Actions of Mibefradil, Efonidipine and Nifedipine Block of Recombinant T- and L-Type Ca²⁺ Channels with Distinct Inhibitory Mechanisms

Abstract

We compared detailed efficacy of efonidipine and nifedipine, dihydropyridine analogues, and mibefradil using recombinant T- and L-type Ca²⁺ channels expressed separately in mammalian cells. All these Ca²⁺ channel antagonists blocked T-type Ca²⁺ channel currents (I_Ca(T)) with distinct blocking manners: I_Ca(T) was blocked mainly by a tonic manner by nifedipine, by a use-dependent manner by mibefradil, and by a combination of both manners by efonidipine. IC₅₀s of these Ca²⁺ channel antagonists to I_Ca(T) and L-type Ca²⁺ channel current (I_Ca(L)) were 1.2 µmol/l and 0.14 nmol/l for nifedipine; 0.87 and 1.4 µmol/l for mibefradil, and 0.35 µmol/l and 1.8 nmol/l for efonidipine, respectively. Efonidipine, a dihydropyridine analogue, showed high affinity to T-type Ca²⁺ channel.

Protein kinase a regulation of T-type Ca2+ channels in rat cerebral arterial smooth muscle

“…Interestingly, the whole-cell Ba 2+ current could be abolished by nifedipine if concentrations were elevated into the micromolar range, ,500-5000X above the IC 50 for Ca V 1.2. This observation was expected, as past studies have documented that T-type Ca 2+ channels are sensitive to this dihyropyridine in this elevated micromolar concentration range (Akaike et al, 1989;Lee et al, 2006). This study and previous investigations have shown that nifedipine-insensitive currents, comparable to those in the preceding paragraph, are blocked by broad spectrum T-type inhibitors such as mibefradil, NNC 55-0396, efonidipine and kurtoxin (Kuo et al, 2010;El-Rahman et al, 2013).…”

“…Note that nifedipine concentrations in the micromolar range did evoke full blockade of the whole-cell current (Fig. 2A); this was an expected result as earlier studies have reported T-type channel sensitivity to dihydropyridine in this concentration range (Akaike et al, 1989;Lee et al, 2006). As depicted in the Fig.…”

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.…”

Impact of renal function on cardiovascular events in elderly hypertensive patients treated with efonidipine

“…26 Indeed, the use of these types of Ca channel blockers in CKD raises concerns because of the potential aggravation of glomerular hypertension, possibly as a result of preferential afferent arteriolar dilation. 16 By contrast, novel types of Ca channel blockers, including efonidipine and benidipine, which possess T-type Ca channel blocking activity, 27,28 confer a greater benefit on renal function. 23,[29][30][31] Of interest, efonidipine possesses renal protective action via efferent arteriolar dilation, [17][18][19][20] the inhibition of Rho kinase 32 and, possibly, the inhibition of aldosterone activity.…”