Interaction Of Verapamil Research Articles

Verapamil, neuromuscular transmission and the nicotinic receptor

The effect of verapamil on neuromuscular transmission was studied in the frog by analysing ionophoretic endplate current (iEPC) trains and the growth and decay phases of miniature endplate currents (mepcs). In addition, single channel data on the interaction of verapamil with the nicotinic acetylcholine receptor were obtained from cultured embryonic chick skeletal muscle cells. Verapamil caused both open and closed channel blockade in the iEPC trains. Mepc amplitude was decreased at low micromolar concentrations, and at higher concentrations there was also accelerated mepc decay indicating open channel blockade. The latter effect oould not be explained by a sequential channel occlusion mechanism. Analysis of the mepc rising phase showed that low micromolar concentrations of the drug decreased the pool of receptors which could be activated. Single channel data confirmed the specific interaction of verapamil with the nicotinic receptor, showing closed channel blockade at low concentrations, and at higher levels the shortening of open channel lifetime. It is suggested that both forms of blockade may involve desensitization processes.

Interaction of Verapamil with Gallamine and Pancuronium and Reversal of Combined Neuromuscular Blockade with Neostigmine and Edrophonium

In this in vitro study, the effects and interactions of verapamil with gallamine and pancuronium and reversal by edrophonium and neostigmine of combined neuromuscular blockade, produced by the muscle relaxants and verapamil, were studied in an avian skeletal muscle. The results show that verapamil reduced the amplitude of indirectly-elicited twitch tension and potentiated the neuromuscular blockade produce by the two muscle relaxants. Edrophonium and neostigmine reversed the neuromuscular blockade produce by the muscle relaxants alone, and in combination with verapamil. Edrophonium was more potent than neostigmine in reversing the combined neuromuscular blockade produced by the muscle relaxants with and without verapamil.

Additive competitive interaction of verapamil and quinidine at alpha-adrenergic receptors of isolated cardiac guinea pig myocytes and human platelets

Recent clinical work has questioned the safety of a combined therapy of oral quinide and intraveneous verapamil, because some patients were reported to react with severe hypotension probably due to drug interactions with vascular alpha-adrenergic receptors. In order to obtain further quantitative information on the underlying mechanism, we used the radioligands ( 3H)-prazosin and ( 3H)-yohimbine to perform binding studies on intact cells, with predominantly alpha-1 (isolated myocytes) or alpha-2 subtypes (human platelets) of adrenergic receptors. Our studies confirm that both verapamil and qunidine possess a distinct alpha-adrenergic receptor blocking activity and do not discriminate between the alpha-1 and alpha-2 subtype (Ki-values were between 0.24 – 0.28 μmol/1 for alpha-1 receptors and 0.49 – 0.50 μmol/1 for alpha-2 receptors). Their interaction was competitive and in the presence of both drugs inhibition of radioligand binding was additive. The alpha-adrenergic blockade by verapamil was stereospecific as D-verapamil increased the dissociation constant of the radioligand to a much lesser degree than L-verapamil (Ki = 1.67 ± 0.29 μmol/1 for D-verapamil). The calcium channel blocker nitrendipine, a 1,4-dihydropyridine derivative, did not show any competition up to concentrations of 10 μmol/1. Our results thus give evidence that verapamil and quinidine have already at therapeutic blood levels significant alpha-adrenergic blocking activies which may be of clinical interest. In addition our results show that adult cardiac myocytes are very well suited for pharmacological adrenergic interaction studies.

Verapamil interaction with the muscarinic receptor: Stereoselectivity at two sites

Verapamil, in addition to blocking calcium channels, exhibits such “non-specific” effects on myocardium as inhibition of sodium and potassium conductances and modifications of muscarinic receptor-ligand interactions. To characterize further the effects of verapamil on the cardiac muscarinic receptor, we examined the abilities of the enantiomers of verapamil to modify the binding of the muscarinic antagonist [ 3H]quinuclidinyl benzilate ([ 3H]QNB) to purified canine sarcolemmal vesicles. Membranes were incubated with [ 3H]QNB and various concentrations of racemic, (+)-, or (−)-verapamil (25 or 37°, pH 7.4), and reactions were terminated by rapid filtration. (−)-Verapamil ( K i ), of 5.3 ± 0.2 μM) was twice as potent an inhibitor of equilibrium binding as (+)-verapamil ( K i ) of 11.4 ± 0.6 μM), and this effect resulted from the ability of each enantiomer to slow [ 3H]QNB-receptor association. This degree of stereoselectivity, albeit at nanomolar concentrations, was similar to that observed for each enantiomer to compete for the specific phenylalkylamine site in this preparation. Verapamil also inhibited [ 3H]QNB-receptor dissociation, but this effect required high concentrations and demonstrated stereoselectivity opposite to that observed for association. These findings support the view that verapamil interacts with two distinct sites, possibly within membrane lipid, each with a different affinity and preference for (+)- and (−)-verapamil, to modify the muscarinic receptor.

Selective interactions of verapamil with anthraquinones in adriamycin-sensitive and -resistant murine and human tumour cell lines in vitro.

Enhancement of the cytotoxicity of adriamycin (ADR) by addition of verpamil (VPM) was selective and, in part, concentration-dependent. In an ADR-resistant murine L5178Y lymphoma subline sensitivity was improved with ADR and 1 microM VPM, whereas the cytotoxic effects of mitoxantrone or esorubicin were not affected by VPM. In human ovarian SK-OV-3 tumour cells ADR cytotoxicity was only enhanced by 6.6 microM VPM and there was no selective advantage against an ADR-resistant subline. Circumvention of ADR resistance by VPM is not a universal phenomenon, appearing least effective against sublines expressing relatively low orders of resistance, which may be those most commonly encountered clinically.

Interaction of verapamil with atracurium and reversal of combined neuromuscular blockade with edrophonium and neostigmine.

In this study, we have demonstrated, in rat phrenic nerve hemidiaphragm preparation, that (a) verapamil (2.2–220 μM) potentiated atracurium (0.8–80 μM)-induced neuromuscular blockade, by enhancing atracurium-induced depression of indirect twitch tension, by 35–45%, (b) neostigmine (60 nM) and edrophonium (50 nM) both effectively (by 18±2% and 25±1%, respectively, means ± S.E., n = 6, P< 0.05, P< 0.01) reversed atracurium and atracurium-verapamil blockade, with no significant difference between the reversals of the latter two blockades, and (c) verapamil may act at both pre- and postjunctional sites at the rat neuromuscular junction.

Interaction of verapamil with d‐tubocurarine and cholinergic agonists at the avian neuromuscular junction

The effect of verapamil on neuromuscular transmission and muscle contraction was studied in the skeletal muscle of chick in vitro. The interactions of verapamil with d-tubocurarine (d-TC)-induced neuromuscular blockade, acetylcholine (ACh) and tetraethylammonium (TEA)-induced contractures were also studied. The purpose of the present investigation was to see if verapamil: intensified the neuromuscular blockade produced by d-TC; modified the cholinergic responses to ACh, TEA; and inhibited both directly and indirectly elicited twitch contractions. The results showed that verapamil (1-100 micrograms/ml, 2-200 mumol/l) had a neuromuscular blocking activity on its own; i.e. it reduced both directly and indirectly evoked twitch contractions, and intensified the neuromuscular blockade produced by d-TC. In addition, verapamil reduced the contractures produced by ACh and TEA in the chick muscle. The results are in favour of the possibility that verapamil acts by a mixture of pre- and post-junctional effects at the chick neuromuscular junction.

Verapamil interaction see Digoxin

Verapamil interaction see Digoxin

The interaction of phenylalkylamine calcium channel blockers with the 1,4-dihydropyridine binding site

The interaction of verapamil and other phenylalkylamine calcium channel blockers 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.

Verapamil intensifies neuromuscular blockade produced by gallamine and pancuronium at the chick neuromuscular junction

Experiments were performed to study the effect of verapamil on neuromuscular transmission and muscle contraction at a chick skeletal muscle-nerve preparation. In addition,the effects and interactions of verapamil with some muscle relaxants were studied in the same preparation. These effects were explored by studying the effects of verapamil on: (a) directly-and indirectly-elicited twitch contractions,and (b) neuromuscular blockade produced by gallamine and pancuronium. The results showed that verapamil (2–200 μM) had a differential effect on the twitch responses; more reductions occurred in the indirectly-elicited twitch tension, whereas the directly-elicited twitch response was reduced only by 20–30% of maximum indirectly-elicited twitch tension. Furthermore, in low concentrations (1–20 μM), verapamil significantly increased the neuromuscular blockade produced by gallamine(28–1280 M) and pancuronium(18–573 nM).In high concentrations (> 200 μM),verapamil completely blocked the indirectly-elicited twitch response and produced a marked contracture in the chick skeletal muscle (1.0±0.1 g, n=6). It was concluded that by reducing twitch tension and inhibiting neuromuscular transmission, verapamil increases (intensifies) neuromuscular blockade produced by muscle relaxants, e.g. gallamine and pancuronium.

Interactions of verapamil, D 600, flunarizine and nifedipine with cerebral histamine-receptors

Experiments conducted on membrane fractions of guinea-pig brain using ligand-binding techniques have shown that certain Ca(2+)-antagonists interact with histamine (H(1) or H(2)) receptors. Flunarizine (inhibition constant, K(i) ? 86 nM) was nearly as potent as diphenhydramine (K(i) ? 44 nM) in inhibiting [(3)H]pyrilamine binding to cerebellar H(1)-receptors, whereas verapamil, D 600 and nifedipine did not interact with this site. Regarding [(3)H]tiotidine binding to H(2)-receptors of cerebral cortex, verapamil (K(i) ? 1400 nM) and D 600 (K(i) ? 1240 nM) were nearly as potent as cimetidine (K(i) ? 910 nM) whereas flunarizine and nifedipine were inactive. The interaction of flunarizine with H(1)-receptors might explain, in part, its sedative side-effect. The interaction of verapamil with H(2)-receptors, demonstrated here for the first time, might be involved in the anti-arrhythmic action of this agent.

Characteristics of the Inhibition of Ligand Binding to Serotonin Receptors in Rat Brain Membranes by Verapamil

AbstractAbstract—Characteristics of the interaction of verapamil with serotonin receptors were studied in rat brain membranes using a radioligand binding technique. While verapamil competed for the [3H]ketansenn binding sites at low concentrations with the K1 value of 0.41 μM. much higher concentrations were needed to inhibit the binding of [3H]serotonm to its binding sites, indicating higher affinity of verapamil binding for 5-HT3 than 5-HT1 receptors. The inhibitory action of verapamil on the [3H]ketanserin binding was stereoselective; the (−)isomer was about ten times more potent than the (+)isomer. The interaction of verapamil with [3H]-ketanserin was competitive and reversible. While D600. a verapamil derivative, also competed for the [3H]ketansenn binding sites, nifedipine and nicardipine had practically no ability to inhibit the ligand binding to 5-HT1 or 5-HT2 receptors. Although diltiazem competed for 5-HT2 receptors, the affinity was much less than verapamil and D600.

Tubocurarine interaction see Verapamil interaction

Tubocurarine interaction see Verapamil interaction

Effect of verapamil on molecular characteristics of myocardial actomyosin in experimental ischemia

Verapamil was shown to be able to recover a significantly depressed actomyosin ATPase activity of the unaffected left ventricular area in experimental myocardial ischemia. The drug also increased Ca-sensitivity of the ATPase reaction, with the amount of actomyosin components (Tn-1, LCM-1, LCM-2, Tn-C) almost reaching the control level. The possibility of direct interaction of verapamil with Ca-binding sites on actomyosin macromolecule is suggested. Its influence on metabolism and gene expression is not excluded.

Verapamil interaction see Digoxin interaction

Verapamil interaction see Digoxin interaction

The interaction of verapamil and norverapamil with beta-adrenergic receptors.

To determine the effect of calcium-channel blockers on beta-adrenergic receptors, we studied the interactions of verapamil, diltiazem, and nifedipine with both human lymphocyte beta 2-adrenergic receptors and rat myocardial beta 1-adrenergic receptors by means of radioligand binding assays. We also determined the functional consequences of these interactions by measuring adenylate cyclase activity. Radioligand binding studies in vitro demonstrated a Ki of verapamil for the lymphocyte beta 2-receptor of 32 +/- 4 microM. Diltiazem and nifedipine were much less potent. In studies of adenylate cyclase activity, verapamil was shown to act as a competitive beta-receptor antagonist. Also, norverapamil, the active metabolite of verapamil, had the highest affinity for the beta-receptor of any of the calcium-channel blockers studied (Ki = 4.2 +/- 0.8 microM). After 1 week of verapamil administration in six normal subjects, isoproterenol-stimulated adenylate cyclase activity in lymphocytes was increased from 60 +/- 4% to 83 +/- 10% over basal activity (p less than .05). This was associated with an increase in lymphocyte beta-receptor affinity for agonist as represented by the decrease in the IC50 for isoproterenol inhibition of [125I] iodocyanopindolol binding from 240 +/- 20 to 170 +/- 10 nM (p less than .05). Additionally, plasma norepinephrine levels were reduced from 206 +/- 58 to 92 +/- 18 pg/ml with 1 week of verapamil treatment (p less than .05). Our data suggest that verapamil affects lymphocyte beta-receptors in vitro and with long-term administration regulates lymphocyte beta-receptor function either directly or indirectly via a reduction in plasma catecholamine levels.

Rifampicin interaction see Verapamil interaction

Rifampicin interaction see Verapamil interaction

Verapamil interaction see Quinidine

Verapamil interaction see Quinidine

Chapter IV: Digoxin—Verapamil Interaction

Chapter IV: Digoxin—Verapamil Interaction

Verapamil is a competitive inhibitor of γ-aminobutyric acid and calcium uptakes by mouse brain subcellular particles

We found that verapamil and its methoxy analogue, D600, were relatively potent (micromolar) inhibitors of Na +-dependent GABA uptake by a mouse brain microsomal subfraction (P 3). Verapamil was competitive with GABA and uncompetitive with Na + in the uptake assay with the P 3 fraction. These substances were much less effective in inhibiting GABA binding in a receptor-related assay system with synaptosomal membranes. Inhibition by verapamil of Na +-dependent 45Ca ++ uptake by the P 3 particles was competitive with Ca ++. A consideration of our results with those in the literature led to the suggestion that the interaction of verapamil and related substances with GABA and 45Ca uptake processes by the P 3 fraction, as well as with many other membrane activities, may be allosteric in nature rather than directly competitive with specific ligands at their binding sites.