Ketamine inhibition of cytoplasmic calcium signalling in rat pheochromocytoma (PC-12) cells.
This study examines the mechanism of action of ketamine, a dissociative anesthetic, with a specific focus on its ability to inhibit changes in the concentration of intracellular free calcium, [Ca2+]i, in PC-12 cells. The resting [Ca2+]i as measured with the fluorescent probe Fura-2 AM in control cells is 184.8 +/- 8.6 nM (mean +/- SEM, n = 15). Changes in [Ca2+]i via influx through voltage-gated calcium channels after membrane depolarization with potassium chloride were monitored in the absence and presence of various concentrations of ketamine. Potassium-depolarization caused a dose-dependent rapid increase in [Ca2+]i, averaging 62 +/- 5%, 33 +/- 2% and 18 +/- 3% (n = 10 each) above control levels for 70 mM, 50 mM and 35 mM KCl, respectively. Ketamine, in the dosage range studied (5-500 microM), inhibited the increase in [Ca2+]i stimulated by potassium-depolarization in a dose-dependent manner. The computer-fitted dose-response curve of the pooled data yielded a half maximal suppression concentration, ED50, of 33 microM. In conclusion, this study demonstrates that ketamine inhibits Ca2+ influx through voltage-gated Ca2+ channels in PC-12 cells at clinically relevant doses, and may play a role in ketamine's action as a general anesthetic agent.
Wong
B S
BS
Department of Biomedical Sciences, Baylor College of Dentistry, Dallas, TX 75246.
Martin
C D
CD
D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000502:physiology; D003593:Cytoplasm / Q000378:metabolism; D005110:Extracellular Space / Q000378:metabolism; D007649:Ketamine / Q000494:pharmacology*; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D016716:PC12 Cells; D011188:Potassium / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D007649:Ketamine; D011188:Potassium; D002118:Calcium