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At least 379 records · Page 21Linked to original sources
PubMed1983

Does [3H]nifedipine label the calcium channel in rabbit myocardium?

The ionic and drug specificities of the [3H]nifedipine binding site in rabbit cardiac homogenates were investigated. Divalent cations inhibited specific [3H]nifedipine binding in the potency order: Ni+2 greater than Ca+2 greater than or equal to Mg+2. Monovalent cations did not affect binding. The inorganic calcium entry blocker La+3 (IC50 = 1.1 mM) was the most potent cation in inhibiting radioligand binding. Calcium entry blocking drugs of different chemical classes inhibited [3H]nifedipine binding, with a rank potency order of: nifedipine much greater than D600 = verapamil greater than tiapamil greater than cinnarizine = prenylamine. The same potency order was observed for these drugs in inducing negative inotropic activity of isolated, electrically stimulated rabbit papillary muscle. The stereoselectivity of verapamil and D600 ((-) much greater than (+) isomers) in depressing papillary muscle contractions was not seen in [3H]nifedipine competition experiments. This presents an obstacle to accepting the equivalence of the [3H]nifedipine binding site with the myocardial Ca+2 channel. It is, however, possible that the myocardial Ca+2 channel may be associated with multiple sites of action for calcium entry blockers.

Animals↗
PubMed1992

Modulation of (+)-[3H]pentazocine binding to guinea pig cerebellum by divalent cations.

The ability of cations to modulate the binding of the sigma 1 receptor-selective ligand (+)-[3H]pentazocine to guinea pig cerebellum was investigated. Di- and trivalent cations biphasically inhibited (+)-[3H]pentazocine binding, revealing multiple affinity states. The rank order of potency of these cations (based on the high affinity component of inhibition) was Zn2+ > Co2+ >> La3+ = Ni2+ = Cd2+ = Mn2+ = Gd2+ > Ba2+ = Sr2+ >> Mg2+ > Ca2+. The inhibition of 1,3-[3H]di(2-tolyl)guanidine binding to the sigma 2 receptor by these cations differed qualitatively and quantitatively from their effects on (+)-[3H]pentazocine binding. Although monovalent cations decreased the Kd for (+)-[3H]pentazocine binding, divalent cations split (+)-[3H]pentazocine binding into low and high affinity components. The Bmax of the high affinity component decreased with increasing divalent cation concentrations. Both mono- and divalent cations significantly reduced the rate of association of (+)-[3H]pentazocine with the sigma 1 receptor without altering the dissociation rate. (+)-[3H]Pentazocine binding was not altered by guanine nucleotides or by treatment with cholera or pertussis toxins. However, nonselective cation channel blockers (cinnarizine, hydroxyzine, prenylamine, amiodarone, and proadifen) potently inhibited (+)-[3H]pentazocine binding. These results indicate that physiologically relevant concentrations of divalent cations allosterically modulate (+)-[3H]pentazocine binding to the sigma 1 receptor, to reveal multiple affinity states. These sites do not represent sigma 1 to sigma 2 subtype interconversion or ternary complex formation with guanine nucleotide-binding proteins. However, the rank order of cation potency and the inhibition of binding by cation channel blockers is consistent with a potential role for sigma receptors as constituents of cation channels.

Animals↗
PubMed1992

Interactions between vasodilator drugs and human hemoglobin.

1. The in vitro effect of the vasodilators papaverine, dipyridamole, nifedipine, prenylamine and glyceryl di-, tri- and tetranitrate on the oxygen saturation curve of human hemoglobin (Hb) was evaluated. The Hb dissociation curve was measured spectrophotometrically both for freshly obtained heparinized blood and for purified Hb A after incubation with the drugs. 2. For both purified Hb and whole blood samples, incubation with papaverine, dipyridamole and nifedipine modified P50 (PO2 for half saturation of the Hb/oxygen sites) at pH 7.4: 30.9 mmHg for 0.72 mM papaverine vs 23.9 mmHg for control; 23.9 mmHg for 1.43 mM dipyridamole vs 20.8 mmHg for control; 1.09 mmHg for 2.73 mM nifedipine vs 1.14 mmHg for control stripped Hb. The effects of the three vasodilators on Hb were correlated with pH, methemoglobin formation, temperature and incubation time. 3. P50 values were determined for Hb of the blood of angina patients treated with one of the vasodilators, and blood 2,3-diphosphoglycerate (2,3-DPG) levels were also measured. In contrast to the in vitro data, neither P50 nor 2,3-DPG levels were significantly modified in the blood of patients treated with one of the vasodilators. 4. These in vitro studies demonstrated that the vasodilators papaverine and dipyridamole decrease, and nifedipine increases the oxygen affinity of Hb in red blood cells or as a purified hemoglobin.

2,3-Diphosphoglycerate↗
PubMed1992

[Polymorph ventricular tachycardia with torsades de pointes caused by administration of terodiline (Mictrol)].

A 63-year-old female was admitted to the hospital because of collapse. She had no history of cardiovascular disease. Prior to admission she used co-trimoxazole, paracetamol, calcium tablets and 50 mg terodiline (Mictrol) daily because of bladder instability. Electrocardiography showed QT prolongation and polymorphous ventricular tachycardia with torsades de pointes. During admission she developed ventricular fibrillation, needing defibrillation. After withdrawal of terodiline and treatment with isoprenaline the symptoms and all ECG abnormalities disappeared. In this case terodiline was suspected of having been the causative agent. Terodiline shows structural resemblance to the anti-arrhythmic agent prenylamine, a known cause of torsades de pointes. Recently terodiline has been temporarily withdrawn from the worldwide market in order to investigate the causal relationship between this drug and cardiac arrhythmia and conduction disturbances.

Butylamines↗
PubMedDate not supplied

[Modulation of serine/threonine protein kinase activity in chloramphenicol-resistant mutants of Streptomyces avermitilis].

A mutation to chloramphenicol resistance (Cmlr) stimulates production of macrolide avermectin in Streptomyces avermitilis; production starts in early stationary growth. By labeling in vivo, the Cmlr mutation was shown to stimulate phosphorylation of Ser and Thr in several proteins in the same growth phase. Autophosphorylation of active protein kinases (PK) was analyzed in gel after one- or two-dimensional PAGE for the original S. avermitilis strain ATCC 31272, its Cmlr mutant, and a Cmls revertant. An increase in in vivo phosphorylation was associated with an increase in autophosphorylation of Ser/Thr-PK 41K, 45K, 52K, 62K, and 85K and complete suppression of autophosphorylation of PK 66K. Comparison of the PK molecular weights and pI with the parameters deduced for putative PK encoded by S. avermitilis genes identified the 41K, 45K, 52K, 62K, and 85K PK as pkn 24, pkn 32, pkn 13, pkn 12, and pkn 5, respectively. Prenylamine lactate, a modulator of calmodulin-dependent processes, substantially reduced the avermectin production, impaired the Cml resistance, and selectively inhibited Ca2+-dependent PK 85K in the Cmlr mutant. It was assumed that PK 85K is involved in regulating the avermectin production.

Chloramphenicol↗
PubMed1992

Antioxidant effect of calmodulin antagonists in rat brain homogenate.

Several calmodulin antagonists, W-7, amitriptyline, trifluoperazine, chlorpromazine, dibucaine, prenylamine, calmidazolium, and compound 48/80, inhibited lipid peroxidation induced non-enzymatically in rat brain homogenate by ascorbate and Fe2+. Suggestions of involvement of calmodulin in various oxidative cellular responses, based on experiments using calmodulin antagonists, may need to be re-evaluated.

Animals↗
PubMed1975

[Indications for permanent electrosystolic pacing in arrhythmia revealed or aggravated by treatment].

The authors report 25 cases of patients, average age 67 years with severe coronary or valvular heart disease, with conduction disorders. The conduction disorder occurred alone in 8 cases and was associated with a disorder of excitability in 17 cases. It was either obvious, as in 14 cases, or latent, as in 11 cases, and precipitated by various forms of treatment, the disadvantage of which was the negative dromotrope effect. This treatment was prescribed for permanent resting angina (amiodarone and prenylamine), heart failure (digitoxin) or excitability disorder (beta-blockaders or procainamide). 11 patients had one or several fainting attacks. Permanent electro-systolic pacing with stimulation on demand, is necessary in all patients to palliate the consequences of treatment. In 11 cases out of 25, prior temporary pacing permitted the authors to assess the efficacy of treatment. The high post-operative mortality (40%) is not due to the apparatus but depends on the severity of the coronary heart disease or heart failure in these patients, In 60% of cases, the result of stimulation was excellent and was maintained permanently.

Aged↗
PubMedDate not supplied

Effect of diverse categories of drugs on human colon tumour cell proliferation.

The effect of a number of drugs belonging to different therapeutic categories on cell proliferation in a human colon cancer cell line (HT 29) was studied. Generally, drugs classified as calcium antagonists had a moderate to strong inhibitory effect on cell growth. The EC50 value for prenylamine, perhexiline and bepridil was 10 microM. The so-called calcium channel blockers (verapamil, nifedipine, diltiazem) were less effective. With the exception of the sodium selective ionophore, monensin, which was extremely potent (EC50 less than 0.1 microM), calmodulin antagonism appeared to be a common feature of compounds inhibiting cell proliferation of human colon tumour cells.

Amiodarone↗
PubMedDate not supplied

[Calmodulin blockaders weaken the short-term plasticity of the neuronal cholinoreceptors in the edible snail].

By means of recording transmembrane ion currents of identified snail neurones PPa3 and LPa3 a reversible weakening was shown of the speed and depth of extinction of neuronal cholinoreceptor membrane reactions to repeated iontophoretic applications of acetylcholine to the soma by a number of calmodulin blockaders: R24571 (20-50 mmol/l), trifluoperazine (50-200 mmol/l), chlorpromazine (20-60 mmol/l) and prenylamine lactate (30-400 mmol/l). The obtained results testify to a positive control by calmodulin of short-term cholinoreceptors plasticity of the studied neurons.

Acetylcholine↗
PubMed1990

Neurotoxic action of veratridine in rat brain neuronal cultures: mechanism of neuroprotection by Ca++ antagonists nonselective for slow Ca++ channels.

The effect of various Ca++ antagonists and local anesthetics on neuronal cell degeneration induced by veratridine was studied in primary rat brain neuronal cultures. Cell death was quantified by measuring lactate dehydrogenase (LDH) released in the culture medium. The neuronal cell degeneration was Ca+(+)-dependent because, in the absence of extracellular Ca++, 16 hr of exposure to 30 microM veratridine failed to produce release of LDH. Ca++ antagonists, nonselective for slow Ca++ channels (flunarizine, cinnarizine, lidoflazine, prenylamine and bepridil) inhibited veratridine-induced release of LDH with IC50 values between 0.11 and 0.47 microM. Ca++ antagonists selective for slow Ca++ channels were less potent and inhibited veratridine-induced release of LDH at concentrations in the following order of potency: nicardipine greater than gallopamil and verapamil greater than niludipine greater than nitrendipine greater than nifedipine greater than nimodipine greater than diltiazem. Tested local anesthetics were incomplete inhibitors of veratridine-induced release of LDH. A good correlation was found between the potency of the drugs to inhibit released LDH induced by 30 microM veratridine in neuronal cultures and their binding affinity for the batrachotoxin binding site of Na+ channels in rat cortex synaptosomal preparation. It is concluded that protection against veratridine-induced neurotoxicity can be mediated by blocking a veratridine-sensitive Na+ channel. It is a property of certain nonselective Ca++ antagonists. There is apparently no direct relationship with Ca++ antagonistic activity. The effect is unrelated to local anesthetic activity.

Anesthetics↗
PubMed1990

[Inhibition of guinea pig sperm capacitation, the acrosome reaction and sperm-egg fusion by dl-propranolol in vitro].

dl-Propranolol (Pro), known to have spermicidal effect, was evaluated for its ability to influence capacitation, the acrosome reaction (AR) and fertilization of guinea pig spermatozoa at non-spermicidal dose levels. A concentration-dependent decrease in AR and the whiplashed motility occurred in Pro as low as 0.05 mmol/L. Pro 1.0 mmol/L completely abolished AR, followed by the loss of sperm capacity to penetrate into zona-free hamster egg. Pro exerted its inhibitory effect of AR primarily by restraining the capacitation stage of sperm but at Pro 0.5 mmol/L by blocking both capacitation and AR stages. % of AR of sperm preincubated with ionophore A-23187 0.2 mumol/L was significantly higher than that of the control, but markedly lower at Pro greater than or equal to mmol/L, implying that Pro prevented sperm Ca2+ influx. Prenylamine was also found to inhibit AR potentially and enhance the action of Pro against ionophore A-23187. Furthermore, Pro inhibition of the fertilizing ability of preincubated spermatozoa was antagonized by cAMP. Pro 0.5 mmol/L even caused the egg vesiculation. The reversibility of the action depends on the dose and time of sperm exposure to Pro. These findings suggest that the inhibitory effects of Pro on guinea pig sperm capacitation, the acrosome reaction and fertilization may be the mechanisms for its antifertility action.

Acrosome↗
PubMed1990

Elevation of leukemic cell intracellular calcium by the ether lipid SRI 62-834.

SRI 62-834 is a novel antineoplastic ether lipid which is currently undergoing a Phase 1 clinical trial in the United Kingdom. Its mechanism of action has not been defined. Incubation of 7.5 X 10(6)/ml HL-60 human myelomonocytic leukemia cells with between 10 and 50 microM SRI 62-834 brought about a concentration-dependent, biphasic rise in intracellular calcium, as measured by the calcium-sensitive fluorescent dye Quin-2 AM. Incubation with 30 microM SRI 62-834 elevated intracellular calcium from 110 to 415 nM after 10 min in a typical experiment; this concentration inhibited cell growth by greater than 90% (50% inhibition of growth was observed at 8 microM). The calcium channel blockers verapamil and prenylamine did not inhibit the SRI 62-834-induced elevation of intracellular calcium. Incubation of SRI 62-834 with K562 erythroblastic leukemia cells also brought about a rise in the intracellular calcium. The growth of K562 cells was less sensitive to SRI 62-834 (dose to produce 50% growth inhibition, 65 microM) compared to HL-60 cells, and significant intracellular calcium rises, which were monophasic, required greater than 40 microM SRI 62-834. At a concentration of SRI 62-834 which inhibited both HL-60 and K562 growth by 90% (30 and 140 microM, respectively) an equivalent rise in intracellular calcium was observed (circa 400 nM). Preincubation of HL-60 or K562 cells with 1 to 100 nM 12-O-tetradecanoylphorbol-13-acetate for 10 min prior to the addition of SRI 62-834 inhibited the rise in intracellular calcium in a concentration-dependent manner. It is suggested that SRI 62-834-induced changes in intracellular calcium may contribute to its cytotoxicity and that the rise is not due to an early and grossly disruptive effect of the agent on membrane structure.

Aminoquinolines↗
PubMed1989

High affinity dextromethorphan binding sites in guinea pig brain. Effect of sigma ligands and other agents.

Dextromethorphan (DM), a non-narcotic antitussive, binds in the guinea pig brain to specific high- and low-affinity sites with Kd values of 57 nM and 24 microM, respectively (Musacchio et al., 1988). The antitussives carbetapentane, caramiphen, butamirate and dimethoxanate competed with the high-affinity binding of [3H]DM at pH 7.4 with nanomolar Ki values. Sigma site ligands showed high affinity for [3H]DM binding sites. The rank order of potency was: haloperidol greater than (+)-pentazocine greater than (+)-cyclazocine greater than 3-(-3-hydroxyphenyl)-N-(1-propyl)piperidine greater than (+)-N-allylnormetazocine greater than (-)-butaclamol much greater than (+)-butaclamol (-)-N-allylnormetazocine. The antipsychotic perphenazine competed with low nanomolar Ki values, whereas rimcazole was weaker. The antidepressant opipramol and the benzomorphan (+)2'methoxyphenazocine were the most effective drugs tested, with Ki values of 0.4 nM. By contrast, MK-801 and phencyclidine hydrochloride were very weak competitors for [3H]DM binding. The diphenylalkylamines were the most effective competitors of the calcium channel blocking agents: prenylamine and cinnarizine had Ki values of 17 and 22 nM, respectively. Lidoflazine and hydroxyzine were slightly less potent, but nifedipine and the benzothiazepine diltiazem were much weaker. Potassium channel blockers inhibited DM binding in pharmacologically relevant concentrations: primaquine was the most effective with a Ki of 0.5 microM. Other antimalarial potassium channel blockers tested inhibited binding in the micromolar range. 4-Aminopyridine and tetraethylammonium had Ki values of 0.76 and 1.40 mM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Comparative renal effects of calcium channel blockers in conscious spontaneously hypertensive rats.

Five calcium channel blockers with diverse chemical structures were studied for potential renal selectivity after oral administration of a single dose to conscious spontaneously hypertensive rats. Nitrendipine (3 and 10 mg/kg) and diltiazem (30 and 100 mg/kg) caused significant increases in sodium and water excretion. In comparison, prenylamine (100 and 300 mg/kg) and flunarizine (100 and 300 mg/kg) failed to augment sodium and water excretion. Verapamil caused significant natriuresis only at 30 mg/kg. These data suggest that the diuretic and natriuretic action is not a common property of all calcium channel blockers. Pretreatment with SCH 23390 (20 mg/kg), a dopamine DA1 antagonist, selectively attenuated the diuresis and natriuresis induced by high doses of diltiazem (100 mg/kg) and nitrendipine (10 mg/kg) without blocking the renal responses to hydrochlorothiazide (1 mg/kg). Similarly, reserpinization abolished the renal but not the hypotensive action of diltiazem. Pretreatment with indomethacin (10 mg/kg), a cyclooxygenase inhibitor also significantly attenuated the diuresis and natriuresis elicited by diltiazem (100 mg/kg). These data suggest that intact dopamine and prostaglandin systems in the kidney are required for optimal expression of the renal effects of diltiazem and nitrendipine.

Animals↗
PubMed1987

Identification of the multidrug resistance-related membrane glycoprotein as an acceptor for calcium channel blockers.

A radioactive photoactive dihydropyridine calcium channel blocker, [3H]azidopine, was used to photoaffinity label plasma membranes of multidrug-resistant Chinese hamster lung cells selected for resistance to vincristine (DC-3F/VCRd-5L) or actinomycin D (DC-3F/ADX). Sodium dodecyl sulfate-polyacrylamide gel electrophoretic fluorograms revealed the presence of an intensely radiolabeled 150-180-kDa doublet in the membranes from drug-resistant but not from the drug-sensitive parental (DC-3F) cells. A similar radiolabeled doublet was barely detected in a drug-sensitive partial revertant (DC-3F/ADX-U) cell line. The 150-180-kDa doublet exhibited a specific half-maximal saturable photolabeling at 1.07 X 10(-7) M [3H]azidopine. The dihydropyridine binding specificity was established by competitive blocking of specific photolabeling with nonradioactive azidopine as well as with nonphotoactive calcium channel blockers nimodipine, nitrendipine, and nifedipine. In addition, [3H]azidopine photolabeling was blocked by verapamil and diltiazem but was stimulated by excess prenylamine and bepridil suggesting a cross-specificity for up to four different classes of calcium channel blockers. The 150-180-kDa calcium channel blocker acceptor co-electrophoresed exactly with the 150-180-kDa surface membrane glycoprotein (gp150-180 or P-glycoprotein) Vinca alkaloid acceptor from multidrug-resistant cells and was immunoprecipitated by polyclonal antibody recognizing gp150-180. [3H]Azidopine photolabeling of the 150-180-kDa component in the presence of excess vinblastine was reduced over 90%, confirming the identity or close relationship of the calcium channel blocker acceptor and the gp150-180 Vinca alkaloid acceptor. The [3H]azidopine photolabeling of gp150-180 also was reduced by excess actinomycin D, adriamycin, or colchicine, demonstrating a broad gp150-180 drug recognition capacity. The ability of gp150-180 to recognize multiple natural product cytotoxic drugs as well as calcium channel blockers suggests a direct function for gp150-180 in the multidrug resistance phenomenon and a role in the circumvention of that resistance by calcium channel blockers.

Animals↗
PubMed1986

Mechanisms involved in reperfusion arrhythmias.

Clinical and experimental studies indicate that reperfusion of the ischaemic myocardium may play an important role in the genesis of life-threatening arrhythmias. Reflow may occur as a result of abrupt cessation of coronary artery spasm or upon dislodgment of platelet aggregates with the attendant washout of products of cellular ischaemia. The released substances exert a transient but potent arrhythmogenic effect. Calcium channel blocking agents, by virtue of their broad spectrum of action, can interrupt the cascade of events leading to arrhythmias. In experimental animals, verapamil has been shown to reduce vulnerability to ventricular fibrillation during sympathetic stimulation and to prevent spontaneous fibrillation during both myocardial ischaemia and reperfusion. Comparable antifibrillatory effects have been observed with diltiazem and prenylamine. Tiapamil is effective during sympathetic stimulation and myocardial ischaemia but not during reperfusion. Nifedipine appears to exert a moderate antifibrillatory influence during myocardial ischaemia and is ineffectual in preventing reperfusion-induced fibrillation. These observations indicate that calcium channel blocking agents differ considerably in their ability to suppress arrhythmias during myocardial ischaemia and reperfusion. Their effectiveness appears to depend critically both on the pathophysiologic mechanisms and on the pharmacologic profile of the individual agent.

Animals↗
PubMed1987

Independent elevation of cytosolic [Ca2+] and pH of mammalian sperm by voltage-dependent and pH-sensitive mechanisms.

Previous work (Babcock, D. F., Rufo, G. A., and Lardy, H.A. (1983) Proc. Natl. Acad. Sci. U.S.A. 80, 1327-1331) established that increased cytosolic pH (pHi) promotes metabolic and swimming activity of bull sperm and that intracellular alkalinization results from elevated extracellular K+, presumably as a consequence of membrane depolarization. The present studies show that a persistent but reversible increase in [Ca2+]i accompanies the increase in pHi that similarly results from treatment of ram sperm with elevated [K+] in alkaline media. Because comparable increases in pHi occur in the presence or absence of external Ca2+ and because [Ca2+]i is unaltered by imposed changes in pHi alone, [Ca2+]i and pHi apparently are neither directly linked by transmembrane Ca2+/H+ exchange nor indirectly linked through Na+/H+ and Na+/Ca2+ exchange under these conditions. Instead, inhibition of K+-induced increases in [Ca2+]i (but not of increases in pHi) by prenylamine, diltiazem, nifedipine, or verapamil (C1/2 = 6, 20, 30, and 60 microM, respectively) indicates that voltage-dependent Ca2+ channels, distinct from previously described voltage-dependent effectors of pHi, operate in mammalian sperm to control [Ca2+]i. Treatment with Cs+ plus valinomycin (as an alternative method of membrane depolarization) increases pHi much more effectively than it increases [Ca2+]i, and thus also partially supports this contention. In contrast to an apparent insensitivity to pHi, K+-dependent increases in [Ca2+]i are promoted reversibly by elevation of pHo, probably reflecting local surface charge effects on channel activity (as suggested by patch-clamp studies in other systems). A selective increase in membrane permeability to Ca2+ that is induced by 12 mM NaF under nondepolarizing conditions is not a consequence of cellular aggregation, but is attenuated by the chelator deferoxamine, suggesting that GTP-binding protein additionally may couple sperm Ca2+ channels to surface receptors and promote channel opening during sperm capacitation, presumably in response to agonists produced within the mammalian female reproductive tract.

Animals↗
PubMed1986

Depressant action of Ca-antagonists on slow action potentials in guinea pig ventricular muscles.

The depressant action of four Ca antagonists, including a novel drug, tiapamil, on Ca channels was investigated using a conventional microelectrode technique. "All or none" slow action potentials were recorded in K+-depolarized guinea-pig papillary muscles. Verapamil and diltiazem decreased the amplitude and maximum rate of rise (Vmax) of the slow action potentials at concentrations up to 2 microM. The depressant effect of a novel Ca-antagonist, tiapamil, on the slow action potentials was as marked as that of verapamil and diltiazem. However, prenylamine was less potent than the other 3 drugs. In addition, the action of all drugs on the slow action potentials was enhanced as the frequency of stimulation was increased between 0.0083 and 1 Hz. It was concluded that tiapamil, as verapamil and diltiazem, produced a frequency-dependent blockade of the slow Ca channel.

Action Potentials↗