INSENSITIVITY OF P-TYPE CALCIUM CHANNELS TO INHALATIONAL AND INTRAVENOUS GENERAL-ANESTHETICS

Background: Voltage-gated Ca2+ channels long have been considered plau sible targets for general anesthetics. Previous anesthetic studies hav e focused on L-, T-, or N-type channels, but there have been no studie s on channels identified as P-type. Since P-type channels may be the m ost important voltage-gated Ca2+ channels involved in synaptic transmi ssion in mammalian brain, it is important to establish their sensitivi ty to clinically relevant concentrations of general anesthetics. Metho ds: Acutely dissociated cerebellar Purkinje neurons were obtained from 7-14-day-old Sprague-Dawley rats. P-type currents were measured using the whole-cell version of the patch-clamp technique, with Ba2+ as the current carrier. General anesthetics were applied to the neurons in a queous solution at room temperature (20-23 degrees C). Results: P-type Ca2+ channels were found to be very insensitive to a variety of gener al anesthetics and ethanol. Inhibitions of less than 10% were produced by 0.35 mM halothane, 0.35 mM isoflurane, 32 mu M thiopental, 50 mu M pentobarbital, 2 mu M propofol, and 200 mM ethanol. Substantial anest hetic inhibition was found only at free aqueous concentrations much gr eater than those that are clinically relevant. For halothane, the dose -response curve showed an IC50 concentration of 1.17 +/- 0.02 mM and a Hill coefficient of 2.02 +/- 0.04 (mean +/- SEM). Conclusions: The re latively small inhibitions of P-type Ca2+ channels produced by volatil e and intravenous anesthetics at their free aqueous EC(50) concentrati ons for general anesthesia in mammals suggest that these channels do n ot play a major role in the induction of general anesthesia.