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J Neurophysiol 79: 240-252, 1998;
0022-3077/98 $5.00
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The Journal of Neurophysiology Vol. 79 No. 1 January 1998, pp. 240-252
Copyright ©1998 The American Physiological Society

Pharmacological Properties of T-Type Ca2+ Current in Adult Rat Sensory Neurons: Effects of Anticonvulsant and Anesthetic Agents

Slobodan M. Todorovic and Christopher J. Lingle

Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110

Todorovic, Slobodan M. and Christopher J. Lingle. Pharmacological properties of T-type Ca2+ current in adult rat sensory neurons: effects of anticonvulsant and anesthetic agents. J. Neurophysiol. 79: 240-252, 1998. We have used the whole cell patch-clamp method to study pharmacological properties of low-voltage-activated (LVA) Ca2+ current in freshly dissociated neurons from dorsal root ganglia of adult rats. Inward barium current [in the presence of internal fluoride to reduce L-type high-voltage-activated (HVA) and external 1 µM omega -conotoxin GVIA to blockN-type HVA current] was evoked from negative holding potentials of -90 mV to test potentials of -25 mV and showed complete inactivation during 200-ms test pulses. Amiloride blocked ~90% of current with half-maximal block (EC50) of 75 µM and a Hill coefficient (n) of 0.99. LVA current was blocked completely by inorganic Ca2+ channel blockers: lanthanum (EC50 = 0.53 µM) > zinc (EC50 = 11.3 µM) > cadmium (EC50 = 20 µM)> nickel (EC50 = 51 µM). The antiepileptics, ethosuximide (EC50 = 23.7 mM, n = 1.4), phenytoin (EC50 = 7.3 µM, n = 1.3), alpha -methyl-alpha -phenylsuccinimide (EC50 = 170 µM, n = 2.1), and valproic acid (EC50 = 330 µM, n = 1.9) maximally blocked ~100, 60, 26, and 17% of T current, respectively. Another antiepileptic, carbamazepine (<= 100 µM), and convulsants such as pentylenetetrazole (1 mM) and tert-butyl-bicyclo [2.2.2] phosphorothionate (50 µM) had no effect on T current. Barbiturates completely blocked T current: thiopental (EC50 = 153 µM, n =1.2) > pentobarbital (EC50 = 334 µM, n = 1.2) > methohexital (EC50 = 502 µM, n = 1.3) > phenobarbital (EC50 = 1.7 mM, n = 1.2). Blockade by thiopental and pentobarbital did not show voltage or use dependence. General anesthetics blocked T current completely and reversibly: propofol (EC50 = 12.9 µM, n = 1.3) > octanol(EC50 = 122 µM, n = 1.2) > etomidate (EC50 = 205 µM, n =1.3) > isoflurane (EC50 = 303 µM, n = 2.3) > halothane (EC50 = 655 µM, n = 2.0) > ketamine (EC50 = 2.5 mM, n = 1.1). Mibefradil, a novel Ca2+ channel blocker, blocked dorsal root ganglion T current in a voltage- and use-dependent fashion with an EC50 of ~3 µM(n = 1.3). When compared with results on other T currents, these data indicate that significant differences exist among different T currents in terms of pharmacological sensitivities. Furthermore, differences in pharmacological sensitivity of T currents among peripheral neurons, CNS, and neuroendocrine cells may contribute to the spectrum of effects of particular analgesic, anticonvulsant, and anesthetic drugs.




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