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Vol. 292, Issue 1, 96-103, January 2000

Effect of Mibefradil on Voltage-Dependent Gating and Kinetics of T-Type Ca2+ Channels in Cortisol-Secreting Cells

Juan Carlos Gomora, Lin Xu, Judith A. Enyeart and John J. Enyeart1

Department of Pharmacology (J.C.G., L.X., J.A.E., J.J.E.) and The Neuroscience Program (J.J.E.), The Ohio State University, College of Medicine and Public Health, Columbus, Ohio

We have studied the effect of the Ca2+ antagonist mibefradil on low voltage-activated T-type Ca2+ channels in whole-cell patch clamp recordings from bovine adrenal zona fasciculata (AZF) cells. AZF cells are distinctive in expressing only T-type Ca2+ channels, allowing the mechanism of pharmacological agents to be explored without interference from other Ca2+ channels. The inhibition of T-type Ca2+ channels by mibefradil was voltage- and use-dependent. When Ca2+ currents were activated from holding potentials of -80 and -60 mV, mibefradil inhibited currents with IC50 values of 1.0 and 0.17 µM, respectively. When T-type Ca2+ current (IT) was activated from a holding potential of -90 mV in the presence of 2 µM mibefradil, a single voltage step to -10 mV inhibited IT by 16.2% ± 2.9% (n = 10). With subsequent voltage steps, applied at 10-s intervals, block reached a steady-state value of 51.9% ± 5.0% (n = 5). Mibefradil (1 µM) produced a leftward shift of 5.7 mV (n = 4) in the voltage-dependent steady-state availability curve such that T-type Ca2+ channels inactivated at more negative potentials, but this drug did not change the voltage-dependence of T channel opening. Mibefradil failed to alter the kinetics of T channel activation, inactivation, or deactivation, but markedly slowed T channel recovery following an inactivating prepulse. Mibefradil inhibited adrenocorticotropin-stimulated cortisol secretion from AZF cells with an IC50 value of 3.5 µM. These results show that mibefradil is a relatively potent antagonist of T-type Ca2+ channels in cortisol-secreting cells. The enhanced potency of mibefradil with sustained or repetitive depolarizations, its shifting of the steady-state inactivation curve, and its slowing of recovery all indicate that this drug preferentially interacts with Ca2+ channels in the open or inactivated state. The inhibition of cortisol secretion by mibefradil at concentrations similar to those that block IT is consistent with a requirement for these channels in corticosteroidogenesis.

1 J.J.E. was supported by National Institute of Diabetes and Digestive and Kidney Grant DK-47875 and by National American Heart Association Grant-in-Aid 94011740.

0022-3565/0/2921-0096$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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