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

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.