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CARDIOVASCULAR ANESTHESIA

Ketamine Suppresses Norepinephrine-Induced Inositol 1,4,5-Trisphosphate Formation Via Pathways Involving Protein Kinase C

Akira Kudoh, MD^*, Emiko Kudoh, MD, Hiroshi Katagai, MD^*, and Tomoko Takazawa, MD^*

Departments of *Anesthesiology and Pediatrics, Hirosaki National Hospital, Hirosaki, Japan

Address correspondence and reprint requests to Akira Kudoh, MD, Department of Anesthesiology, Hirosaki National Hospital, 1 Tominocho, Hirosaki 036-8545, Aomori, Japan.

Inositol 1,4,5-trisphosphate (IP₃) 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 IP₃ formation in neonatal rat cardiomyocytes. Ketamine 1 and 10 µM significantly decreased the IP₃ response to 1 µM NE by 27% and 43%, respectively. One micromolar TMB-8 (an intracellular calcium antagonist) produced 42% more decreases in IP₃ production than produced by ketamine alone. One hundred micromolar anthranilic acid (a phospholipase A₂ inhibitor) significantly decreased NE (1 µM)-induced IP₃ formation, and the inhibition was further enhanced by ketamine. Ten micromolar U 73122 (a phospholipase C inhibitor) did not significantly affect NE-induced IP₃ 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 IP₃ formation. In conclusion, ketamine suppresses NE-induced IP₃ production, and the inhibition is caused through pathways including protein kinase C and a decrease in intracellular Ca²⁺ concentrations.

IMPLICATIONS: 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 Ca²⁺ concentrations.

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999