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Vol. 295, Issue 1, 302-308, October 2000

Mibefradil Block of Cloned T-Type Calcium Channels1

Ruth L. Martin, Jung-Ha Lee, Leanne L. Cribbs, Edward Perez-Reyes and Dorothy A. Hanck

Department of Medicine, The University of Chicago, Chicago, Illinois (R.L.M., D.A.H.); Department of Physiology and Cardiovascular Institute, Loyola University of Chicago, Maywood, Illinois (L.L.C.); and Department of Physiology, University of Virginia, Charlottesville, Virginia (J.-H.L., E.P.-R.)

Mibefradil is a tetralol derivative chemically distinct from other calcium channel antagonists. It is a very effective antihypertensive agent that is thought to achieve its action via a higher affinity block for low-voltage-activated (T) than for high-voltage-activated (L) calcium channels. Estimates of affinity using Ba2+ as the charge carrier have predicted a 10- to 15-fold preference of mibefradil for T channels over L channels. However, T channel IC50 values are reported to be ~1 µM, which is much higher than expected for clinical efficacy because relevant blood levels of this drug are ~50 nM. We compared the affinity for mibefradil of the newly cloned T channel isoforms, alpha 1G, alpha 1H, and alpha 1I with an L channel, alpha 1C. In 10 mM Ba2+, mibefradil blocked in the micromolar range and with 12- to 13-fold greater affinity for T channels than for L channels (~1 µM versus 13 µM). When 2 mM Ca2+ was used as the charge carrier, the drug was more efficacious; the IC50 for alpha 1G shifted to 270 nM and for alpha 1H shifted to 140 nM, 4.5- and 9-fold higher affinity than in 10 mM Ba. The data are consistent with the idea that mibefradil competes for its binding site on the channel with the permeant species and that Ba2+ is a more effective competitor than Ca2+. Raising temperature to 35°C reduced affinity (IC50 792 nM). Reducing channel availability to half increased affinity (~70 nM). This profile of mibefradil affinity makes these channels good candidates for the physiological target of this antihypertensive agent.

1 This research was supported by the National Heart, Lung and Blood Institute, National Institutes of Health Grants HL-PO1-20592 (D.A.H.) and HL-58728 (E.P.-R.) and by a grant-in-aid from the American Heart Association to D.A.H.

0022-3565/00/2951-0302$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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