Interaction Of Verapamil Research Articles

Effect of verapamil on <em>Enterococcus faecalis</em>, <em>Escherichia coli </em>and on DNA damage induced by copper and iron

Verapamil is commonly used oral drug for treatment of high blood pressure and heart diseases worldwide. Here, we investigated the effect of verapamil on two of human intestinal flora bacterial strains Enterococcus faecalis and Escherichia coli using the broth medium dilution method and agar disc diffusion method. In addition, DNA was treated with verapamil, verapamil plus H2O2, verapamil plus ascorbic acid, verapamil plus iron and verapamil plus copper and analyzed by agarose gel electrophoresis. The interaction of verapamil with DNA was investigated by UV-Vis spectrophotometer and in silico methods. Verapamil inhibited the growth of both E. faecalis and E. coli up to 90% at concentrations of 9, 18 and 25 mM. The concentration of 9 mM (480 mg dose) of the drug was found as both MIC and MBC value for the two bacterial strains. The drug did not show any breaking or protective effect on the supercoiled plasmid DNA. In the UV-Vis spectrophotometer analysis, verapamil did not show any interaction with the DNA. In contrast, in silico analysis showed the drug to bind to a minor groove of double helix DNA by hydrogen bonds and hydrophobic interactions with the binding energy of 7.3 kcal/mol and binding constant (Kb) value of 2.3×105 M-1.

Is the efflux pump inhibitor Verapamil a potential booster for isoniazid against Mycobacterium tuberculosis?

The membrane-based efflux pump systems are recognized to have an important role in pathogenicity and drug resistance in Mycobacterium tuberculosis by the extrusion of toxic substrates and drugs from the inner bacillus. This study aimed to investigate the in vitro interaction of Verapamil (VP), an efflux pump inhibitor, with the classical first-line anti-tuberculosis drug isoniazid (INH) in resistant and susceptible M. tuberculosis clinical isolates. Seven multidrug-resistant (MDR), three INH monoresistant and four susceptible M. tuberculosis clinical isolates were tested for the INH and VP combination by modified Resazurin Microtiter Assay Plate (REMA). Fractional Inhibitory Concentration (FIC) and Modulation Factor (MF) were determined. The INH plus VP combination showed no significant change in the Minimum inhibitory concentration (MIC) values of INH (FIC≥ 0.5; MF=1 or 2).The use of VP in tuberculosis therapy should be managed carefully, considering the resistance caused by specific mutation in katG and inhA genes, in which the use of these EPIs may have no success. The use of EPIs as an adjunctive drug in the anti-tuberculosis therapy should be further investigated on a larger number of M. tuberculosis clinical isolates with different resistant profile.

IN-VITRO INTERACTION STUDIES OF VERAPAMIL WITH FLUOROQUINOLONES USING FIRST ORDER DERIVATIVE UV SPECTROPHOTOMETRY AND RP-HPLC

Verapamil, a calcium channel blocker, is classified as a class IV anti-arrhythmic agent. It is used in the treatment of hypertension, as an important therapeutic agent for angina pectoris, ischemic heart disease, hypertension and hypertrophic cardiomyopathy. Many in-vivo studies have been carried out to find out the effects on concurrent use of calcium channel blocker with various groups of drugs. In the present paper an in-vitro approach was adapted to study the interaction of verapamil with commonly administered fluoroquinolones i.e. ciprofloxacin, levofloxacin, norfloxacin and sparfloxacin. The interaction studies were carried out in different simulated body fluids pH ranges from 1-9 at 37 oC. To perform these studies first-derivative UV spectrophotometric (using zero-crossing technique) and simultaneous RP-HPLC methods were developed and validated. HPLC analysis was conducted on Shimpack CLC-ODS (6.0 X 150 mm) column. The mobile phase constituted of acetonitrile: water (45:55), whose pH was adjusted to 2.8 and pumped at a flow rate of 1.2 mL min-1 at 230 nm. The results obtained from both methodologies indicated that the availability of verapamil was not affected by simultaneous administration

Synergistic effects of verapamil on pingyangmycin‐induced cytotoxicity and apoptosis in KB cells

Previous studies have shown that pingyangmycin (PYM; bleomycin A5) can induce two distinct modes of cell death (necrosis, apoptosis). At high concentrations, PYM can be considered as an apoptosis mimetic drug. In this study, we explored the possibility that the membrane-modifying agent verapamil might affect the transport function of PYM through the plasma membrane, resulting in inducing apoptosis of tumor cells at low concentration of PYM. Cytotoxicity, flow cytometry and DNA fragmentation assays were used to detect the interaction of verapamil and PYM in human oral carcinoma cell line KB cells. Our results indicated that verapamil can enhance the cytotoxicity of PYM against KB cells with the non-toxic doses (P<0.05). The cell viability at a concentration of 500 microg ml-1 of PYM was 35+/-2% compared with control and 10 microg ml-1 verapamil decreased the cell viability lower to 28+/-1%. In addition, because of the synergistic effect of verapamil, KB cells apoptosis was found to be induced when treated with a lower concentration of PYM (50 microg ml-1) for 24 h by flow cytometry and DNA fragmentation assays. Verapamil was found to enhance PYM-induced cytotoxicity and apoptosis in KB cells. The responsiveness of PYM might be explained by the effective accumulation of PYM by verapamil in KB cells mediated by the inhibition of PYM efflux function of the cells.

Interaction of Verapamil with Lipid Membranes and P-Glycoprotein: Connecting Thermodynamics and Membrane Structure with Functional Activity

Verapamil and amlodipine are calcium ion influx inhibitors of wide clinical use. They are partially charged at neutral pH and exhibit amphiphilic properties. The noncharged species can easily cross the lipid membrane. We have measured with solid-state NMR the structural changes induced by verapamil upon incorporation into phospholipid bilayers and have compared them with earlier data on amlodipine and nimodipine. Verapamil and amlodipine produce a rotation of the phosphocholine headgroup away from the membrane surface and a disordering of the fatty acid chains. We have determined the thermodynamics of verapamil partitioning into neutral and negatively charged membranes with isothermal titration calorimetry. Verapamil undergoes a pK-shift of ΔpKa=1.2 units in neutral lipid membranes and the percentage of the noncharged species increases from 5% to 45%. Verapamil partitioning is increased for negatively charged membranes and the binding isotherms are strongly affected by the salt concentration. The electrostatic screening can be explained with the Gouy-Chapman theory. Using a functional phosphate assay we have measured the affinity of verapamil, amlodipine, and nimodipine for P-glycoprotein, and have calculated the free energy of drug binding from the aqueous phase to the active center of P-glycoprotein in the lipid phase. By combining the latter results with the lipid partitioning data it was possible, for the first time, to determine the true affinity of the three drugs for the P-glycoprotein active center if the reaction takes place exclusively in the lipid matrix.

Calcium enhances antiinflammatory activity of aspirin in albino rats

<b>Objective:</b> To evaluate the effects of calcium carbonate and calcium gluconate on acute and subacute inflammation, and to study their possible interactions with aspirin, verapamil and magnesium sulphate.<br><b> Materials and Methods: </b> Calcium carbonate in the dose of 10, 25, 50 mg/kg, calcium gluconate in the dose of 5, 10, 25, 50 mg/kg, and aspirin in the dose of 54, 200 mg/kg were administered orally in different groups of albino rats, to study their effect on inflammation induced by carrageenan or a foreign body. Aspirin (54 mg/kg) was administered either with calcium carbonate (10 mg/kg) or calcium gluconate (5 mg/kg) to separate groups in order to study their interaction, especially with reference to gastric ulceration. Similarly, possible interactions of verapamil (4 mg/kg) with calcium carbonate (10 mg/kg) and magnesium sulfate (500 mg/kg) with calcium carbonate (50 mg/kg) were also studied. <br><b> Results:</b> Both calcium carbonate and calcium gluconate produced significant antiinflammatory activity in acute as well as subacute inflammation models and was comparable to that of aspirin. Sub-antiinflammatory dose of calcium salts potentiated the antiinflammatory activity of aspirin. Verapamil also potentiated the anti-inflammatory activity of calcium carbonate while magnesium sulfate antagonized the antiinflammatory activity of calcium carbonate in both the models of inflammation.<br><b> Conclusion:</b> Co-administration of calcium salt potentiated the antiinflammatory response and minimized the gastro-toxicity of aspirin.

Stereoselective Pharmacokinetics and Pharmacodynamics of Verapamil and Norverapamil in Rabbits.

We have estimated the pharmacokinetic and pharmacodynamic interactions of verapamil (VP) enantiomers and also the interaction between VP and its metabolite, norverapamil (NVP). ECGs of conscious rabbits were studied to determine the pharmacokinetics of VP enantiomers and racemic NVP in relation to their prolongation effect on PR intervals, which were used as an index of VP's antiarrhythmic effect. Plasma free fractions of VP enantiomers showed constant values at concentrations ranging from 0.022 to 1.10 microm. There were no interactions between enantiomers or between VP and NVP. The pharmacological effect of the S-enantiomer (S-VP), which was determined by linear regression analysis, showed it was about 20 times more potent than that of the R-enantiomer (R-VP). The effect of racemic VP was the simple sum of those elicited by both enantiomers. These relationships were not significantly different between intravenous infusion and bolus injection. Simultaneous intravenous infusion of NVP had no influence on the PR intervals. In conclusion, we demonstrated that the relationship between plasma unbound concentration of VP enantiomers and their pharmacological effect was the simple sum of two enantiomers.

P-GLYCOPROTEIN SYSTEM AS A DETERMINANT OF DRUG INTERACTIONS: THE CASE OF DIGOXIN–VERAPAMIL

Digoxin, which has a very narrow therapeutic window, is one of the most commonly prescribed drugs in the treatment of congestive heart failure. In some cases of atrial fibrillation digoxin is used in combination with verapamil. Verapamil can increase the plasma concentration of digoxin up to 60–90%. So far the precise mechanism of this pharmacokinetic drug–drug interaction is not known. Many studies suggest that verapamil reduces the renal clearance of digoxin. The energy-dependent membrane-bound transport enzyme, P-glycoprotein, may also be involved. Reports from oncology research show that verapamil can interact with P-glycoprotein as a modulator. Also taking into account that digoxin, like many anticancer drugs, is a substrate for P-glycoprotein, it is likely that P-glycoprotein modulation accounts for the digoxin–verapamil interaction. Current knowledge suggest that the non-competitive digoxin–verapamil interaction is due to inhibition of P-glycoprotein activity by verapamil resulting in a decreased renal tubular elimination of digoxin.

Effect of Volatile Anesthetics With and Without Verapamil on Intracellular Activity in Vascular Smooth Muscle

Comment: This sophisticated, detailed, and meticulously worked laboratory report furnishes further data on the intracellular mechanisms of action of halothane and isoflurane in preparations of rat thoracic aorta smooth muscle strips and the interactions of calcium and calcium channel blockers (in this case, verapamil). Previous studies on the interaction of verapamil with volatile anesthetics suggested that verapamil abolished the decrease in cardiac output induced by low calcium and exaggerated the increase in stroke volume and left ventricular contractility induced by high levels of calcium.1 The effects of calcium channel blockers when used in combination with enflurane were also studied and were an exaggeration of the reduction of cardiac output and stroke volume induced by hypocalcemia. Other studies comparing the combination of nifedipine and volatile anesthetics found the prime interaction to be with enflurane, causing an exaggerated reduction in atrial rate and contractility unaccompanied by any effects on atrioventricular conduction.2 The impact of verapamil on enflurane was not examined in this study. The clinical implications regarding the use of calcium channel blockers in the presence of volatile anesthetics from these in vivo and in vitro studies are, as yet, unclear.

Docking of Verapamil in a Synthetic Ca2+Channel: Formation of a Ternary Complex Involving Ca2+Ions

The mechanism by which diverse drugs modulate voltage-dependent Ca2+channels is ill-understood. We have approached this problem by examining the interaction of verapamil with a 97-residue synthetic channel peptide (SCP) that exhibits functional similarities to authentic L-type Ca2+channels in terms of cation selectivity and permeation as well as interaction with channel-activating and blocking drugs (Groveet al.(1991)Proc. Natl. Acad. Sci. USA88, 6418). Different possibilities of binding of verapamil inside the Ca2+-bound SCP were simulated using the Monte Carlo-with-energy-minimization method. In the optimal mode of the binding, verapamil adopted a folded conformation and fit snugly in the pore. The dimethoxyphenyl groups of the drug interacted with two Ca2+ions coordinated to the acidic residues of SCP, thus forming a ternary complex of the drug, Ca2+, and channel. The isopropyl group of verapamil abetted a ring of four Ile residues constituting the putative SCP gate. The occlusion of this gate by verapamil in this manner was strikingly similar to that accomplished by the methyl group of dihydropyridine drugs. In conjunction with an earlier study on SCP bound to dihydropyridine drugs (Zhorov and Ananthanarayanan (1996)Biophys. J.70, 22), our data suggest that, in general, drug modulation of SCP would involve the interaction of the ligands with the pore-bound Ca2+and with the hydrophobic gate. In light of the functional similarity between SCP and L-type Ca2+channel, it is likely that the latter would also interact with drugs in a similar fashion.

Kinetics and state-dependent effects of verapamil on cardiac L-type calcium channels.

The voltage dependence and the kinetics of block by verapamil of L-type calcium current (ICa) were investigated in ventricular myocytes from rat hearts using the whole-cell patch-clamp technique. ICa was elicited repetitively in response to depolarizing voltage pulses from -80 mV to 0 mV at different pulse intervals and durations. Verapamil reduced the magnitude of ICa in a frequency-dependent manner without tonic component. The time course of ICa remained unchanged suggesting that not open but inactivated channels were affected by the drug. The interaction of verapamil with inactivated channels was investigated by the application of twin pulses. In the presence of verapamil, the duration of the first pulse significantly determined the magnitude of ICa during the second pulse. Variation of the duration of the first pulse between 12 and 3000 ms, followed by a pulse interval of 100 ms, resulted into a gradual decrease of ICa during the second pulse (180 ms), described by concentration-dependent monoexponential decay curves (tau = 1060 +/- 138 ms at 0.3 microM (n = 3); tau = 310 +/- 24 ms at 1 microM (n = 6), and tau = 125 +/- 7 ms at 10 microM (n = 5); means +/- SEM). Under control conditions, the changes in ICa were comparably negligible. The recovery of ICa from block was analyzed by the application of a twin pulse protocol in which two depolarising voltage pulses at fixed length (1. pulse at 3 s and 2. pulse at 180 ms) were interrupted by variable pulse intervals (6 ms-60 s). Under control conditions, recovery from inactivation was fast (tau = 11 +/- 0.7 ms; means +/- SEM; n = 3). In the presence of verapamil, recovery from block was about 500 times slower than under control conditions, independent of the drug concentration (tau = 5.05 +/- 0.44 s at 0.3 microM (n = 3), tau = 6.7 +/- 0.69 s at 1 microM (n = 4), and tau = 6.02 +/- 0.9 s at 10 microM (n = 5); means +/- SEM). Since development of block was dependent on the concentration of verapamil, whereas recovery from block was independent from the drug concentration, it is assumed that the described time constants for block and unblock reflect voltage-dependent net binding (tau on) and unbinding (tau off), respectively, of verapamil at its receptor sites. A computer simulation, including the time constants of block development at 0 mV and of recovery from block at -80 mV, predicted reasonably well the observed frequency-dependent block of ICa by verapamil. The development of either measured or calculated block of ICa, using 180 ms depolarising voltage pulses from -80 mV to 0 mV, was fitted by identical monoexponential association curves (tau = 7 s each at 0.2 Hz and tau = 1.7 s each at 1 Hz). When Ba2+ was used as the charge carrier, which removes the calcium-dependent inactivation of the current, verapamil (3 microM) was less efficient: ICa was decreased by 57 +/- 6% (means +/- SEM; n = 6), whereas IBa was decreased by 24 +/- 4% (means +/- SEM; n = 5). It is proposed that verapamil binds to calcium channels in their inactivated state at more positive potentials and dissociates from the channels in the resting state at more negative potentials. In the proposed scheme of periodical drug binding and unbinding, dependent on the state of the channels, the development of frequency-dependent block of ICa by verapamil is adequately predicted by the construction of cumulative association/ dissociation curves which include the experimentally determined time constants of development and recovery from block at 0 mV and -80 mV, respectively.

P157 interaction of verapamil and cimetidine in human liver microsomes

P157 interaction of verapamil and cimetidine in human liver microsomes

Chronic verapamil administration alters phenytoin pharmacokinetics in the rat

The interaction of verapamil (4 and 8 mg/kg twice daily for 7 days) and i.v. phenytoin (10 mg/kg) in male Wistar rats has been studied. Increases occurred in phenytoin plasma elimination half-life (61%; p < 0.01 and 80%; p < 0.05), the area under the plasma concentration curve (32% n.s. and 48; p < 0.05) and volume of distribution (17%; p < 0.05 and 14% n.s.) after 4 and 8 mg/kg verapamil, respectively. The clearance was reduced to 75% (n.s.) and 67% ( p < 0.05) of the control value; changes were not dose-dependent.

Verapamil interaction with phenytoin

Verapamil interaction with phenytoin

Atropine and verapamil interactions in healthy volunteers

The calcium antagonist falipamil, a chemical congener of verapamil, has anticholinergic properties. It was decided to study the interaction of verapamil with the anticholinergic drugs, atropine and pirenzepine, using healthy male volunteers. After atropine alone a significant tachycardia developed at 2 min and remained significant up to 90 min. Verapamil pretreatment followed by atropine administration resulted in a significantly greater tachycardia. Pirenzepine alone caused a bradycardic response which was accentuated after verapamil pretreatment. It is postulated that short term verapamil administration is accompanied by reflex activation of the sympathetic nervous system which does not manifest with a tachycardia owing to combined influence of verapamil and vagus on the sino-atrial node. Reduction of vagal tone with atropine treatment results in sympathetic overriding of the sino-atrial suppression, thus causing an additive tachycardia. The clinical use of atropine for prolonged verapamil-induced atrio-ventricular conduction is supported by these results.

The molecular and pharmacological basis for using calcium antagonists in hypertension

The interaction of verapamil and other phenylalkylamine calcium channelblockers with the 1,4-dihydropyridine receptor was examined. Studies characterizing the interaction and relationship between calcium channel blocking potency and binding affinity were performed in rat myocardium. The 1,4-dihydropyridines, nifedipine and nitrendipine, interacted competitively. The apparent Kd and Bmax of nitrendipine were 270±140 pm and 390±76 fmol/mg protein, respectively. In contrast, the interaction of the phenylalkylamines with the 1,4-dihydropyridine receptor was not competitive. At a 3H-nitrendipine concentration of 0.12 nm, verapamil displaced only 60% of specifically bound radioactivity and progressively less as the concentration of 3H-nitrendipine increased. Kinetic data indicated that the interaction of both D600 and verapamil with the 1,4-dihydropyridine receptor was not cooperative. At infinite dilution the dissociation rate constant (k−1) was not altered in the presence of 10−5 m D600. We examined the hypothesis that 3H-nitrendipine interacts at several sites with similar affinities and that the phenylalkylamines interact at one of these sites. Although D600 could not further displace 3H-nitrendipine in the presence of a maximally displacing concentration of nifedipine (10−6 m), nifedipine could further displace 3H-nitrendipine in the presence of a maximally displacing concentration of D600 (10−5 m). These results are consistent with competitive interactions at multiple sites but do not explain the diminished ability of the phenylalkylamines to displace progressively less radioactivity at increasing 3H-nitrendipine concentrations. No relationship between binding affinity and pharmacologic potency of the phenylalkylamines was found suggesting that the interaction of the phenylalkylamines with the 1,4-dihydropyridine receptor is not responsible for their calcium channel blocking effects.

Direct binding of verapamil to the ryanodine receptor channel of sarcoplasmic reticulum

Radioligand binding experiments and single channel recordings demonstrate that verapamil interacts with the ryanodine receptor Ca2+ release channel of the sarcoplasmic reticulum of rabbit skeletal muscle. In isolated triads, verapamil decreased binding of [3H]Ryanodine with an IC50 of approximately 8 microM at an optimal pH 8.5 and pCa 4.3. Nitrendipine and d-cis-diltiazem did not interfere with binding of [3H]Ryanodine to triads, suggesting that the action of verapamil does not involve the dihydropyridine receptor. Single channel recordings showed that verapamil blocked Ca2+ release channels by decreasing open probability, duration of open events, and number of events per unit time. A direct interaction of verapamil with the ryanodine receptor peptide was demonstrated after purification of the approximately 400 kDa receptor protein from Chaps-solubilized triads. The purified receptor displayed high affinity for [3H]Ryanodine with a Kd of approximately 5 nM and a Bmax of approximately 400 pmol/mg. Verapamil and D600 decreased [3H]Ryanodine binding noncompetitively by reducing the Bmax. Thus the presence of binding sites for phenylalkylamines in the Ca2+ release channel was confirmed. Verapamil blockade of Ca2+ release channels may explain some of the paralyzing effects of phenylalkylamines observed during excitation-contraction coupling of skeletal muscle.

Time Course of Verapamil Interaction with Morphine Effects on Physiological Parameters in Rats

The effects of subcutaneous doses of morphine and verapamil on respiratory and cardiovascular parameters have been assessed in conscious rats. Verapamil (10 mg kg-1) was injected simultaneously with morphine (16 mg kg-1) or at 10, 30, or 60 min before morphine administration. Morphine induced respiratory depression, as indicated by marked hypercapnia, hypoxia and acidosis, and caused marked tachycardia. Although morphine produced only a minor and inconsistent (but statistically significant, P less than 0.01) reduction of mean arterial blood pressure, morphine potentiated verapamil-induced hypotension. Verapamil suppressed morphine-induced hypercapnia only when injected simultaneously with morphine. Verapamil alone did not affect arterial blood gases or pH, but decreased heart rate and mean arterial blood pressure. Verapamil attenuated and delayed the maximum positive chronotropic effects of morphine at all times tested. Antagonism by verapamil of respiratory depression and tachycardia produced by morphine was unrelated to morphine levels in plasma. Thus, the explanation of verapamil-morphine interactions on respiration and cardiovascular function is not pharmacokinetic.

Interaction of verapamil and halogenated inhalation anesthetics on hypoxic pulmonary vasoconstriction.

Calcium channel blockers and halogenated inhalation anesthetics reduce hypoxic pulmonary vasoconstriction (HPV) when administered separately to isolated rat lungs. This study was undertaken to investigate the effect of combining the calcium channel blocker verapamil with halothane or isoflurane. HPV was elicited in three groups of experiments. First, we studied the effect of halothane 1.3 MAC and varying concentrations of verapamil. Halothane reduced HPV as a mean by 34.7%, and a dose-dependent reduction was seen with verapamil. The depressant effect of the combination of halothane and verapamil was significantly greater than when the drugs were administered alone. We further investigated in separate groups the effects of varying concentrations of halothane and isoflurane, administered both separately and in combination with a constant dose of verapamil (1.02 nmol). Both anesthetics depressed HPV in a dose-dependent fashion. Verapamil reduced HPV as a mean by 34.2% and 39.3% in the halothane and isoflurane groups, respectively. The inhibition caused by combining verapamil with an anesthetic was significantly greater than when administered separately. We conclude that verapamil in combination with halothane or isoflurane has an additive dampening effect on HPV.

Effects and interaction of verapamil and volatile anesthetics on the isolated perfused guinea pig heart.

The direct cardiac effects of volatile anesthetics and calcium channel blockers are obscured in vivo by autonomic reflexes and other extrinsic influences. The authors examined the direct in vitro effects of verapamil and the volatile anesthetics, halothane (HAL), enflurane (ENF), and isoflurane (ISO), in the isolated guinea pig heart. Each heart (N = 36) was perfused at constant pressure with an oxygenated Krebs-Ringer solution at 36 degrees C. Recording electrodes were placed in the right atrium, septum, and right ventricular wall. Left ventricular pressure (LVP) and coronary flow were measured. The combination of 75 or 150 ng/ml verapamil and 0.7 or 1.4 minimum alveolar concentrations (MAC) of each of the three anesthetics dose-dependently depressed spontaneous atrial rate (HR) and peak LVP, and prolonged atrial-septal (AV) time and intraventricular conduction time (IVCT). ENF decreased HR and LVP and increased IVCT more than did HAL or ISO at each anesthetic level. The combination of either level of ENF and 150 ng/ml verapamil reduced HR more than did the same level of verapamil with HAL or ISO; 1.4 MAC ENF with 150 ng/ml verapamil also caused sinus arrest in 17% of hearts. Although ENF, HAL, and ISO alone similarly depressed AV time, 1.4 MAC ENF synergistically increased, and 1.4 HAL and ISO additively increased, the delay in AV time due to each level of verapamil. In addition, 1.4 MAC ENF caused significant 25% and 67% incidences of complete AV block with low and high verapamil levels, respectively. Both levels of ENF with verapamil also increased IVCT more than did HAL or ISO with verapamil.(ABSTRACT TRUNCATED AT 250 WORDS)