Identification of R(−)‐isomer of efonidipine as a selective blocker of T‐type Ca²⁺ channels

Abstract

1 Efonidipine, a derivative of dihydropyridine Ca 2 þ antagonist, is known to block both L-and T-type Ca 2 þ channels. It remains to be clarified, however, whether efonidipine affects other voltagedependent Ca 2 þ channel subtypes such as N-, P/Q-and R-types, and whether the optical isomers of efonidipine have different selectivities in blocking these Ca 2 þ channels, including L-and T-types. 2 To address these issues, the effects of efonidipine and its R(À)-and S( þ )-isomers on these Ca 2 þ channel subtypes were examined electrophysiologically in the expression systems using Xenopus oocytes and baby hamster kidney cells (BHK tk-ts13). 3 Efonidipine, a mixture of R(À)-and S( þ )-isomers, exerted blocking actions on L-and T-types, but no effects on N-, P/Q-and R-type Ca 2 þ channels. 4 The selective blocking actions on L-and T-type channels were reproduced by the S( þ )-efonidipine isomer. 5 By contrast, the R(À)-efonidipine isomer preferentially blocked T-type channels. 6 The blocking actions of efonidipine and its enantiomers were dependent on holding potentials. 7 These findings indicate that the R(À)-isomer of efonidipine is a specific blocker of the T-type Ca 2 þ channel.

Species Difference in the Contribution of T-Type Calcium Current to Cardiac Pacemaking as Revealed by R(−)-Efonidipine

“…The molecular identity of the Ttype Ca 2+ current in the sinoatrial node in each of the species used in the present study has not yet been established, although the abundance of α 1G in the mouse has been reported (16). Concerning the inhibitory action of R(−)-efonidipine, an IC 50 value of 0.9 μM was reported with expressed α 1G (12), and an IC 50 value of 0.35 μM was reported for efonidipine on α 1H channels (17). Thus, the inhibitory potency of R(−)-efonidipine for the two channel subtypes are roughly the same, indicating that species difference in the subtypes would not affect the total inhibitory potency of R(−)-efonidipine on T-type Ca 2+ channels in the sinoatrial node.…”

“…In isolated cardiomyocytes, 10 −6 M R(−)-efonidipine blocked the T-type Ca 2+ current by 85% while it had no effect on the L-type Ca 2+ current (13). (±)-Efonidipine (10 −6 M) had no effect on other major ionic currents in the myocardium (9,12). Thus, R(−)-efonidipine (10 −6 M) is the first specific blocker of the T-type Ca 2+ channel and would be a useful pharmacological tool to examine the contribution of the T-type Ca 2+ channel in various cellular functions.…”

“…Recently, the R(−)-enantiomer of efonidipine was found to block the T-type Ca 2+ current much more potently than the L-type one based on voltage clamp experiments (12,13). In isolated cardiomyocytes, 10 −6 M R(−)-efonidipine blocked the T-type Ca 2+ current by 85% while it had no effect on the L-type Ca 2+ current (13).…”

The T-type Ca2+ Channel Inhibitor Mibefradil Inhibits Voltage-Dependent K+ Channels in Rabbit Coronary Arterial Smooth Muscle Cells

“…Several functional studies in both basic and clinical areas indicated that the blockade of T-type Ca 2+ channels using mibefradil effectively controlled hypertension and ischemic heart disease (2,4,5). Unfor-tunately, this drug was withdrawn from the market because it inhibited cytochrome P450 enzymes (antihistamines), leading to drug-drug interactions (6 -8 (9,10).…”

The Ca2+ Channel Iinhibitor NNC 55-0396 Inhibits Voltage-Dependent K+ Channels in Rabbit Coronary Arterial Smooth Muscle Cells

“…Mibefradil, a tetralol derivative, was developed as a specific T-type Ca 2+ -channel inhibitor in the 1990s (15). Although this drug effectively reduced hypertension and ameliorated ischemic heart disease (14,16,17), it also inhibited L-type Ca 2+ channels via the production of an active metabolite through intracellular hydrolysis (18 (21,22). Among these, the K V channel plays a key role in regulating resting membrane potential and thereby maintaining basal vascular tone (21,23,24).…”