Frequency-dependent blockade of T-type Ca2+ current by efonidipine in cardiomyocytes

ArticleinLife Sciences 68(3):345-51 · January 2001with2 Reads
DOI: 10.1016/S0024-3205(00)00932-2 · Source: PubMed
Efonidipine is a dihydropyridine Ca2+ antagonist with inhibitory effects on both L-type and T-type Ca2+ channels and potent bradycardiac activity especially in patients with high heart rate. In the present study, we examined the frequency dependence of efonidipine action on the T-type Ca2+ channel in isolated guinea-pig ventricular myocytes. The potency of efonidipine to inhibit the T-type Ca2+ current was higher under higher stimulation frequencies. The IC50 values were 1.3 x 10(-8), 2.0 x 10(-6) and 6.3 x 10(-6) M under stimulation frequencies of 1, 0.2 and 0.05 Hz, respectively. The reduction of T-type Ca2+ current amplitude was not accompanied by change in the time course of current decay. Efonidipine (10 microM) inhibited T-type Ca2+ current elicited by depolarization from holding potentials ranging from -90 to -30 mV by about 30%; the voltage-dependence of steady-state inactivation was not changed by the drug. Efonidipine slowed the recovery from inactivation following an inactivating prepulse. In conclusion, efonidipine was shown to have frequency-dependent inhibitory effects on the T-type Ca2+ channel, which could be explained by slow dissociation of the drug from the inactivated state of the channel.
    • "For example, efonidipine blocked recombinant L-type channels with an IC 50 value of approximately 2 nmol/L in one study (Lee et al. 2006), whereas in another study using a similar voltage protocol (Furukawa et al. 2004) efonidipine as well as its S(+)-enantiomer blocked the expressed L-type currents with an IC 50 of approximately 1 mmol/L. The variability in its reported effects between studies may arise because the potency of this drug against Ca 2+ channels is affected not only by the type of cell in which the current is expressed (Furukawa et al. 2004 ), but also because its efficacy increases with the frequency of applied depolarizations (Masumiya et al. 2000). The application of high-K + solution to intact arterioles does not constitute high-frequency stimulation ; nonetheless, we cannot compare our Ca 2+ influx data directly with the reported electrophysiologic data. "
    [Show abstract] [Hide abstract] ABSTRACT: The largest peripheral blood pressure drop occurs in terminal arterioles (<40 microm lumen diameter). L-type voltage-dependent Ca2+ channels (VDCCs) are considered the primary pathway for Ca2+ influx during physiologic activation of vascular smooth muscle cells (VSMC). Recent evidence suggests that T-type VDCCs are expressed in renal afferent and efferent arterioles, mesenteric arterioles, and skeletal muscle arterioles. T-type channels are small-conductance, low voltage-activated, fast-inactivating channels. Thus, their role in supplying Ca2+ for contraction of VSMC has been disputed. However, T-type channels display non-inactivating window currents, which may play a role in sustained Ca2+ entry. Here, we review the possible role of T-type channels in vasomotor tone regulation in rat mesenteric terminal arterioles. The CaV3.1 channel was immunolocalized in VSMC, whereas the CaV3.2 channel was predominantly expressed in endothelial cells. Voltage-dependent Ca2+ entry was inhibited by the new specific T-type blockers R(-)-efonidipine and NNC 55-0396. The effect of NNC 55-0396 persisted in depolarized arterioles, suggesting an unusually high activation threshold of mesenteric T-type channels. T-type channels were not necessary for conduction of vasoconstriction, but appear to be important for local electromechanical coupling in VSMC. The first direct demonstration of endothelial T-type channels warrants new investigations of their role in vascular biology.
    Full-text · Article · Feb 2009
    • "It has been shown that some calcium antagonists demonstrate a general affinity for blocking both I Ca.L and I Ca.T . For example, bepridil (Yatani et al., 1986; Uchino et al., 2005), mibefradil (Mehrke et al., 1994), and efonidipine (Masumiya et al., 1998Masumiya et al., , 2000) block I Ca.L and I Ca.T with different efficacies and affinities. Lubic et al. (1994) studied the interaction of amiodarone with receptors for the 1,4-dihydropyri- dine in rat and rabbit myocardial membranes and found that amiodarone completely inhibited the specific binding to myocardial membrane receptors by 1,4-dihydropyridine Ca 2 channel blockers. "
    [Show abstract] [Hide abstract] ABSTRACT: Low-voltage-activated T-type Ca2+ channels have been recognized recently in the mechanisms underlying atrial arrhythmias. However, the pharmacological effects of amiodarone on the T-type Ca2+ channel remain unclear. We investigated short- and long-term effects of amiodarone on the T-type (Cav 3.2) Ca2+ channel. The Cav3.2 alpha1H subunit derived from human heart was stably transfected into cells [human embryonic kidney (HEK)-Cav3.2] cultured with or without 5 muM amiodarone. Patch-clamp recordings in the conventional whole-cell configuration were used to evaluate the actions of amiodarone on the T-type Ca2+ channel current (ICa.T). Amiodarone blockade of ICa.T occurred in a dose- and holding potential-dependent manner, shifting the activation and the steady-state inactivation curves in the hyperpolarization direction, when amiodarone was applied immediately to the bath solution. However, when the HEK-Cav3.2 cells were incubated with 5 microM amiodarone for 72 h, ICa.T density was significantly decreased by 31.7+/-2.3% for control,-93.1+/-4.3 pA/pF (n=8), versus amiodarone,-56.5+/-3.2 pA/pF (n=13), P<0.001. After the prolonged administration of amiodarone, the activation and the steady-state inactivation curves were shifted in the depolarization direction by -7.1 (n=41) and -5.5 mV (n=37), respectively, and current inactivation was significantly delayed [time constant (tau): control, 13.3+/-1.1 ms (n=6) versus amiodarone, 39.6+/-5.5 ms (n=6) at -30 mV, P<0.001)]. Nevertheless, short-term inhibitory effects of amiodarone on the modified T-type Cav3.2 Ca2+ channel created by long-term amiodarone treatment were functionally maintained. We conclude that amiodarone exerts its short- and long-term inhibitory actions on ICa.T via distinct blocking mechanisms.
    Article · May 2006
    • "Inhibition is frequency-dependent, with an increasing potency at higher stimulation frequencies. In fact, in myocardial cells, efonidipine was shown to inhibit native T-type calcium currents in a frequency-dependent manner with IC 50 values of 13 nM, 2 mM, and 6.3 mM with stimulation frequencies of 1, 0.2, and 0.05 Hz, respec- tively [Masumiya et al., 2000]. Clinically, efonidipine decreases heart rate and has favourable effects on the nervous system supporting its significance in improving the prognosis in patients with hypertension and its protective influence on the heart and other organs [Harada et al., 2003]. "
    [Show abstract] [Hide abstract] ABSTRACT: It has become generally accepted that presynaptic high voltage–activated N-type calcium channels located in the spinal dorsal horn are a validated clinical target for therapeutic interventions associated with severe intractable pain. Low voltage–activated (T-type) calcium channels play a number of critical roles in nervous system function, including controlling thalamocortical bursting behaviours and the generation of spike wave discharges associated with slow wave sleep patterns. There is a growing body of evidence that T-type calcium channels also contribute in several ways to both acute and neuropathic nociceptive behaviours. In the one instance, the Cav3.1 T-type channel isoform likely contributes an anti-nociceptive function in thalamocortical central signalling, possibly through the activation of inhibitory nRT neurons. In another instance, the Cav3.2 T-type calcium channel subtype acts at the level of primary afferents in a strongly pro-nociceptive manner in both acute and neuropathic models. While a number of classes of existing clinical agents non-selectively block T-type calcium channels, there are no subtype-specific drugs yet available. The development of agents selectively targeting peripheral Cav3.2 T-type calcium channels may represent an attractive new avenue for therapeutic intervention. Drug Dev. Res. 67:404–415, 2006. © 2006 Wiley-Liss, Inc.
    Full-text · Article · Apr 2006
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