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At least 307 records · Page 17Linked to original sources
PubMed1985

Involvement of intracellular Ca2+ in chemotaxis and metabolic burst by neutrophils: the use of antagonists of intracellular Ca2+.

The effect of TMB-8, quin2, chlortetracycline, chlorpromazine and prenylamine on two neutrophil functions - chemotaxis towards fMLP and metabolic burst activated by PMA or fMLP - was compared. All drugs inhibited both functions in the absence of extracellular Ca2+. The inhibitory effect of all drugs on chemotaxis, and the effect of TMB-8, quin2 and chlortetracycline on the metabolic burst was antagonized by extracellular Ca2+. There were differences between inhibition of chemotaxis and the metabolic burst, and between inhibition of PMA activated and fMLP-activated metabolic burst. The results are consistent with the view that intracellular Ca2+ is required in chemotaxis, and in PMA or fMLP activated metabolic burst, but that the role of Ca2+, or the location where Ca2+ is derived from, is different and depends on function and the type of activator.

Animals↗
PubMed1979

[Verapamil and torsade de pointe (author's transl)].

A long QT syndrome is described, followed by "torsade de pointe" that is ascribed to an hypopotassemia in a patient submitted to administration of prenylamine, vincamine, digitalis and furosemide. The efficacy of verapamil i.v. is related.

Aged↗
PubMed1980

Experimental prevention of venous thrombosis.

Modern antithrombotics are no more represented merely by anticoagulants. The experiments with a series of thrombosis models enabled us to redefine several new groups appearing as yet under the name "antiplatelet agents" or "antiaggregants". The group comprises particularly acetylsalicylic acid, dipyridamole, hydroxychloroquine, sulfinpyrazone, clofibrate and suloctidyl. It was demonstrated experimentally that these drugs act predominantly by increasing endothelial stability against various noxious agents. This stabilizing effect, independent on the anticoagulant activity, is present also after the administration of oral anticoagulants in doses by one order lower in comparison with the anticoagulant dosage. In fact, the latter dosage has an opposite effect on endothelium and increases the number of circulating endothelial cells. Nevertheless, this unfavourable effect may be inhibited by suitable endotheloprotective drugs (e. g. prenylamine) and in this way an important portion of bleeding complications after oral anticoagulants may be abolished.

Animals↗
PubMed1980

[Clinical evaluation of a new antianginal drug: droprenylamine].

In this study the antianginal action of droprenylamine, a cycloaliphatic derivative of prenylamine, was evaluated. Forty patients were included in three groups: in the first group a double blind study was carried out, while in the other two groups, both treated with droprenylamine for a 12 weeks period, were evaluated the effects on workload tolerance or the efficacy in reducing the number of angina pectoris episodes per week and the assumption of nitroglycerine. The double blind study shows that droprenylamine is able to reduce significantly the nitroglycerine assumption. Furthermore, during the 12 week treatment with droprenylamine we can observe a significant reduction of the ST segment depression, at comparable workloads, a significantly increased tolerance to stress test and an early and significant reduction of the angina attacks and, subsequently, of the assumption of nitroglycerine. In conclusion, this drug, which appears free of side effects, may be useful in the treatment of angina pectoris; in particular, the possible association with other antianginal drugs should be evaluated.

Adult↗
PubMed1995

[Effects of calcium channel blockers on electrical and mechanical responses of rat phrenic nerve-diaphragm preparations].

The effects of diltiazem, prenylamine and verapamil on the electrical and mechanical responses of a rat phrenic nerve-diaphragm preparation were investigated as a function of the indirect stimulating frequency. The amplitude of the muscle compound action potential was depressed by all three drugs with stimulation between 3 and 50 Hz. The contractile force of the diaphragm was increased by these drugs in concentrations of 3 x 10(-8)-3 x 10(-5) mol/l at low frequency (3-10 Hz), but the contractility was decreased at higher concentrations (above 3 x 10(-5) mol/l). In contrast, a facilitating effect was not observed at a higher stimulating frequency (above 20 Hz), but a concentration depressant effect did develop above 1 x 10(-6) mol/l. The literature data and our results suggest that low concentrations of calcium channel blocking agents can not influence the trigger calcium current at low frequency (under 15 Hz), but calcium liberation and the contractile force are increased by these drugs. The intracellular calcium liberation triggered by the calcium current or the muscle force was inhibited by these drugs at higher concentrations. Above 15 Hz, the liberated intracellular calcium is insufficient for the contraction, so an adequate quantity of calcium is obtained from the extracellular space. It is suggested that an adequate calcium uptake is inhibited at low concentrations of these drugs at higher frequency, and the contractility is thereby inhibited.

Animals↗
PubMed1975

[Calcium-antagonism, a new principle in coronary vasodilation].

As in all other vessels, coronary contractile tone depends on the availability of Ca ions. Thus, Ca-antagonistic drugs such as verapamil, prenylamine or nifedipine produce a loss of muscle tone in depolarized coronary strips. One molecule of these compounds successfully blocks the action of thousands of Ca ions in excitation-contraction coupling. Nitroglycerine and other nitrites exert a similar action, though in their case relaxation is more rapid, incomplete and spontaneously reversible. In analogy to their well-known Ca-synergistic action on heart muscle fibres, cardiac glycosides are also capable of increasing the coronary vascular tone even in very low concentrations. If, however, suitable doses of Ca-antagonistic compounds are simultaneously administered, the hearts are protected against this unpleasant coronary side effect without an appreciable loss of the inotropic glycoside action on the myocardium.

Animals↗
PubMed1976

[Drug therapy of tachycardial arrhythmias].

In recent years the antiarrhythmic armamentarium has been widened by several new drugs. The effects and side effects of amiodarone, verapamil, prenylamine and prajmalium bitartrate are described. With the introduction of the newer drugs, new recommendations have to some extent emerged with regard to treatment of tachyarrhythmias. For a national understanding of antiarrhythmic agents, regard must be had to their effects on both normal and damaged cells.

Amiodarone↗
PubMed1999

Mechanisms underlying the hemolytic and ichthyotoxic activities of maitotoxin.

Maitotoxin (MTX), a putative Ca(2+) channel activator produced by the dinoflagellate Gambierdiscus toxicus showed extremely potent hemolytic and ichthyotoxic activities. Hemolysis of 1% mouse blood cell suspension in saline occurred at 15 nM of MTX. The activity was enhanced six-fold in the presence of 10 microM of Ca(2+) and completely blocked by EDTA2Na, indicating its dependency on external Ca(2+). The MTX-induced hemolysis was little affected by L-type Ca(2+) channel blockers (diltiazem, nifedipine, verapamil) but was strongly inhibited by calmodulin blockers (prenylamine and chlorpromazine) or a phospholipase A2 inhibitor (quinacrine). MTX was mimicked by a calcium ionophore, calcimycin. Based on these results, a series of cellular events triggered by MTX were presumed to occur in the following sequence: increased Ca(2+) entry in cells, activation of calmodulin, promotion of phospholipase A2 activity, and finally destruction of cell membrane resulting from hydrolysis of membrane lipids. The sensitivity of blood cells to MTX varied significantly, dependent on the animal sources. Nucleated blood cells of carps and chickens were 100 times more resistant than those of mammals. LC(50) of MTX to freshwater fish Tanichthys albonubes in Ca(2+) free media (pH 8) was 5 nM but was markedly lowered to 3 pM by raising pH to 8 and increasing Ca(2+) concentration to 2 mM. In a marine environment MTX was 2000 times more toxic to fish than 42-di-hydrobrevetoxin-B (PbTx-3), one of the best known ichthyotoxins of red-tide origins.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1984

Effect of Ca2+-antagonists on virally-induced cell-permeability changes.

Sendai virus-mediated permeability changes in cells are affected by extracellular Ca2+ or Mn2+ as follows: the lag period to onset of permeability changes is lengthened and the subsequent extent of leakage is reduced. Drugs that block Ca2+ action in excitable cells, such as verapamil and prenylamine, and drugs that inhibit the action of calmodulin, such as trifluoperazine and R24571, have an effect opposite to that of Ca2+: lag is shortened and extent of leakage is increased. The concentration at which either type of drug shows 50% of maximal effect is similar to the concentration at which 50% of binding by drug to calmodulin is achieved. It is concluded that calmodulin may be involved in protecting cells against virally-mediated membrane damage; alternatively the action of calmodulin-binding drugs may not be as specific as currently thought.

Calcium↗
PubMed1994

Tamoxifen aziridine, a novel affinity probe for P-glycoprotein in multidrug resistant cells.

In this study for the first time we used an electrophilic analog of tamoxifen, [3H]tamoxifen aziridine, and demonstrated that it covalently and specifically binds to P-glycoprotein in multidrug resistant cells. Tamoxifen and its metabolites, N-desmethyltamoxifen and 4-hydroxytamoxifen, were potent inhibitors of [3H]tamoxifen aziridine binding to P-glycoprotein with 4-hydroxytamoxifen > tamoxifen > N-desmethyltamoxifen. The multidrug resistance-related drugs inhibited [3H]tamoxifen aziridine binding with vinblastine > vincristine > doxorubicin > actinomycin D, while colchicine enhanced the binding. Moreover, the multidrug resistance modulators verapamil, nicardipine, diltiazem, prenylamine, cyclosporin A, FK506, dibucaine, reserpine, monensin and progesterone were all potent inhibitors of [3H]tamoxifen aziridine binding to P-glycoprotein. Our data provide the first evidence that [3H]tamoxifen aziridine directly binds to P-glycoprotein and interacts with the binding sites for multidrug resistance-related drugs and modulators.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1984

Interactions between a "calcium channel agonist", Bay K 8644, and calcium antagonists differentiate calcium antagonist subgroups in K+-depolarized smooth muscle.

The proposal that calcium antagonists have different sites of action has been tested by attempting to reverse their inhibitory effects with a dihydropyridine which augments Ca2+ entry into cells, Bay K 8644. Bay K 8644 (1-1000 nmol/l) increased the sensitivity to Ca2+ of K+-depolarized taenia preparations from the guinea-pig caecum. Thus Bay K 8644 augmented established submaximal Ca2+-induced contractions and also shifted cumulative concentration-response curves to Ca2+ to the left, even in the presence of an optimal K+-depolarization. The inhibitory effects of nifedipine (10 nmol/l), verapamil (0.2 mumol/l), diltiazem (1 mumol/l) and diclofurime (1 mumol/l) on Ca2+-induced contractions were reversed by Bay K 8644 (1-1000 nmol/l). In contrast, Bay K 8644 did not reverse the effects of cinnarizine (1 mumol/l), flunarizine (1 mumol/l), fendiline (3 mumol/l), prenylamine (3 mumol/l), pimozide (1 mumol/l), bepridil (3 mumol/l), perhexiline (10 mumol/l) or the calmodulin antagonist W-7 (200 mumol/l). Bay K 8644 (1-100 nmol/l) was less effective at reversing the effects of nisoldipine (10 nmol/l), a slowly dissociating dihydropyridine, than the effects of nifedipine. However, preincubation with Bay K 8644 (1 mumol/l) protected the taenia from the inhibitory effects of nisoldipine (10 nmol/l). These findings are compatible with interactions of nisoldipine and Bay K 8644 at a common site. Taenia preparations incubated with Bay K 8644 (1 mumol/l) were protected from the inhibitory effects of nifedipine (10 nmol/l), nisoldipine (10 nmol/l) and to a lesser extent verapamil (0.2 mumol/l) and diltiazem (1 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1976

Ca2+ -uptake into noradrenaline-storing granules of bovine splenic nerves.

Noradrenaline-storing granules, a mitochondrial fraction and a microsomal fraction of bovine splenic nerve trunks were prepared by differential centrifugation. These particulate fractions were characterized by their noradrenaline content, succinate dehydrogenase and glucose-6-phosphatase activity. In the presence of ATP-Mg2+ all three fractions accumulated 45Ca2+ during incubation with 0.1 mM 45 CaCl2, buffered with potassium phosphate or glycylglycine (pH 7.5; 28 degrees C). The accumulated 45 Ca2+ was not removable by EGTA, and the uptake was absent at 0 degrees C or after destruction of the particles by sonication. The behaviour of the 45 Ca2+ -uptake into all three fractions against varying ATP-concentrations, metabolic inhibitors (pentachlorophenol, desaspidine, 2,4-dinitrophenol, N-ethylmaleimide, p-chloromercuribenzoate, sodium azide, amobarbital) and drugs (phenoxybenzamine, verapamil, prenylamine, reserpine, bretylium, phentolamine) was studied. Under nearly all conditions there were differences between the 45 Ca2+ -uptake into mitochondria and that into microsomes, which suggests two distinct uptake processes. The 45 Ca2+ -uptake into the granule fraction behaved intermediate between the two other fractions under many conditions, but not under all. Therefore, it is not possible to explain the 45 Ca2+ -uptake into the granule fraction as being due to contamination with mitochondria and microsomes; an inherent ATP-Mg2+ -dependent 45Ca2+ -uptake into the nerve granules must be postulated, which is not directly coupled with the noradrenaline transport into these particles. A particulate fraction (14000-100000 g), containing noradrenaline granules, was prepared from the vas deferens of the rat. Incubation with 5 X 10(-6) M (-)-noradrenaline and 0.1 mM 45Ca2+ showed that the particles of this fraction take up noradrenaline and 45Ca2+. The uptake of both was dependent on ATP-Mg2+. The ATP-Mg2+ -dependent uptake of both noradrenaline and 45Ca2+ was substantially reduced in the corresponding tissue fraction prepared from denervated vasa deferentia.

Adenosine Triphosphate↗
PubMed1993

The tyramine binding site in the central nervous system: an overview.

The [3H]Tyramine (TY) binding site is proposed as a high affinity marker of the membrane carrier for dopamine (DA) in synaptic vesicles from DA-rich brain regions. Under precise assay conditions, there is neither a consistent association of TY with the neuronal, cocaine-sensitive DA transporter, nor with mitochondrial or microsomal targets. TY-labeled sites have a high affinity for selected toxins such as the Parkinsonian agent MPP+ (1-methyl-4-phenylpyridinium ion), or drugs such as diphenylalkylamine Ca(2+)-channel antagonists. The MPP+/TY site interaction, which in the striatum leads to depletion of vesicular DA, occurs in dopaminergic as well as in noradrenergic regions, though with different kinetic profiles. TY-labeled carriers for DA and noradrenaline (NA) in respective vesicles seem to be different entities, which might result in a region-specific rate of toxin sequestration and/or release from heterogeneous vesicles. Whereas MPP+ is a potent competitive-type inhibitor of [3H]TY binding, prenylamine-like Ca(2+)-channel antagonists can compete with TY for the vesicle site, in a tetrabenazine- or reserpine-like manner, and also inhibit TY binding thanks to the extra-channel directed impairment of membrane bioenergetics they are proposed to provoke. This follows from the generally-accepted assumption that similar mechanisms are operational for secretory organelles in adrenals and CNS, and from the marked sensitivity of TY binding to miscellaneous energy-disrupting agents.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1996

Cell calcium signalling induced by endogenous lectin carbohydrate interaction in the Jurkat T cell line.

The effects of the beta-galactoside-binding lectin from human placenta (HPL14) on intracellular calcium concentration ([Ca2+]i) were examined in the human Jurkat T cell line. The lectin induces a concentration dependent increase in [Ca2+]i. This calcium signalling effect is clearly mediated through complementary cell surface galactoglycoconjugates because it can be blocked by beta-galactosides. The observed Ca2+ - response involves both the release of calcium from intracellular stores and a calcium influx from the extracellular space. It is sustained in the presence of 1 mM extracellular calcium whereas it becomes transient when the influx of extracellular calcium was blocked by calcium chelation to EGTA. Voltage-sensitive calcium channel blockers like verapamil and prenylamine were without effect on the action of HPL14. Protection of the sugar binding activity of HPL14 in the absence of a thiol-reducing reagent by carboxamidomethylation (CM-HPL14) or by substitution Cys2 with serine (C2S) results in lectin proteins with considerably decreased calcium signalling efficiency. The recombinant lectin (Rec H) and the mutant protein obtained by substitution of highly conservative Trp68 with tyrosine (W68Y) induce lower levels of [Ca2+]i compared to wild type lectin.

Binding Sites↗
PubMedDate not supplied

Influence of different calcic antagonists on the Caco-2 cell monolayer integrity or "TEER, a measurement of toxicity?".

The purpose of this work was to investigate the interest of the TEER measurement, a quite simple measure, as an evaluation of toxicity, in function of time and level of drug in the experimental medium, for different anticalcic agents. The extend of the increase and decrease of TEER, was evaluated by measuring the TEERmax and calculating the TEER50 respectively. Three groups of compounds could be therefore considered. The first, characterized by a quite short period of TEER increase, followed by an extremely rapid decrease (high values of TEER50), included perhexiline and prenylamine. The most toxic compounds, the second one, characterized by the smallest variations of TEER, included verapamil and diltiazem. This group was related with the less toxic compounds, the third group, represented by bepridil, characterized by dependant-dose TEERmax and TEER50. Therefore, the TEER measurement appeared as a quite simple approach of comparative toxicity of anticalcic agents.

Bepridil↗
PubMed1996

Hair analysis for drugs of abuse. XIII. Effect of structural factors on incorporation of drugs into hair: the incorporation rates of amphetamine analogs.

In order to clarify the incorporation mechanism of drugs from blood into hair, seven effects of structural factors on the incorporation rate (ICR) were studied using 32 amphetamine analogs: (1) effect of a straight chained N-alkyl group; (2) effect of benzene and furan ring at N-position; (3) effect of aliphatic and aromatic hydroxy groups; (4) effect of triple bond group at N-position; (5) effect of N-acyl group and ketone group; (6) effect of methylenedioxy and methoxy groups on benzene ring; and (7) comparison between phenyltertiarybutylamines and phenylisopropylamines. After shaving the back hair and i.p. administration of drugs to Dark-Agouti rats (5 mg/kg, 10 days, n = 3), the areas under the concentration versus time curve (AUCs) of drugs in the plasma and the concentrations in hair newly grown for 4 weeks were determined by gas chromatography-mass spectrometry. The ICRs represented by the ratios of hair concentrations to AUCs were compared with those of amphetamine (AP) and methamphetamine (MA). The ICRs of N-alkyl AP increased depending on the length of carbon branches from proton to propyl (C3 > C2 > C1 > H) at N-position. The compounds containing a benzene or furan ring at the N-position (benzphetamine, clobenzorex, norbenzphetamine, prenylamine, furfenorex, and norfurfenorex) had much higher ICRs than those of AP or MA, suggesting that a benzene or furan ring increases their ICRs. The ICRs of deprenyl, nordeprenyl, and fenproporex were significantly low, implying that triple bonds such as of a propargyl or cyano group serve as a negative factor for the ICRs. An ephedrine group (ephedrine, methylephedrine, phenylpropanolamine) showed slightly lower ICRs than the corresponding amphetamine group. However, a hydroxy group on benzene ring apparently decreased the ICRs. Methoxy and methylenedioxy groups on benzene ring distinctly increased their ICRs. The lack of basicity such as N-formyl MA, N-acetyl AP, and N-acetyl MA dramatically lowered their ICRs to zero or nearly zero. Moreover, the compounds containing a ketone group adjacent to benzene ring, e.g., cathinone and amfepramone, showed very low ICRs. Chlorine on propyl group (mefenorex) or benzene ring (clobenzorex) seemed to act positively for the ICR. These results showed that structural factors related to the lipophilicity and basicity clearly affect the drug incorporation into hair from blood.

Amphetamines↗
PubMed1979

Polymorphous ventricular tachycardia: clinical features and treatment.

Thirty-four cases of ventricular tachyarrhythmia characterized by polymorphy of the QRS complexes with changing R-R intervals and a heart rate of 150 to 300 beats/min, termed polymorphous ventricular tachycardia, are described. The factors involved in the appearance of this arrhythmia were the administration of antiarrhythmic drugs (quinidine 22 patients, procainamide 5 patients, ajmaline 1 patient), antianginal drugs (prenylamine [Synadrin] 4 patients) and antidepressant drugs (thioridazine 1 patient). Twenty-one patients were treated for premature ventricular complexes, three for chronic recurrent ventricular tachycardia, six for atrial flutter and fibrillation, three for anginal pain and one patient for mental depression. All patients except one had a drug-induced prolonged corrected Q-T interval before the appearance of polymorphous ventricular tachycardia. Most of the patients with this arrhythmia were considered to have severe myocardial disease. Lidocaine and electric cardioversion were administered to all patients, but were effective only in seven patients whose tachycardia occurred in short, single episodes. The most effective treatment (17 patients) was temporary ventricular pacing at rates ranging from 100 to 140 beats/min. Intravenous isoproterenol proved to be successful in another 10 cases. It is concluded that patients with severe myocardial involvement receiving antiarrhythmic drugs for premature ventricular complexes, especially the multiform variety, are at high risk for the development of polymorphous ventricular tachycardia.

Adult↗
PubMed1983

Allosteric interactions among drug binding sites on calmodulin.

Felodipine is a fluorescent dihydropyridine Ca2+-antagonist. It binds to calmodulin in a Ca2+-dependent manner, and undergoes a fluorescence increase which allows us to monitor its interaction with calmodulin. Hydrophobic ligands including the calmodulin antagonist, R24571 and Ca2+ antagonists, prenylamine and diltiazem, bind to calmodulin and potentiate felodipine binding by as much as 20 fold. These studies suggest that allosteric interactions occur among different drug binding sites on calmodulin. Our results are discussed in terms of the mechanism of action of calmodulin.

Allosteric Site↗