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Research ArticleCARDIOVASCULAR

Mibefradil Block of Cloned T-Type Calcium Channels

Ruth L. Martin, Jung-Ha Lee, Leanne L. Cribbs, Edward Perez-Reyes and Dorothy A. Hanck
Journal of Pharmacology and Experimental Therapeutics October 2000, 295 (1) 302-308;
Ruth L. Martin
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Jung-Ha Lee
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Leanne L. Cribbs
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Edward Perez-Reyes
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Dorothy A. Hanck
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Abstract

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 IC50values 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, α1G, α1H, and α1I with an L channel, α1C. 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 α1G shifted to 270 nM and for α1H 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.

Footnotes

  • Send reprint requests to: D. A. Hanck, Ph.D., Cardiology (MC6094), University of Chicago, 5841 South Maryland Ave., Chicago, IL 60637. E-mail: d-hanck{at}uchicago.edu

  • ↵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.

  • Abbreviations:
    hMTC
    human medullary thyroid carcinoma
    • Received March 13, 2000.
    • Accepted June 30, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 295 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 295, Issue 1
1 Oct 2000
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Research ArticleCARDIOVASCULAR

Mibefradil Block of Cloned T-Type Calcium Channels

Ruth L. Martin, Jung-Ha Lee, Leanne L. Cribbs, Edward Perez-Reyes and Dorothy A. Hanck
Journal of Pharmacology and Experimental Therapeutics October 1, 2000, 295 (1) 302-308;

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Research ArticleCARDIOVASCULAR

Mibefradil Block of Cloned T-Type Calcium Channels

Ruth L. Martin, Jung-Ha Lee, Leanne L. Cribbs, Edward Perez-Reyes and Dorothy A. Hanck
Journal of Pharmacology and Experimental Therapeutics October 1, 2000, 295 (1) 302-308;
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