Ketamine suppresses norepinephrine-induced inositol 1,4,5-trisphosphate formation via pathways involving protein kinase C.
Inositol 1,4,5-trisphosphate (IP(3)) is not only involved in the physiologic regulation of excitation-contraction coupling, but could also play a role in cardiac pathophysiology. We investigated the mechanism of ketamine modulation of norepinephrine (NE)-induced IP(3) formation in neonatal rat cardiomyocytes. Ketamine 1 and 10 microM significantly decreased the IP(3) response to 1 microM NE by 27% and 43%, respectively. One micromolar TMB-8 (an intracellular calcium antagonist) produced 42% more decreases in IP(3) production than produced by ketamine alone. One hundred micromolar anthranilic acid (a phospholipase A(2) inhibitor) significantly decreased NE (1 microM)-induced IP(3) formation, and the inhibition was further enhanced by ketamine. Ten micromolar U 73122 (a phospholipase C inhibitor) did not significantly affect NE-induced IP(3) in the presence or absence of ketamine. One micromolar ketamine significantly inhibited staurosporine (a nonselective protein kinase C antagonist)-, bisindolylmaleimide (a selective protein kinase C antagonist)-, and wortmannin (a phosphatidylinositide 3-kinase antagonist)-stimulated IP(3) formation. In conclusion, ketamine suppresses NE-induced IP(3) production, and the inhibition is caused through pathways including protein kinase C and a decrease in intracellular Ca(2+) concentrations.


CONCLUSIONS
Ketamine inhibits norepinephrine-induced inositol 1,4,5-triphosphate formation in a dose-dependent manner via pathways that involve protein kinase C and a decrease in intracellular Ca(2+) concentrations.
Kudoh
Akira
A
Department of Anesthesiology, Hirosaki National Hospital, Hirosaki, Japan.
Kudoh
Emiko
E
Katagai
Hiroshi
H
Takazawa
Tomoko
T
D000778:Anesthetics, Dissociative / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis*; D007649:Ketamine / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology*; D010741:Phospholipases A / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology*; D051381:Rats; D010738:Type C Phospholipases / Q000502:physiology; D062367:ortho-Aminobenzoates / Q000494:pharmacology
D000778:Anesthetics, Dissociative; D062367:ortho-Aminobenzoates; C031385:anthranilic acid; D007649:Ketamine; D015544:Inositol 1,4,5-Trisphosphate; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D010741:Phospholipases A; D010738:Type C Phospholipases; D002118:Calcium; D009638:Norepinephrine