KETAMINE INHIBITION OF CYTOPLASMIC CALCIUM SIGNALING IN RAT PHEOCHROMOCYTOMA (PC-12) CELLS

This study examines the mechanism of action of ketamine, a dissociativ e 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). Cha nges in [Ca2+]i via influx through voltage-gated calcium channels afte r membrane depolarization with potassium chloride were monitored in th e absence and presence of various concentrations of ketamine. Potassiu m-depolarization caused a dose-dependent rapid increase in [Ca2+]i, av eraging 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 muM), inhibited the increase in [Ca2+]i stimulated by potassium-depolarization in a dose-dependent manner. Th e computer-fitted dose-response curve of the pooled data yielded a hal f maximal suppression concentration, ED50, of 33 muM. In conclusion, t his study demonstrates that ketamine inhibits Ca2+ influx through volt age-gated Ca2+ channels in PC-12 cells at clinically relevant doses, a nd may play a role in ketamine's action as a general anesthetic agent.