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ANESTHETIC PHARMACOLOGY

The Inhibitory Effect of Local Anesthetics on Bradykinin-Induced Phospholipase D Activation in Rat Pheochromocytoma PC12 Cells

Jinen Chen, MD^*, Shuji Dohi, MD, PhD^*, Zhiming Tan, MD, PhD^*, Yoshiko Banno, PhD, and Yoshinori Nozawa, MD, PhD

*Departments of Anesthesiology and Critical Care Medicine and Biochemistry, Gifu University School of Medicine; and Gifu International Institute of Biotechnology, Gifu City, Gifu, Japan

Address correspondence and reprint requests to Shuji Dohi, MD, PhD, Department of Anesthesiology and Critical Care Medicine, Gifu University School of Medicine, Tsukasamachi-40, Gifu City, Gifu 500-8705, Japan. Address e-mail to shu-dohi{at}cc.gifu-u.ac.jp

Bradykinin induces activation of phospholipase D (PLD) via B₂ receptors in neuronal cells. To demonstrate molecular mechanism(s) of local anesthetics, we examined whether and how local anesthetics affect bradykinin-induced PLD activation in PC12 cells. Using [³H]Palmitic acid-labeled PC12 cells stimulated with bradykinin, formation of [³H]phosphatidylbutanol was measured as a variable of PLD activity. Bradykinin-stimulated PLD activity seemed to peak at 2 min. Procaine, lidocaine, ropivacaine, bupivacaine, and tetracaine suppressed the bradykinin-induced PLD activation. We chose tetracaine, the most potent drug among the local anesthetics tested, to examine how local anesthetics affect phospholipase C, protein tyrosine kinase, and extracellular signal-regulated kinase, which are the molecules upstream of PLD. Tetra- caine at clinically relevant concentrations (110 x 10^-4 M) inhibited the bradykinin-induced PLD activation in a dose- and time-dependent manner, but neither tetrodotoxin nor nifedipine affected the PLD activation. Tetracaine (5 x 10^-4 M) slightly potentiated brady-kinin-induced phospholipase C activation. Bradykinin-stimulated protein tyrosine-phosphorylation and extracellular signal-regulated kinase activation were not affected by tetracaine. Tetracaine significantly decreased PLD activity of membrane fraction in PC12 cells. These results indicate that local anesthetics depress bradykinin-induced lipid signaling pathway(s) and may provide some clues to understanding the molecular mechanisms of these drugs for anesthesia or analgesia.

IMPLICATIONS: Local anesthetics depressed the bradykinin-induced activation of phospholipase D (PLD) in PC12 cells. The effects of tetracaine, the most potent among the anesthetics tested, on the bradykinin-induced intracellular signaling molecules were examined. The bradykinin-induced PLD activation could be one of the potential intracellular signaling molecular sites of local anesthetic action.