Effects of nifedipine,verapamil, and diltiazem on tip growth inFunaria hygrometrica

Protonemata ofFunaria hygrometrica Sibth. were treated with nifedipine, verapamil, or diltiazem. Responses to each of the drugs were, on the one hand, reduction of growth rate and tip cell length and, on the other hand, formation of apical swellings in caulonema tip cells and of anomalously oriented separation walls between main filaments and young side branches. The first effect is regarded as a more general expression of inhibition while the second complex of effects is attributed to perturbations in directed vesicle transport. Replacement of drug-containing media by normal Knop agar demonstrated the reversibility of inhibitor action: growth parameters were comparable to those of control protonemata within a few hours. A fast reaction, the formation of subapical vacoules, occurred within minutes of drug application and was only observed with verapamil and diltiazem. In connection with this process, rapid migrations of chloroplasts took place, but examination of the microtubule cytoskeleton in such cells by indirect immunofluorescence with a monoclonal antibody against tubulin showed an intact microtubule network. callose deposits in tip cells treated with verapamil. They were polarly distributed and started to appear in cell apices about 2h after the beginning of verapamil application. Two mechanisms of action for the tested inhibitors are discussed: (i) perturbations of membrane permeability by interference with one or more of the cell's Ca²⁺-transport systems, and (ii) a more indirect mechanism affecting vesicle transport via the microfilament system.     

Interactions of digoxin with nifedipine and diltiazem

Biological serum halt-life, relative volume of distribution and digoxin clearance following a single oral dose of digoxin with diltiazem or nifedipine were evaluated. Blood serum digoxin following its administration with diltiazem and nifedipine for 8 days were assayed. It was found that diltiazem and nifedipine did not affect tested pharmacokinetic parameters of digoxin and did not change digoxin serum levels during a 8-day administration in combination with diltiazem and nifedipine.     

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 Ca²⁺-antagonists interact with histamine (H₁ or H₂) receptors. Flunarizine (inhibition constant, K_i ∼ 86 nM) was nearly as potent as diphenhydramine (K_i ∼ 44 nM) in inhibiting [³H]pyrilamine binding to cerebellar H₁-receptors, whereas verapamil, D 600 and nifedipine did not interact with this site. Regarding [³H]tiotidine binding to H₂-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 H₁-receptors might explain, in part, its sedative side-effect. The interaction of verapamil with H₂-receptors, demonstrated here for the first time, might be involved in the anti-arrhythmic action of this agent.     

Comparison of verapamil and nifedipine in thrombosis models

Calcium blockers and calmodulin antagonists have been reported to inhibit the aggregation of blood platelets in vitro. In the present study, the effects of two calcium blockers, verapamil and nifedipine, were compared in several rodent thrombosis models. In rat and mouse platelet-rich plasma, preincubation with either verapamil or nifedipine had a dose-dependent inhibitory effect on collagen-induced aggregation (P less than 0.01). The concentration required for 50% inhibition of rat platelet aggregation was 0.91 X 10(-4) M for verapamil and 1.77 X 10(-4) M for nifedipine. In in vivo thrombosis models in mice, acute pretreatment with nifedipine had a significant, dose-dependent protective effect (P less than 0.05). At a dose of 500 micrograms/kg, nifedipine inhibited thrombotic sudden death provoked by arachidonic acid, a thromboxane agonist (U46619), or a combination of collagen and epinephrine. In vivo platelet depletion induced by U46619 was also inhibited by this calcium blocker. Thus, nifedipine is protective against a variety of thrombotic stimuli, and its antiplatelet aggregatory effect apparently extends to the in vivo situation. In contrast, no in vivo antithrombotic activity was observed for verapamil. Two additional calcium blockers, perhexilene and diltiazem, and three calmodulin antagonists, W-7, chlorpromazine, and trifluoperazine, were also tested in the U46619-induced thrombotic sudden death model. Of these, only diltiazem (5 and 10 mg/kg) had an acute protective effect.     

A comparative study of clinically well-characterized human atherosclerotic plaques with histological, chemical, and ultrastructural methods

Atherosclerotic plaques (six cases) with well-documented clinical history were analysed using histology, scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy-dispersive X-ray (EDX) spectroscopy, infrared spectroscopy (IR), thermogravimetry (TG), and high-resolution synchrotron X-ray diffraction. All samples contained about 60-70 wt% biological carbonated apatite (in dry state) in a nanocrystalline form with particle sizes of about 20 nm. Structurally, there are strong similarities to bone mineral. Ultrastructural investigations documented typical calcospherites, mineralisation processes starting at collagen fibrils and ring-shaped crystalline mineralised structures. There were no significant ultrastructural or chemical differences between the calcifications of individual patients.     

Effect of diumancal,foridon, nifedipine,and verapamil on the myometrium potentials in pregnant rats

All the preparations under study were i.v. administered to pregnant Wistar rats in the doses adequate to therapeutic those on pregnant woman basis. Within 10 minutes, a drop both in the amplitude and in the rate of the myometrium potentials were found.     

Effects of nifedipine and verapamil on body temperature in cats

Nifedipine and verapamil injected into the cerebral ventricles of unanaesthetized cats produced a longlasting rise in the body temperature. The hyperthermic effect of nifedipine and verapamil were not dose-dependent. The hyperthermic effect of verapamil was preceded by a shortlasting fall in the body temperature, which was not dose-dependent. Calcium antagonists, nifedipine and verapamil also produced mydriasis, tachypnoea, dyspnoea, ataxia, tremor and muscular weakness. These symptoms were inconsistent and of slight intensity. In agreement with the theory of ionic set point controlling the body temperature, the most probable explanation is that calcium antagonists, nifedipine and verapamil produced changes in the body temperature by acting on sodium and calcium fluxes in the posterior hypothalamus.     

Nifedipine, verapamil and diltiazem block shock-wave-induced rises in cytosolic calcium in MDCK cells

Nifedipine and verapamil have been shown previously to protect against renal function alterations induced by shock wave lithotripsy (SWL) in humans and rats; however, the mechanism is unclear. This study was aimed to examine whether these drugs could protect cultured kidney cells following shock wave exposure (SWE). The effect of nifedipine, verapamil and diltiazem on Madin Darby canine kidney (MDCK) cells following SWE was examined by determining the release of glutamate oxalactate transferase (GOT) and lactate dehydrogenase (LDH) in cell suspensions; and also cytosolic Ca2+ concentration ([Ca2+]i). Immediately after SWE, there was a transient release of GOT and LDH (16% and 4 fold, respectively). In contrast, [Ca2+]i measured within 1-6 hr after SWE gradually increased by 15-156%. The Ca2+ entry blockers (1 or 10 microM) failed to inhibit the enzyme release; however, they abolished the progressive rises in [Ca2+]i. The Ca2+ entry blockers may protect the cells from damage of SWE via maintaining a low resting [Ca2+]i.     

Comparison of nifedipine and diltiazem with salbutamol for prevention of preterm delivery in the ovariectomized, oestrogen-treated late pregnant rat

The ovariectomized, oestrogen-treated, late pregnant rat has been used to compare the ability of two calcium antagonists, diltiazem and nifedipine, with an agonist at beta-adrenoceptors, salbutamol, to prevent the development of uterine contractions, prolong gestation and maintain fetal survival in utero. Preterm delivery of the fetuses was not prevented in the animals infused with salbutamol (2 micrograms/kg/min), occurring at the same time, 30-40 h after ovariectomy, as in the saline-infused rats. The overall integral of uterine contractions was significantly reduced in the salbutamol-treated compared with the saline-treated animals due to decreased contractions after abortion. Both diltiazem (100 micrograms/kg/min) and nifedipine (3.1 and 6.2 micrograms/kg/min) produced significant inhibition of uterine contractions and in contrast to salbutamol prolonged gestation and improved fetal survival in utero as assessed at post mortem on Day 21. However, maternal survival was low (57%) with the higher dose of nifedipine, possibly reflecting the relaxant effect of this compound on vascular smooth muscle with consequent underperfusion of vital organs.     

Effect of verapamil and nifedipine on the adhesion, migration and phagocytosis of human neutrophilic granulocytes

The calcium antagonists Verapamil and Nifedipin have a different effect on adherence, migration and phagocytosis of human neutrophilic granulocytes. Whereas Verapamil (10(-4) mol/1) will inhibit the leukocyte function, Nifedipin is ineffective. The leukocyte function cannot be expected to be impaired by using Nifedipin and Verapamil in therapeutic doses. The differences in efficiency and their possible causes are discussed.     

Tetracyclines,verapamil and nifedipine induce callose deposition at specific cell sites in Riella helicophylla

The Ca²⁺ indicator 7-chlorotetracycline has been shown to bind to a pore complex on both outer surfaces of all non-meristematic cells in the unistratose thallus of Riella (chlorotetracycline-binding surface region=CSR; Grotha, 1983, Planta 158, 473–481). Prolonged treatment of the thallus with 7-chlorotetracycline, 5-hydroxytetracycline, verapamil and desmethoxyverapamil induces the deposition of callose at the same region. The influence of various treatments on verapamil-induced CSR-callose was measured in situ by microfluorometry of aniline-blue-stained material. Callose deposition is maximal at 10^-4M verapamil or 5·10^-5M desmethoxyverapamil with 2·10^-4M Ca²⁺ or Mg²⁺ in the medium. The reaction is completely inhibited at pH 5.5 and is optimal between pH 6.5 and 7.5. The production of CSR-callose is absolutely light-dependent with callose being first visible after 30 min of light. La³⁺, ethylene glycol-bis(-aminoethylether)-N,N,N,N-tetraacetic acid and amiprophosmethyl, antagonists of Ca²⁺ functions, and 2-deoxy-D-glucose suppress the verapamil induction of CSR-callose. Furthermore the ionophores A 23187, valinomycin and monensin effectively block the reaction. The deposition of CSR-callose is diminished at increasing external osmolarity and is abolished at osmotic values that stimulate plasmolysis-callose. Wounding causes the formation of wound-callose but inhibits the induction of CSR-callose in cells of the wound edge. Nifedipine increases or prolongs callose synthesis in cell plates. The Ca²⁺-channel blocker diltiazem is completely ineffective. It is suggested as a working hypothesis that verapamil-induced CSR-callose synthesis is caused by a local change in membrane permeability, possibly as a consequence of the opening of Ca²⁺ channels being involved in Golgi-vesicle mediated exocytosis (A. Kramer and H. Lehmann, 1986, Ber. Dtsch. Bot. Ges. 99, 111–121).Abbreviations APM amiprophosmethyl - APW artificial pond water - CSR chlorotetracycline-binding surface region - CTC 7-chlorotetracycline - DDG 2-deoxy-D-glucose - EGTA ethylone glycol-bis(2-aminoethylether)-N,N,N,N-tetraacetic acid - OTC 5-hydroxytetracycline - Pipes 1,4-piperazinediethane sulfonic acid Dedicated to Professor Luise Stange on the occasion of her 60^th birthday     

Effects of amlodipine, diltiazem, and verapamil on the anticonvulsant action of topiramate against maximal electroshock-induced seizures in mice

To assess the effect of 3 calcium channel antagonists (amlodipine, diltiazem, and verapamil) on the anticonvulsant action of topiramate (a new generation antiepileptic drug) in the mouse maximal electroshock seizure (MES) model. Amlodipine (20 mg/kg) significantly enhanced the anticonvulsant activity of topiramate in the MES test in mice, reducing its ED50 value from 54.83 to 33.10 mg/kg (p < 0.05). Similarly, diltiazem (5 and 10 mg/kg) markedly potentiated the antiseizure action of topiramate against MES, lowering its ED50 value from 54.83 to 32.48 mg/kg (p < 0.05) and 28.68 mg/kg (p < 0.01), respectively. In contrast, lower doses of amlodipine (5 and 10 mg/kg) and diltiazem (2.5 mg/kg) and all doses of verapamil (5, 10, and 20 mg/kg) had no significant impact on the antiseizure action of topiramate. Pharmacokinetic verification of the interaction of topiramate with amlodipine and diltiazem revealed that neither amlodipine nor diltiazem affected total brain topiramate concentration in experimental animals, and thus, the observed interactions were concluded to be pharmacodynamic in nature. The favorable combinations of topiramate with amlodipine or diltiazem deserve more attention from a clinical viewpoint because the enhanced antiseizure action of topiramate was not associated with any pharmacokinetic changes in total brain topiramate concentration.     

Platelet aggregation in patients with coronary disease treated with nifedipine

The effect of nifedipine on the aggregation of blood platelets has been studied in patients with coronary heart disease. The study involved 78 males, aged between 36 and 64 years (mean age 51 years). The level of aggregation was evaluated before and after a single nifedipine dose of 10 mg (in 15 patients) and of 20 mg (in 34 patients) as well as before and after the treatment with nifedipine (of 29 patient) with a daily dose of 30 mg for two weeks. Aggregation of blood platelets induced by adenosine--diphosphate in of concentrations 1 microM/ml and of 5 microM/ml were estimated by the Born method. It was found that nifedipine reduces the aggregation of the blood platelets in patients with coronary heart disease following single and long-term treatment.     

Lack of melatonin response to acute administration of nifedipine and diltiazem in healthy men

Calcium antagonists have been shown to influence some endocrinological processes in mammals. The use of calcium channel blockers in clinical practice is well documented. The current study monitored nocturnal melatonin, prolactin, and cortisol levels in 19 healthy volunteers before and after administration of calcium channel blockers. The effect of nifedipine was tested in 9 subjects, while diltiazem was administered in 10 men. The nocturnal profile of the given parameters was studied between 23:00 and 05:00 h. At midnight (zero time), the participants were given placebo, nifedipine (in a sublingual dose of 20 mg) or diltiazem (in a single dose of 90 mg). The hypothesis that calcium channel blockers decrease nocturnal melatonin secretion has not been confirmed. The mean nocturnal levels of melatonin between 01:00 and 05:00 h were: 78.1+/-8.8 (control study) vs. 82.4+/-10.2 ng/l (nifedipine study) and 73.0+/-5.3 ng/l (control study) vs. 75.1+/-5.1 ng/l (diltiazem study). In conclusion, the calcium channel blockers used in this study do not alter the nocturnal melatonin secretory process in healthy men.