Interaction Of Calcium Channel Blockers Research Articles

Electrochemical, spectroscopic and molecular docking studies on the interaction of calcium channel blockers with dsDNA

This study presents evaluation of the possible interaction mechanism between calf thymus dsDNA and three calcium antagonists; nifedipine, lercanidipine and amlodipine. The interactions between Nifedipine-dsDNA and Lercanidipine-dsDNA were investigated by differential pulse voltammetry using two different interaction methods; at the dsDNA-electrochemical biosensor surface and in bulk incubated solution. Amlodipine was used as model drug in bulk incubated solution. The decrease in the peak current of guanine and adenine were used as an indicator for confirmation of the interaction event in acetate buffer of pH 4.70. In bulk incubated solution, after interaction with Nifedipine and Amlodipine the guanine signal was almost disappeared. At the dsDNA modified glassy carbon electrode surface, the peak currents of guanine and adenine were decreased while Nifedipine and Lercanidipine interacts with DNA. The interactions between Nifedipine-dsDNA and Lercanidipine-dsDNA were further studied by UV–Vis absorption spectroscopy which indicates the intermolecular interaction between these drugs and ds-DNA can be mainly through hydrogen bonding and van der Waals forces. Molecular docking calculations shown that the AMP-1-2, NDP and LDP-1-2-ctDNA having groove binding. Beside spectral data, docking studies elicited that AMP-1-2, NDP and LDP-1-2 complexes have different interaction and conformation trends to target (ctDNA).

CYP4A/CYP2C modulation of the interaction of calcium channel blockers with cyclosporine on EDHF-mediated renal vasodilations in rats

The endothelium-derived hyperpolarizing factor (EDHF) serves as a back-up mechanism that compensates for reduced nitric oxide (NO)/prostanoids bioavailability. Here we investigated whether (i) under conditions of vascular endothelium dysfunction, the immunosuppressant drug cyclosporine (CSA) upregulates EDHF-dependent renal vasodilations through altering CYP4A/CYP2C signaling, and (ii) calcium channel blockers modulate the CSA/EDHF/CYP interaction. Rats were treated with CSA, verapamil, nifedipine, or their combinations for 7days. Blood pressure (BP) was measured by tail-cuff plethysmography. Kidneys were then isolated, perfused with physiological solution containing L-NAME (NOS inhibitor) and diclofenac (cyclooxygenase inhibitor, DIC), and preconstricted with phenylephrine. CSA (25mgkg−1day−1 for 7days) increased BP and augmented carbachol renal vasodilations. The co-treatment with verapamil (2mgkg−1day−1) or nifedipine (3mgkg−1day−1) abolished CSA hypertension and conversely affected carbachol vasodilations (increases vs. decreases). Infusion of MSPPOH (epoxyeicosatrienoic acids, EETs, inhibitor) reduced carbachol vasodilations in kidneys of all rat groups, suggesting the importance of EETs in these responses. By contrast, 20-Hydroxyeicosatetraenoic Acid (20-HETE) inhibition by HET0016 increased carbachol vasodilations in control rats, an effect that disappeared by CSA treatment, and reappeared in rats treated with CSA/verapamil or CSA/nifedipine. Renal protein expression of CYP2C and CYP4A as well as their vasoactive products (EETs/20-HETE) were increased in CSA-treated rats. Whereas the CYP2C/EETs effects of CSA were abolished by verapamil and intensified by nifedipine, the CYP4A/20-HETE effects were reduced by either CCB. Overall, nifedipine and verapamil blunts CSA hypertension but variably affected concomitantly enhanced EDHF-dependent renal vasodilations and alterations in CYP2C/CYP4A signaling.

CYP4A/CYP2C Modulation of the Interaction of Calcium Channel Blockers with Cyclosporine on EDHF‐Mediated Renal Vasodilations in Rats

The endothelium‐derived hyperpolarizing factor (EDHF) is a back‐up mechanism that compensates for reduced nitric oxide (NO)/prodtanoids bioavailability. Here we investigated whether (i) cyclosporine (CSA, immunosuppressant drug) upregulates EDHF‐dependent renal vasodilations through altering CYP4A/CYP2C signaling, and (ii) calcium channel blockers modulate the CSA/EDHF/CYP interaction. Rats were treated with CSA, verapamil, nifedipine, or their combination for 7 days. Systolic blood pressure (SBP) was measured by Tail‐cuff plethysmography. Kidneys were then isolated, perfused with physiological solution containing L‐NAME (NOS inhibitor) and diclofenac (cyclooxygenase inhibitor), and preconstricted with phenylephrine. Carbachol vasodilations were established before and after the inhibition of 20‐HETE or EETs. CSA (25 mg.kg−1.day−1 for 7 days) increased SBP and augmented carbachol renal vasodilations. The concurrent administration of verapmil (2 mg.kg−1.day−1) or nifedipine (3 mg.kg−1.day−1) abolished the hypertensive effect of CSA and produced divergent effects on carbachol vasodilations (increases versus decreases). The infusion of MSPPOH (EETs inhibitor) reduced carbachol vasodilations in perfused kidneys of all rat groups, suggesting the importance of EETs in these responses. Moreover, HETE‐20 inhibition by HET0016 increased carbachol vasodilations in control rats, an effect that disappeared in CSA‐treated, and reappeared in rats treated with CSA/verapamil or CSA/nifedipine. The renal protein expression of CYP2C and CYP4A as well as their vasoactive products (EETs and 20‐HETE) were increased in CSA‐treated rats. Whereas the CYP2C/EETs effects of CSA were abolished by verapamil and intensified by nifedipine, the CYP4A/20‐HETE effects were reduced by verapamil only. Overall, CYP2C/EETs and CYP4a/20‐HETE pathways variably modulate the contracting effects of nifedipine and verpamil on CSA‐evoked facilitation of EDHF‐dependent renal vasodilations. These effects may not be related to changes in SBP.Support or Funding InformationSupported by the Lebanese National Council for Scientific Research (CNRS) Grant Award for Lebanese graduates (Awardee: Safaa Hammoud).

Interaction of calcium channel blockers and grapefruit juice in healthy adults

Interaction of calcium channel blockers and grapefruit juice in healthy adults

Pharmacokinetic drug-drug interaction of calcium channel blockers with cyclosporine in hematopoietic stem cell transplant children.

Cyclosporine (CsA) is frequently responsible for hypertension in bone marrow transplant children. Calcium channel blockers (CCBs) are considered to be the best treatment for CsA-induced hypertension, but they may alter the exposure and the effect of CsA by inhibiting the CYP3A4 pathway of CsA metabolism or P-gp. However, the inhibitory effect on CYP3A4 may vary among CCBs. This study aimed to quantify the pharmacokinetic drug-drug interaction between CsA and nicardipine, amlodipine, and lacidipine. In all, 51 children who received CsA and CCB concomitantly were included. Dose-normalized CsA trough blood concentrations significantly increased in patients treated with nicardipine and amlodipine, whereas they remained stable in patients treated with lacidipine. Because lacidipine appears to have no effect on CsA exposure, it may be the best option among CCBs for treating high blood pressure caused by CsA in children.

Formation of DNA-damaging N-nitroso compounds from the interaction of calcium-channel blockers with nitrite

A large number of drugs have been shown to react with nitrite to give genotoxic–carcinogenic N-nitroso compounds (NOC). However, the majority of drugs remain to be examined in this respect, among which calcium-channel blockers, all theoretically nitrosatable and widely used in the therapy of hypertension and other cardiovascular diseases. In this preliminary investigation, seven calcium-channel blockers have been examined either for their in vitro nitrosation according to the procedure recommended by the WHO, or for occurrence of liver DNA fragmentation, as detected by the Comet assay, in rats given by gavage 1/2 LD50 of the drug and 80 mg/kg of sodium nitrite. After 6 h incubation the yields of NOC formed in vitro from nicardipine, nifedipine, nimodipine and nitrendipine ranged from 37 to 45% of the theoretical one, whereas the yields of NOC formed from diltiazem, gallopamil and verapamil ranged from 2 to 5%. In vivo, as compared with the effect of the same dose of the drug alone, a significant increase of both tail length and tail moment, indicative of an increased frequency of DNA single-strand breaks and alkali-labile sites, was produced in rat liver DNA by the administration with nitrite of gallopamil, nifedipine, nimodipine and nitrendipine, the ratio [tail length of drug + NaNO 2/tail length of drug alone] being 3.2 for nimodipine, 3.1 for gallopamil 2.2 for nifedipine, and 2.1 for nitrendipine. Even if present, the increase in the degree of DNA fragmentation did not reach the statistical significance in rats given with nitrite nicardipine, diltiazem and verapamil. Further studies should be performed to investigate the formation of NOC in conditions simulating those occurring in the stomach of humans treated with a therapeutic dose, and to quantitate their genotoxic potency.

New insights into the therapeutic mechanism of action of calcium channel blockers in salt-dependent hypertension: their interaction with endothelin gene expression.

It appears that the beneficial action of calcium channel blockers (CCBs) in hypertension may be related to short-term and long-term effects. This paper summarises pharmacological studies aiming to characterise those effects. The primary consequence of the short-term effects is the decrease of blood pressure related to a selective interaction of CCBs with calcium channels in hypertensive vessels. The long-term effects may additionally control the disease through prevention of end organ damage, accompanying the interaction of CCBs with the pathways, leading to the re-expression of embryonic genes and to the overactivation of type I collagen gene, which are amplified by a high-salt diet. ET-1 and tumour growth factor beta-1 could be among the main factors activating those pathways. The processes leading to overexpression of those factors and to tissue remodelling may be controlled by lacidipine, independent of the reduction of blood pressure.

Interaction of Calcium Channel Blockers and Excitatory Amino Acid Antagonists with Conventional Antiepileptic Drugs

Interaction of Calcium Channel Blockers and Excitatory Amino Acid Antagonists with Conventional Antiepileptic Drugs

The comparative effects of verapamil and a new dihydropyridine calcium channel blocker on digoxin pharmacokinetics

Conflicting conclusions have been reported about interaction of calcium channel blockers with digoxin. The effects of verapamil (240 mg/day) and a new dihydropyridine calcium channel blocker, isradipine (15 mg/day), on the pharmacokinetics of 1 mg intravenous digoxin were compared. All 24 volunteer subjects were healthy, male, nonobese, and aged 18 to 38 years. Groups of 12 subjects received each oral agent over 15 days, with collections of blood and urine for 72 hours after intravenous digoxin. Significant (P less than 0.05) reduction in nonrenal (7.01 +/- 1.97 to 4.00 +/- 1.86 L/hr) and total clearance (14.1 +/- 2.6 to 11.5 +/- 2.5 L/hr) were induced by verapamil, without change in renal clearance. A near-significant (P less than 0.1) increase in peripheral volume of distribution contributed to prolonged elimination half-life (23.1 +/- 4.4 to 34.3 +/- 9.7 hours). By contrast, isradipine caused only a 9% reduction in volume of distribution. Verapamil causes digoxin accumulation by reducing nonrenal elimination. No evidence of clinically relevant interaction of isradipine with digoxin was seen.

Interaction of calcium channel blockers with non-neuronal benzodiazepine binding sites.

The ability of calcium channel blockers to displace the binding of benzodiazepine ligands was investigated in rat heart, kidney, and brain. The dihydropyridine calcium channel blockers nifedipine and nitrendipine displaced the binding of the non-neuronal-site ligand [3H]Ro5-4864, but not that of the neuronal-site ligands [3H]flurazepam or [3H]clonazepam. The inhibition was competitive, with Ki values in the micromolar range. Other calcium channel blockers--i.e., verapamil and diltiazem--were inactive at both sites. Thus, non-neuronal benzodiazepines bind to a class of sites that also binds dihydropyridines. This implies a role for benzodiazepines in the mediation of calcium-dependent phenomena.

Interaction of verapamil and other calcium channel blockers with alpha 1- and alpha 2-adrenergic receptors.

To determine the specificity of the previously demonstrated competition of verapamil with radioligand binding to alpha-adrenergic receptors, we examined the interaction of calcium channel blockers with alpha 1- and alpha 2-adrenergic receptors on several tissues. Verapamil competed for [3H] prazosin binding to alpha 1-adrenergic receptors and for [3H]yohimbine binding to alpha 2-adrenergic receptors in several tissues (human platelets, rat kidney and heart, and cultured muscle cells) with dissociation constants of 0.6-6 microM. The calcium channel blockers D600, D591, fendiline, and prenylamine--which are structural analogues of verapamil--also competed for [3H]yohimbine binding to human platelets. Two other calcium channel blockers, diltiazem and nifedipine, did not compete for [3H] yohimbine binding to human platelets or [3H]prazosin binding to membranes prepared from rat ventricles. We used [3H]nitrendipine binding to identify putative calcium channels on rat myocardial membranes. Nifedipine and verapamil blocked these [3H]nitrendipine-binding sites on ventricular membranes, but epinephrine and prazosin did not, indicating that the ventricular alpha 1 receptors and calcium channels are distinct. We found no specific [3H]nitrendipine binding to human platelets. We conclude that the interaction of verapamil with alpha-adrenergic receptors is not receptor subtype or tissue specific, that interaction with alpha-adrenergic receptors is not a property of all calcium channel blockers, and that the interaction of verapamil with alpha-adrenergic receptors and its interaction with calcium channels occur at at least two distinct sites.