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

Department of Pharmacology, Toho University School of Pharmaceutical Sciences, Funabashi, Chiba, Japan.
Life Sciences (Impact Factor: 2.7). 01/2001; 68(3):345-51. 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.

0 Reads
  • Source
    • "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, respectively [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.
    Drug Development Research 04/2006; 67(4):404 - 415. DOI:10.1002/ddr.20103 · 0.77 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dihydropyridine Ca antagonists cause reflex tachycardia related to their hypotensive effects. Efonidipine hydrochloride has inhibitory effects on T-type Ca channels, even as it inhibits reflex tachycardia. In the present study, the influence of efonidipine hydrochloride on heart rate and autonomic nervous function was investigated. Using an electrocardiogram and a tonometric blood pressure measurement, autonomic nervous activity was evaluated using spectral analysis of heart rate/systolic blood pressure variability. Three protocols were used: (1) a single dose of efonidipine hydrochloride was administered orally to healthy subjects with resting heart rate values of 75 beats/min or more (high-HR group) and to healthy subjects with resting heart rate values less than 75 beats/min (low-HR group); (2) efonidipine hydrochloride was newly administered to untreated patients with essential hypertension, and autonomic nervous activity was investigated after a 4-week treatment period; and (3) patients with high heart rate values (>/=75 beats/min) who had been treated with a dihydropyridine L-type Ca channel inhibitor for 1 month or more were switched to efonidipine hydrochloride and any changes in autonomic nervous activity were investigated. In all protocols, administration of efonidipine hydrochloride decreased the heart rate in patients with a high heart rate, reduced sympathetic nervous activity, and enhanced parasympathetic nervous activity. In addition, myocardial scintigraphy with (123)I-metaiodobenzylguanidine showed significant improvement in the washout rate and H/M ratio of patients who were switched from other dihydropyridine Ca antagonists to efonidipine hydrochloride. Efonidipine hydrochloride inhibits increases in heart rate and has effects on the autonomic nervous system. It may be useful for treating hypertension and angina pectoris, and may also have a cardiac protective function.
    Circulation Journal 02/2003; 67(2):139-45. DOI:10.1253/circj.67.139 · 3.94 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although several lines of recent studies fail to demonstrate the beneficial action of calcium antagonists, a novel dihydropyridine efonidipine, which possesses dilatory action of both afferent and efferent arterioles and, therefore, shares the renal microvascular action with angiotensin converting enzyme (ACE) inhibitors, is reported to exhibit renal protection in experimental animals. The present study evaluated the effect of efonidipine and ACE inhibitors on blood pressure (BP) and proteinuria. Sixty-eight hypertensive patients with renal impairment (serum creatinine, >1.5 mg/dL) or chronic renal parenchymal disease were randomly assigned to efonidipine or ACE inhibitor treatment. Of the 68 patients, 23 were treated with efonidipine and 20 with ACE inhibitors; these patients were analyzed for the 48-week study. Both efonidipine and ACE inhibitors produced a similar degree of reductions in BP (efonidipine, from 161 +/- 2/93 +/- 2 to 142 +/- 5/82 +/- 2 mm Hg; ACE inhibitor, from 163 +/- 3/95 +/- 2 to 141 +/- 5/83 +/- 2 mm Hg), and maintained creatinine clearance for 48 weeks. Proteinuria tended to decrease in both groups, and a significant reduction was observed in proteinuric patients (>1 g/day) (efonidipine, from 2.7 +/- 0.3 to 2.1 +/- 0.3 g/day; ACE inhibitor, from 3.0 +/- 0.4 to 2.0 +/- 0.5 g/day). Of interest, efonidipine decreased proteinuria in proteinuric patients who failed to manifest decreases in systemic BP. Finally, the incidence of adverse effects, including hyperkalemia and cough, was less in the efonidipine-treated group. Both efonidipine and ACE inhibitors preserved renal function in hypertensive patients with renal impairment. The antiproteinuric effect was apparent in patients with greater proteinuria. The beneficial action of efonidipine, along with fewer side effects, may favor the use of this agent in the treatment of hypertension with renal impairment.
    American Journal of Hypertension 02/2003; 16(2):116-22. DOI:10.1016/S0895-7061(02)03147-3 · 2.85 Impact Factor
Show more