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PubMed2000

Diltiazem and mibefradil increase the plasma concentrations and greatly enhance the adrenal-suppressant effect of oral methylprednisolone.

OBJECTIVE: To examine the possible interaction of the calcium channel blockers diltiazem and mibefradil with orally administered methylprednisolone. METHODS: In this randomized, double-blind, placebo-controlled, three-phase crossover study, nine healthy SUBJECTS received 60 mg diltiazem three times a day, 50 mg mibefradil once a day, or placebo orally for 3 days. On day 3, each subject received a 16-mg oral dose of methylprednisolone. Plasma concentrations of methylprednisolone and cortisol were determined by HPLC up to 47 hours. RESULTS: Compared with placebo, diltiazem and mibefradil increased the total area under the plasma concentration-time curve of methylprednisolone [AUC(0-infinity)] 2.6-fold (P < .001) and 3.8-fold (P < .001), the peak plasma concentration 1.6-fold (P < .001) and 1.8-fold (P < .001), and the elimination half-life 1.9-fold (P < .001) and 2.7-fold (P < .001), respectively. The nighttime exposure to methylprednisolone [AUC(12-23)] was increased 28.2-fold (P < .01) and 72.1-fold (P < .001) by diltiazem and mibefradil, respectively, and correlated negatively (r = -0.81, P < .001) with the morning plasma cortisol concentration (measured at 8 AM, 23 hours after the administration of methylprednisolone). During the diltiazem phase, the morning plasma cortisol concentration was 12% of that during the placebo phase (P < .001); during the mibefradil phase, the morning plasma cortisol concentration was 2% of that during the placebo phase (P < .001). CONCLUSIONS: Coadministration of diltiazem or mibefradil with methylprednisolone resulted in increased plasma concentrations and a greatly enhanced adrenal-suppressant effect of oral methylprednisolone. Care should be taken if methylprednisolone is coadministered with a potent CYP3A4 inhibitor for a long period.

Adrenal Glands↗
PubMed2001

Comparative effects of mibefradil and nifedipine gastrointestinal transport system on autonomic function in patients with mild to moderate essential hypertension.

BACKGROUND: L-type dihydropyridine calcium channel blockers (CCBs) have been implicated in increased cardiovascular events in patients with hypertension, perhaps due to adverse effects on autonomic nervous system (ANS) function. Blockade of T-type calcium channels may limit ANS dysfunction by inhibition of T channel-mediated neuroendocrine effects. OBJECTIVE AND DESIGN: This double-blind, parallel group study compared the effect of nifedipine gastrointestinal transport system (GITS) (L-type CCB) versus mibefradil (T-type CCB) on ANS function in patients with mild-moderate essential hypertension. METHODS: Sixteen patients (10 male, 6 female; age 57.2 +/- 2.3 years), diastolic blood pressure (DBP) < 95 mmHg were randomized to nifedipine 30 mg daily or mibefradil 50 mg daily (2 weeks), then nifedipine 60 mg daily or mibefradil 100 mg daily (4 weeks). Sympathetic nervous system activity (SNSA) was assessed using norepinephrine kinetics. Parasympathetic nervous system activity (PSNA) was assessed from 24 h Holter recordings of heart rate variability (HRV). Non-invasive baroreflex sensitivity (BRS) provided integrated assessment of ANS. RESULTS: Patient groups were well matched at baseline. Achieved DBP was lower in patients treated with mibefradil compared with nifedipine, (83.4 +/- 1.7 versus 95.25 +/- 3.3 mmHg). There were no significant differences in SNSA and BRS between groups, however the root mean square of successive differences and high frequency power (HFP) were increased in mibefradil compared with nifedipine-treated patients [(+ 1.07 +/- 1.6 versus -3.36 +/- 1.2 ms, P < 0.05) and (+ 0.28 +/- 0.1 versus -0.23 +/- 0.1 ms2, P < 0.01), respectively]. Furthermore, Ln HFP/Ln total power was increased from week 0 to week 6 in the mibefradil-treated group, (0.71 +/- 0.02 versus 0.74 +/- 0.03, P = 0.046). CONCLUSION: No differences existed between effect of L- and T-type CCBs on SNSA and BRS. However, T-type CCBs increased PSNA, independent of achieved changes in heart rate.

Autonomic Nervous System↗
PubMed1996

Mibefradil, a selective calcium T-channel blocker, in stroke-prone spontaneously hypertensive rats.

Several types of antihypertensive agents, including calcium antagonists, have been reported to prevent stroke and prolong survival in stroke-prone spontaneously hypertensive rats (SHR-SP). We investigated whether mibefradil, a new calcium antagonist acting selectively at the level of T-type calcium channels, would be able to (a) limit or prevent the structural and functional alterations that develop in the cerebral arteries of SHR-SP before stroke and (b) suppress stroke and prolong survival. Mibefradil (30 mg/kg/day) was given orally to young salt-loaded SHR-SP from age 5 weeks to age 20 weeks. Blood pressure (BP) (in conscious animals), diuresis, and proteinuria were determined weekly. After 1012 weeks of treatment, middle cerebral arteries and aortas were removed from randomly selected control and treated SHR-SP. Aortic media thickness and collagen density were evaluated by histomorphometry. Middle cerebral arteries were mounted in a myograph for wall thickness determination and isometric tension recordings. Mibefradil completely prevented stroke and mortality, significantly limited the increase in BP, and opposed the increases in diuresis and proteinuria observed in controls. Simultaneously, mibefradil abolished vascular fibrinoid necrosis formation in the brain and reduced arterial thickening in the cerebral artery as well as in the aorta. The maximal contractile responses of the cerebral arteries to potassium chloride and serotonin were greater in mibefradil-treated animals than in controls, as were the endothelium-dependent relaxant responses. Mibefradil, chronically administered to young SHRSP in a dose that limits the development of hypertension not only prevents stroke and mortality but also affords protection against the vascular structural alterations which develop with age in these animals and preserves or improves the cerebral artery's smooth muscle and endothelial cell functions.

Animals↗
PubMed1996

Effects of mibefradil on large and small coronary arteries in conscious dogs: role of vascular endothelium.

The systemic and coronary hemodynamic effects of mibefradil, a "nondihydropyridine" calcium antagonist acting on both L- and T-type calcium channels, were investigated in chronically instrumented conscious dogs before and after local endothelium removal of the circumflex coronary artery by angioplasty. After intravenous infusion, mibefradil (0.2 mg kg-1 min-1) decreased mean arterial blood pressure (MAP; -15 +/- 1%), increased heart rate (HR; 58 +/- 9%), and coronary blood flow (CBF; 103 +/- 14%) (all p < 0.05). Before endothelium removal, mibefradil increased the diameter of the left circumflex epicardial coronary artery (LCX) by 7.8 +/- 1.2% from 3,006 +/- 219 microns, but this dilatory effect was significantly reduced by 69% (p < 0.001) and 45% (p < 0.01), 3 and 21 days after endothelium removal, respectively. Mibefradil also reduced by 46% (p < 0.01) the potent coronary constrictor effect of ergonovine (300 micrograms intravenous bolus). These results demonstrate that mibefradil is a potent dilator of large and small coronary arteries in conscious dogs and that approximately 30% of its dilatory effect on large coronary artery is endothelium-independent. In addition, mibefradil prevents ergonovine-induced epicardial coronary constriction.

Animals↗
PubMed1999

The effects of mibefradil and enalapril on 24-hour blood pressure control and left ventricular mass in patients with mild to moderate hypertension: double-blind, randomized trial.

In this prospective, double-blind, monocenter drug trial, 48 primary care patients with mild to moderate essential hypertension were randomized to mibefradil, 50 mg, titrated to 100 mg, or enalapril, 20 mg, titrated to 2 x 20 mg. Ambulatory 24-h blood pressure measurements (ABPM) and echocardiography were performed at baseline and after 12 weeks' treatment. Complete data from 43 patients were analyzed. Mibefradil (n = 22; titration, 13 patients) reduced mean 24-h ABP from 159+/-14/102+/-7 mm Hg to 140+/-10/89+/-7 mm Hg after 12 weeks. Enalapril (n = 21; titration, six patients) reduced baseline ABP from 156+/-12/100+/-9 mm Hg to 140+/-17/89+/-10 mm Hg (12 weeks). Trough-to-peak ratios in DBP were 86% for mibefradil and 75% with enalapril. Left ventricular mass (LVM) decreased from 199+/-65 to 193+/-62 g [M-mode modified American Society of Echocardiography (ASE)] and from 184+/-65 to 173+/-50 g (truncated ellipsoid method) after 12 weeks in response to mibefradil (p > 0.2), and from 212+/-50 to 196+/-57 g and from 182+/-39 to 170+/-40 g (mean +/- SD, p < 0.02) with enalapril. Mibefradil matched enalapril in 24-h ABP control. Enalapril reduced LVM significantly after 12 weeks (p < 0.02). Mibefradil did not significantly reduce LVM after 12 weeks.

Antihypertensive Agents↗
PubMed2001

Inhibition of T-type and L-type calcium channels by mibefradil: physiologic and pharmacologic bases of cardiovascular effects.

Ca2+ channel antagonists of the dihydropyridine, benzothiazepine, and phenylalkylamine classes have selective effects on L-type versus T-type Ca2+ channels. In contrast, mibefradil was reported to be more selective for T-type channels. We used the whole-cell patch-clamp technique to investigate the effects of mibefradil on T-type and L-type Ca2+ currents (I(CaT) and I(CaL)) recorded at physiologic extracellular Ca2+ in different cardiac cell types. At a stimulation rate of 0.1 Hz, mibefradil blocked I(CaT) evoked from negative holding potentials (HPs) (-100 mV to -80 mV) with an IC50 of 0.1 microM in rat atrial cells. This concentration had no effect on I(CaL) in rat ventricular cells (IC50: approximately3 microM). However, block of I(CaL) was enhanced when the HP was depolarized to -50 mV (IC50: approximately 0.1 microM). Besides a resting block, mibefradil displayed voltage- and use-dependent effects on both I(CaT) and I(CaL). In addition, inhibition was enhanced by increasing the duration of the step-depolarizations. Similar effects were observed in human atrial and rabbit sinoatrial cells. In conclusion, mibefradil combines the voltage- and use-dependent effects of dihydropyridines and benzothiazepines on I(CaL). Inhibition of I(CaL), which has probably been underestimated before, may contribute to most of the cardiovascular effects of mibefradil.

Action Potentials↗
PubMed2007

Long-term calcium antagonist treatment of human hypertension with mibefradil or amlodipine increases sympathetic nerve activity.

OBJECTIVES: Calcium antagonists are vasodilating drugs, which may cause reflex activation of the sympathetic nervous system with potentially untoward effects. We studied the effects of long-term treatment with amlodipine, a long-acting dihydropyridine-type calcium antagonist, and mibefradil, a phenylalkylamine-type calcium antagonist, on sympathetic nerve activity. METHODS: Fourteen patients with primary hypertension participated in a double-blind, cross-over study comparing the effects of 6 weeks of treatment with mibefradil 100 mg daily and amlodipine 10 mg daily. Heart rate, direct arterial blood pressure and cardiac output by echocardiography were registered. Global sympathetic activity was estimated using a [3H]noradrenaline isotope dilution method with arterial and venous sampling; cardiac sympathetic activity was assessed indirectly by heart rate variability and tissue velocity echocardiography. RESULTS: Both drugs lowered mean arterial pressure; the decrease was more pronounced with mibefradil (from 118 +/- 3 to 99 +/- 2 mmHg, compared to 118 +/- 3 to 104 +/- 2 mmHg for amlodipine, P < 0.01 between drugs). Mibefradil decreased heart rate (66 +/- 2 to 57 +/- 2 bpm), whereas amlodipine caused a slight increase (66 +/- 2 to 70 +/- 2 bpm; P < 0.001 between drugs) and tended to increase cardiac output. Noradrenaline spillover increased similarly with the two drugs, from 3.44 +/- 0.27 to 5.20 +/- 0.48 nmol/min per m2(P < 0.01) during mibefradil and to 5.72 +/- 0.49 nmol/min per m2 (P < 0.001) during amlodipine. There were minor effects on cardiac sympatho-vagal balance, but systolic and diastolic myocardial velocities were increased similarly by both drugs. CONCLUSIONS: Mibefradil and amlodipine treatment increase global sympathetic nerve activity similarly during long-term treatment, despite opposite effects on heart rate. Increases in myocardial velocities suggest concomitant cardiac sympathetic activation.

Aged↗
PubMed2005

Effect of mibefradil on sodium and calcium currents.

Interstitial cells of Cajal (ICC) generate the electrical slow wave. The ionic conductances that contribute to the slow wave appear to vary among species. In humans, a tetrodotoxin-resistant Na+ current (Na(V)1.5) encoded by SCN5A contributes to the rising phase of the slow wave, whereas T-type Ca2+ currents have been reported from cultured mouse intestine ICC and also from canine colonic ICC. Mibefradil has a higher affinity for T-type over L-type Ca2+ channels, and the drug has been used in the gastrointestinal tract to identify T-type currents. However, the selectivity of mibefradil for T-type Ca2+ channels over ICC and smooth muscle Na+ channels has not been clearly demonstrated. The aim of this study was to determine the effect of mibefradil on T-type and L-type Ca2+ and Na+ currents. Whole cell currents were recorded from HEK-293 cells coexpressing green fluorescent protein with either the rat brain T-type Ca2+ channel alpha(1)3.3b + beta(2), the human intestinal L-type Ca2+ channel subunits alpha(1C) + beta(2), or Na(V)1.5. Mibefradil significantly reduced expressed T-type Ca2+ current at concentrations > or = 0.1 microM (IC(50) = 0.29 microM), L-type Ca2+ current at > 1 microM (IC(50) = 2.7 microM), and Na+ current at > or = 0.3 microM (IC(50) = 0.98 microM). In conclusion, mibefradil inhibits the human intestinal tetrodotoxin-resistant Na+ channel at submicromolar concentrations. Caution must be used in the interpretation of the effects of mibefradil when several ion channel classes are coexpressed.

Calcium↗
PubMed1999

The T-type Ca(2+) channel blocker mibefradil prevents the development of a substrate for atrial fibrillation by tachycardia-induced atrial remodeling in dogs.

BACKGROUND: Ca(2+) overload is believed to play a role in tachycardia-induced atrial electrophysiological remodeling. L-type Ca(2+) channel blockers attenuate effective refractory period (ERP) changes caused by 24 hours of atrial tachycardia but may not substantially alter atrial fibrillation (AF) inducibility. This study assessed the effects of the T-type Ca(2+) channel blocker mibefradil on tachycardia-induced atrial remodeling. METHODS AND RESULTS: Dogs subjected to rapid atrial pacing (400 bpm) for 7 days were treated with mibefradil (100 mg/d, n=8) or matching placebo (n=10) in blinded fashion. Radiofrequency ablation of atrioventricular conduction and ventricular pacing were used to control ventricular rate. Placebo dogs showed significant decreases in atrial ERP (76+/-5 ms at a cycle length of 300 ms) and increases in ERP heterogeneity (27.7+/-2.4%), AF duration (414+/-232 seconds), and AF inducibility by single extrastimuli (41+/-10% of sites) compared with 10 unpaced control dogs (ERP 114+/-3 ms, ERP heterogeneity 13.8+/-0.9%, AF duration 7+/-3 seconds, AF inducibility 1.9+/-1.0% of sites). The changes caused by atrial tachycardia were strongly attenuated in mibefradil dogs, with ERPs averaging 102+/-7 ms, ERP heterogeneity 18.8+/-1.4%, AF duration 3+/-1 seconds, and AF inducibility 9.6+/-4.0% of sites. Among mibefradil-treated dogs, ERP, AF duration, and inducibility correlated with plasma drug concentration. Acute mibefradil administration did not alter ERP or AF. CONCLUSIONS: Mibefradil, a drug with strong T-type Ca(2+) channel blocking properties, prevents AF-promoting electrophysiological remodeling by atrial tachycardia. These findings have important potential implications for the mechanisms of tachycardia-induced atrial remodeling and demonstrate the feasibility of preventing electrical remodeling caused by several days of atrial tachycardia.

Animals↗
PubMed1997

Efficacy of mibefradil compared with amlodipine in suppressing exercise-induced and daily silent ischemia: results of a multicenter, placebo-controlled trial.

BACKGROUND: Mibefradil is a new benzimidazolyl-substituted tetraline-derivative calcium antagonist. Its vasodilatory activity combined with an ability to lower heart rate without negative inotropic effects as well as its long duration of action make it a promising anti-ischemic agent. METHODS AND RESULTS: Three hundred nine patients with coronary artery disease, stable angina pectoris, and positive exercise tests were randomized to receive mibefradil (50, 100, or 150 mg), amlodipine (10 mg), or placebo. The anti-ischemic effects of mibefradil on exercise test and silent ischemia parameters were assessed. At doses of 100 and 150 mg, mibefradil increased exercise duration (by 55.5 and 51.0 seconds, respectively; P<.001 for both), increased time to onset of angina (by 98.3 and 82.7 seconds, respectively; P<.001), and increased time to 1-mm ST depression (by 81.7 and 94.3 seconds, respectively; P<.001). By comparison, a 10 mg/d dose of amlodipine significantly improved only time to onset of angina (treatment effect: 38.5 seconds, P=.036). Mibefradil 100 mg and 150 mg decreased the number of episodes of silent ischemia (treatment effects: -3.1 and -3.6, respectively; P<.001) and the duration of silent ischemia (treatment effects: -9.2 minutes, P=.048, and -14.6 minutes, P=.002, respectively). The decrease in the number of episodes of silent ischemia was also statistically significant in the group receiving 10 mg of amlodipine (-1.5; P=.036). CONCLUSIONS: Once-daily doses of 100 and 150 mg mibefradil were effective in improving exercise tolerance and reducing ischemic episodes during ambulatory monitoring in patients with coronary artery disease.

Adult↗
PubMed1999

Effects of mibefradil, a selective T-type Ca2+ channel antagonist, on sino-atrial node and ventricular myocardia.

The effects of mibefradil, a non-dihydropyridine Ca2+ channel antagonist, on the action potential configuration of isolated rabbit sino-atrial node preparations, membrane currents of guinea-pig ventricular myocytes and the contractile force of isolated ventricular papillary muscles were examined. In sino-atrial node preparations, 10 microM mibefradil decreased the slope of the pacemaker depolarization (phase 4 depolarization) and maximum rate of rise, and shifted the threshold potential to the positive direction with no effect on action potential duration. In ventricular myocytes, 1 microM mibefradil inhibited the T-type Ca2+ current by about 40% while it had no effect on the L-type Ca2+ current. At 10 microM, mibefradil inhibited the L-type and T-type Ca2+ currents by about 40% and 90%, respectively. Mibefradil had no effect on contractile force at concentrations up to 1 microM. Thus, mibefradil was shown to produce potent prolongation of the pacemaker depolarization, mainly through inhibition of the T-type Ca2+ current. It is suggested that the T-type Ca2+ current may not be involved in ventricular contraction.

Action Potentials↗
PubMed2000

Mibefradil block of cloned T-type calcium channels.

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 Ba(2+) as the charge carrier have predicted a 10- to 15-fold preference of mibefradil for T channels over L channels. However, T channel IC(50) values are reported to be approximately 1 microM, which is much higher than expected for clinical efficacy because relevant blood levels of this drug are approximately 50 nM. We compared the affinity for mibefradil of the newly cloned T channel isoforms, alpha1G, alpha1H, and alpha1I with an L channel, alpha1C. In 10 mM Ba(2+), mibefradil blocked in the micromolar range and with 12- to 13-fold greater affinity for T channels than for L channels (approximately 1 microM versus 13 microM). When 2 mM Ca(2+) was used as the charge carrier, the drug was more efficacious; the IC(50) for alpha1G shifted to 270 nM and for alpha1H 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 Ba(2+) is a more effective competitor than Ca(2+). Raising temperature to 35 degrees C reduced affinity (IC(50) 792 nM). Reducing channel availability to half increased affinity ( approximately 70 nM). This profile of mibefradil affinity makes these channels good candidates for the physiological target of this antihypertensive agent.

Barium↗
PubMed2004

Comparison of cardioprotective effects of mibefradil and ramipril in stroke-prone spontaneously hypertensive rats.

AIM: To elucidate the cardioprotective effects of T-type calcium channel blocker mibefradil and compare with that of the angiotensin-converting enzyme inhibitor ramipril in a stroke-prone spontaneously hypertensive rats (SHR-SP) model of congestive heart failure (CHF) after myocardial infarction (MI). METHODS: SHR-SP rats were subjected to permanent ligation of the left anterior decending coronary artery. Treatment with mibefradil (10 mg.kg(-1).d(-1)), ramipril (10 mg.kg(-1).d(-1)), or placebo was initiated 4 weeks before surgery and continued up to 6 weeks after induction of MI. Sham-operated rats served as controls. RESULTS: In placebo-treated MI rats, six weeks after MI, left ventricular circumference, inner diameter, and left ventricular end-diastolic pressure (LVEDP) were increased, whereas mean arterial blood pressure (MAP) and maximum rate of rise of left ventricular pressure (dp/dt(max)) were decreased compared with sham-operated controls (P<0.01). In ramipril-treated MI rats, heart weight, heart weight to body weight ratio and interstitial collagen content were reduced (P<0.05, P<0.01), LVEDP was slightly decreased (P>0.05), and dp/dt(max) was improved (P<0.01) compared with placebo-treated MI rats. In contrast, in mibefradil-treated MI rats, heart weight, heart weight to body weight ratio were slightly but not significantly reduced, LVEDP was slightly elevated compared with placebo-treated MI rats, and was elevated (P<0.05) compared with ramipril-treated MI rats, although interstitial collagen content were reduced (P<0.01) compared with placebo-treated MI rats. CONCLUSION: Chronic treatment with ramipril diminishes cardiac remodeling of heart failure after MI to a greater extent than mibefradil. Moreover, 6 weeks after MI, mibefradil treatment results in a slight rise in LVEDP compared with placebo-treated rats. Therefore, treatment with mibefradil might be deleterious rather than beneficial compared with ramipril or even placebo treatment in experimental MI.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

The effects of mibefradil, a novel calcium channel antagonist on ventricular arrhythmias induced by myocardial ischemia and programmed electrical stimulation.

Calcium channel antagonists can reduce calcium overload induced by myocardial ischemia and thereby protect against malignant arrhythmias. However, these drugs may also adversely affect cardiac contractile function. Mibefradil is a new calcium antagonist that can inhibit cardiac calcium current without reducing myocardial force development. The effects of mibefradil on the inducibility of arrhythmias both before and during ischemia were therefore evaluated in animals with healed infarctions. First, a 2-min coronary occlusion was made during the last minute of exercise (n = 48): 25 animals had ventricular fibrillation (susceptible), whereas 23 did not (resistant). On a subsequent day, programmed electrical stimulation (PES, 8 paced beats followed by two extrastimuli) induced ventricular tachycardia in 19 of 25 susceptible animals but in none of the resistant animals (chi square = 24.6, P < .001). Verapamil (n = 14), diltiazem (n = 13) and mibefradil (n = 14) elicited significant dose-dependent decreases in refractory period and in the Q-Tc interval (except mibefradil) yet failed to prevent PES-induced arrhythmias. Diltiazem and verapamil also increased P-R interval and reduced the maximum rate of change of left ventricular pressure, whereas mibefradil did not. However, all three drugs abolished arrhythmias induced by PES during ischemia. In contrast, lidocaine suppressed PES-induced arrhythmias but failed to prevent ischemically induced arrhythmias. Thus mibefradil can prevent ischemically induced ventricular fibrillation without adverse actions on either A-V nodal conduction or contractile function. These data further suggest that calcium entry may play a critical role in the initiation of ventricular fibrillation during ischemia, whereas other factors must be responsible for the extrasystoles induced by PES.

Animals↗
PubMed1998

Life-threatening interaction of mibefradil and beta-blockers with dihydropyridine calcium channel blockers.

Mibefradil is a T-type and L-type calcium channel blocker (CCB) released in the United States in 1997 for management of hypertension and chronic stable angina. Postmarketing surveillance revealed a potential serious interaction between mibefradil and beta-blockers, digoxin, verapamil, and diltiazem, especially in elderly patients. The manufacturer voluntarily withdrew mibefradil on June 8, 1998. We describe 4 cases of cardiogenic shock in patients taking mibefradil and beta-blockers who began taking dihydropyridine CCBs. One case resulted in death; the other 3 survived episodes of cardiogenic shock with intensive support of heart rate and blood pressure. Physicians who are preparing to switch patients' medications from mibefradil to other antihypertensive agents should be aware of these potentially life-threatening drug-drug interactions.

Adrenergic beta-Antagonists↗
PubMed1999

Capillary blood cell velocity in finger nailfold: effect of enalapril and mibefradil in patients with mild to moderate hypertension.

Outpatients with essential hypertension were randomized to receive antihypertensive treatment with either mibefradil or enalapril. Ambulatory blood pressure measurement (ABPM) and video capillary microscopy of the finger nailfold were performed at baseline and after 12 weeks of treatment. In the enalapril group (n = 21) baseline ABP was 156 +/- 12/100 +/- 9 mm Hg and decreased to 140 +/- 17/89 +/- 10 mm Hg after 12 weeks. In the mibefradil group (n = 22) mean 24-h ABP decreased from 159 +/- 14/102 +/- 7 to 140 +/- 10/89 +/- 7 mm Hg. Capillary blood cell velocity (CBV) without treatment was 0.90 +/- 0.58 mm/s (mean +/- SD) and 0.83 +/- 0.46 mm/s at rest and 0.30 +/- 0.22 and 0.21 +/- 0.20 mm/s immediately after local finger cooling in the mibefradil and the enalapril group, respectively. In the Enalapril group CBV at week 12 was 0.99 +/- 0. 60 mm/s (n.s.) at rest and 0.40 +/- 0.28 mm/s immediately after local cooling (P = 0.005 compared to 0.21 +/- 0.20 mm/s without treatment). Twelve weeks after initiation of treatment CBV was 0.76 +/- 0.48 mm/s (n.s.) at rest and 0.31 +/- 0.28 mm/s (n.s.) immediately after local cooling in the mibefradil group. Finger nailfold CBV immediately after local finger cooling was increased by enalapril compared to baseline. The T-channel-inhibiting calcium antagonist mibefradil did not change CBV in finger nailfold capillaries.

Adult↗
PubMed2004

Induction of apoptosis by the calcium antagonist mibefradil correlates with depolarization of the membrane potential and decreased integrin expression in human lens epithelial cells.

BACKGROUND: Posterior capsule opacification is still the major complication in cataract surgery and is caused by migration and proliferation of residual lens epithelial cells. The challenge of a suitable therapy to inhibit capsule opacification is to specifically interfere with cellular mechanisms. Our approach using the T-calcium channel antagonist mibefradil is based on the hypothesis that this drug inhibits the signaling pathways mediated by cell adhesion. METHODS: The influence of mibefradil dihydrochloride was investigated on primary human lens epithelial cells (hLEC) from cataract surgery and on the human lens cell line HLE-B3. Apoptosis was quantitatively analyzed by flow cytometry (% increase of the sub-G1 peak), and verified by confocal microscopy (annexin V-biotin, TUNEL reaction). The membrane potential was detected by a membrane potential-sensitive dye. Integrin expression and proliferation were measured by flow cytometry. T-calcium channels in hLEC were verified by the whole-cell configuration of the patch-clamp technique. RESULTS: Mibefradil induced apoptosis in hLEC. Early signs of apoptosis were observed after only 4 h of incubation with mibefradil, accompanied by a significantly reduced cell area. Apoptosis correlated with inhibited integrin expression, reduced proliferation and the depolarization of the membrane potential. We could identify calcium channels of the T-type in our primary hLEC. CONCLUSIONS: We suggest that depolarization of the membrane potential and the inhibition of integrin expression leads to the loss of cell adhesion, which is the reason for the induction of apoptosis. Thus, mibefradil seems to be a suitable drug to prevent cell adhesion, migration and proliferation.

Actins↗
PubMed2005

The antihyperalgesic effects of the T-type calcium channel blockers ethosuximide, trimethadione, and mibefradil.

The purpose of the present study was to explore the analgesic effects of the low voltage-activated T-type Ca2+ channel blockers ethosuximide, trimethadione, and mibefradil in persistent and acute nociceptive tests. The anticonvulsant effects of the compounds were also determined in the intravenous pentylenetetrazol seizure model. Following intraperitoneal administration, ethosuximide and trimethadione dose-dependently reversed capsaicin-induced mechanical hyperalgesia. Similarly, the highest dose of mibefradil tested (30 microg, intracisternal) reversed capsaicin-induced mechanical hyperalgesia. Ethosuximide and mibefradil produced statistically significant analgesic effects in both early and late phase formalin-induced behaviors and trimethadione reduced late phase behaviors. Additionally, ethosuximide and trimethadione produced antinociceptive effects in the rat-tail flick reflex test. In contrast, following intracisternal administration, mibefradil had no effect in the tail flick reflex test. In addition, the anticonvulsants ethosuximide and trimethadione increased the doses of pentylenetetrazol required to produce both first twitch and clonic seizures. In contrast however, mibefradil had no anticonvulsant effect. The present results demonstrate that the clinically used anticonvulsants ethosuximide and trimethadione provide analgesic effects at doses, which are anticonvulsant. Furthermore, the data further supports the idea that T-type Ca2+ channels may be important targets for treating persistent pain syndromes.

Animals↗