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.