de muscle lisse (trachéal) humain des voies aériennes (MLHVA). Les cellules, prétraitées ou non, d’une culture in vitro de MLHVA ont été marquées avec de l’adénine [3H] afin de produire de l’ATP [3H] et, à la suite de la stimulation avec l’ISO ou la FSK pour convertir l’ATP [3H] en AMPc[3H], l’accumulation intracellulaire d’AMPc[3H] a été mesurée par Chromatographie séquentielle sur des colonnes Dowex et d’alumine.
Résultats
Le prétraitement de cellules de MLHVA avec la kétamine (10−3 et 10−4 M) a réduit l’accumulation d’AMPc induite par l’ISO, mais n’a pas eu d’effet sur l’accumulation d’AMPc (P < 0,05 comparé aux cellules non traitées) à la suite d’une stimulation avec la FSK. Cet effet de la kétamine a été plus important à 120 min de prétraitement qu’à 60 min (kétamine 10−3 M seulement) (P < 0,05). Aucun effet n’a été enregistré aux temps repères suivant le prétraitement des cellules de MLHVA avec la kétamine 10−5M.
Conclusion
Ces résultats démontrent que le prétraitement des cellules MLHVA avec la kétamine réduit l’accumulation d’AMPc induite par l’ISO. Puisque seule l’AMPc induite par l’ISO a subi l’effet de la kétamine, on peut penser que la kétamine inhibe la production d’AMPc en amont de l’AC dans la chaîne de production de l’AMPc. On peut aussi conclure qu’un mécanisme autre que celui qui implique le RA et l’accumulation intracellulaire d’AMPc est
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Hill, G.E., Anderson, J.L. & Whitten, C.W. Ketamine inhibits agonist-induced cAMP accumulation increase in human airway smooth muscle cells. Can J Anesth 46, 1172–1177 (1999). https://doi.org/10.1007/BF03015528
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DOI: https://doi.org/10.1007/BF03015528