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At least 289 records · Page 16Linked to original sources
PubMed2002

Arylalkylamines are a novel class of positive allosteric modulators at GABA(B) receptors in rat neocortex.

Using grease-gap recording from rat neocortical slices, the gamma-aminobutyric acid(B) (GABA(B)) receptor agonists baclofen (3-100 microM) and SKF 97541 (3-aminopropyl-methylphosphinic acid) (1-30 microM) elicited reversible and concentration-dependent hyperpolarizing responses, with EC(50) values of 10 and 3 microM, respectively. The hyperpolarizations were antagonised by the GABA(B) receptor antagonist Sch 50911 ((+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid) (1, 5 and 10 microM). Fendiline (N-[3,3-diphenylpropyl)-alpha-methylbenzylamine) (5-50 microM) and its congeners, prenylamine (N-[3,3-diphenylpropyl)-alpha-methylphenylethylamine) (10-100 microM) and F551 (N-[3,3-diphenylpropyl)-alpha-methyl-3-methoxybenzylamine) (1-30 microM) reversibly enhanced hyperpolarizing responses to the agonists; such effects were reduced by Sch 50911. These arylalkylamines produced leftward shifts of the concentration-response curves, with a marked increase in the maximal hyperpolarization obtained, compared with the agonists alone, F551 being the most potent. These findings suggest that these arylalkylamines represent a new class of positive modulators of GABA(B) receptor-mediated function.

Animals↗
PubMed1991

The effect of calcium channel blockers on the H(+)-ATPase and bioenergetics of catecholamine storage vesicles.

A number of commonly used calcium channel blockers have been compared with respect to their effects on the bioenergetics of catecholamine storage vesicles. Chromaffin granule ghosts with a well-preserved ability to actively transport and store catecholamines, were used as a model for adrenergic synaptic vesicles due to their functional similarity. Nicardipine, verapamil, terodiline and diltiazem were found to have effects comparable to that of prenylamine (Grønberg, M., O. Terland, E.S. Husebye and T. Flatmark, 1990. Biochem. Pharmacol. 40, 351) by inhibiting the generation of a transmembrane proton electrochemical gradient driven by the vesicular H(+)-ATPase, mainly by loose-coupling/uncoupling of this ATPase. Amlodipine inhibited the internal acidification of the vesicles in a tyramine-like manner and increased the steady-state membrane potential (positive inside) generated by the MgATP-dependent proton translocation. Nifedipine and felodipine also inhibited the efficiency of the proton pump, but their mechanisms of action require further investigation. The concentrations giving 50% inhibition of the H(+)-ATPase-dependent generation of a pH-gradient were found to be: 12 microM felodipine, 16 microM nicardipine, 25 microM terodiline, 50 microM nifedipine, 60 microM verapamil, 65 microM amlodipine and 150 microM diltiazem. The effects of the calcium channel blockers on the bioenergetics of chromaffin granules explain the release of catecholamines from sympathetic nerves and ganglia in vitro by the calcium channel blockers.

Adrenal Medulla↗
PubMed2000

Characteristics of the inhibitory effect of calmodulin on specific [125i]omega-conotoxin GVIA binding to crude membranes from chick brain.

The characteristics of the inhibitory effect of calcium ion (Ca2+)/calmodulin (CaM) on specific [125I]-omega-conotoxin GVIA (125I-omega-CTX) binding and on the labeling of 125I-omega-CTX to crude membranes from chick brain were investigated. The inhibitory effect of Ca2+/CaM depended on the concentrations of free Ca2+ and CaM. The IC50 values for free Ca2+ and CaM were about 2.0 x 10(-8) M and 3.0 microg protein/ml, respectively. The inhibitory effect of Ca2+/CaM was attenuated by the CaM antagonists W-7, prenylamine and CaM-kinase II fragment (290-309), but not by the calcineurin inhibitor FK506. Ca2+/CaM also inhibited the labeling of a 135-kDa band (which was considered to be part of N-type Ca2+ channel alpha1 subunits) with 125I-omega-CTX using a cross-linker. These results suggest that Ca2+/CaM affects specific 125I-omega-CTX binding sites, probably N-type Ca2+ channel alpha1 subunits, in crude membranes from chick whole brain.

Animals↗
PubMedDate not supplied

Effects of 2-substituted 3-dimethylamino-5,6-methylenedioxyindenes on calcium-induced arrhythmias.

Pharmacological, biochemical, and electrophysiological studies have demonstrated that the 2-n-propyl (Pr) and 2-n-buty (Bu) 3-dimethylamino-5,6-methylenedioxyindenes (MDIs) are intracellular calcium antagonists. The MDIs exhibit coronary dilating properties in the in vitro rabbit heart and possess antiarrhythmic activity in vivo in the anesthetized ouabain-toxic dog. The results of the present investigation demonstrate that the MDIs possess significant antiarrhythmic activity against calcium-induced arrhythmias in anesthetized rats and dogs. Pretreatment of dogs with an acute dose (30 mg/kg, i.v.) of either MDI significantly delayed both the onset of intravenous infusion of calcium (500 mg/kg/hr, CaCl2 . 2H2O). Pretreatment of rats with an acute dose (3.75 mg/kg, i.v.) of either MDI provided virtually complete protection against bradycardia, arrhythmias, and death induced by an acute intravenous dose of calcium (1 ml/kg of a 10% CaCl2 . 2H2O solution. The antiarrhythmic potency of the MDIs in rats was equivalent to that of verapamil, but the latter drug produced bradycardia, electrocardiographic alterations, and atrioventricular block, whereas the MDIs exhibited no intrinsic deleterious effects of cardiac function. Prenylamine (a membrane calcium antagonist) and diphenylhydantoin demonstrated no antiarrhythmic properties in this rat model at comparable doses to the MDIs.

Animals↗
PubMed1987

Solubilization and characterization of the nitrendipine receptor in rat brain.

The nitrendipine receptor associated with the voltage-dependent calcium channel in rat brain was solubilized by detergent extraction and sonication. The detergent solution used for extraction consisted of 10 mM 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), 0.25% (wt/vol) polyoxyethylene 20 cetyl ether (Brij 58), and 0.025% (wt/vol) polyoxyethylene 17 cetyl stearyl ether (Lubrol WX) in the presence of 30% (wt/vol) glycerol as a stabilizer. The molecular weight of the receptor was estimated to be 1,800K by Sephacryl S-500 gel filtration and 800K by sucrose density gradient sedimentation. The equilibrium dissociation constant of [3H]nitrendipine to the solubilized receptors was 5.6 nM, which is approximately 10 times that of the membrane-bound receptor. The binding of nitrendipine to the receptor was inhibited noncompetitively by the structurally unrelated calcium channel inhibitors verapamil and prenylamine; their concentrations for 50% inhibition were both 1.0 X 10(-7) M, and they caused maximal inhibitions of 70 and 100%, respectively.

Animals↗
PubMed1969

Brain monoamines and adrenocortical activation.

1. The effect of a pharmacologically induced increase or depletion of brain monoamines (5-hydroxytryptamine, noradrenaline, dopamine) was investigated with respect to adrenocortical function.2. No strict correlation was found between the depletion of brain amine stores induced by prenylamine or p-chlorophenylalanine and adrenocortical activation, even at times in which the peak effect of brain amine depletion occurs.3. Restraint stress causes a manifest increase in brain 5-hydroxytryptamine while decreasing the cerebral noradrenaline and dopamine content. This stress strongly stimulates corticosterone secretion by the adrenals.4. A monoamine oxidase inhibitor, nialamide, at a dose which causes an evident increase in brain amine concentrations, does not modify plasma corticosterone. At the same dose it was, furthermore, unable to prevent the adrenocortical stimulation induced by restraint stress.5. Brain amine content does not seem to play an important part in the control of corticotrophin releasing factor in corticotrophin secretion by the pituitary gland. The relationship between hypothalamic monoamines and other neurohumours is discussed.

Adrenal Glands↗
PubMed1988

Slow channel inhibitor effects on brain function: tolerance to severe hypoxia in the rat.

1. The protective effects of ten slow channel inhibitor drugs against severe progressive hypoxia were investigated in rats breathing spontaneously during light anaesthesia. Respiration, heart rate, electrocorticogram (ECoG) and/or electroencephalogram (EEG) were recorded. 2. Tolerance times were monitored from hypoxia onset until cessation of respiration, ECoG, EEG synchronization, and 'background-EEG'. Drugs were administered i.v. 5 min before the onset of hypoxia. 3. Verapamil, gallopamil, and nimodipine resulted in a significant increase of tolerance times; fendiline and bepridil showed a small increase (not significant); bencyclan and prenylamine were ineffective; cinnarizine and diltiazem slightly reduced tolerance times as did flunarizine at low doses. 4. At protective doses, verapamil, gallopamil, and nimodipine significantly raised the respiration rate but had little or no cardiac depressor effects. Bencyclan showed ventilatory drive but cardiocirculatory depression. A clear-cut ventilatory drive did not occur with the other ineffective slow channel inhibitors. 5. It is suggested that the protective actions observed were not due to slow channel inhibition per se, nor to spasmolytic potency or increased cerebral blood flow. Ventilatory drive associated with other cardiopulmonary actions which secondarily raise the brain oxygen supply are likely to be responsible for this effect.

Animals↗
PubMed1979

Therapeutic trials in hamster dystrophy.

Verapamil and prenylamine, which antagonize calcium influx into heart muscle cells, Dibenamine and propanolol, alpha and beta adrenergic bockers, respectively, and prostaglandin E1, which acts on permeability of cell membranes and on adrenergic neurotransmission, were all shown to markedly reduce the severity of heart lesions in UM-X7.1 cardiomyopathic hamsters. The beneficial effects of these compounds seen essentially preventive, in that they do not afford protection for fully developed skeletal muscle lesions. The occurrence of the pathologic changes in the myocardium coincides with an increased adrenergic nerve activity, and it is believed that these drugs function mainly by decreasing calcium conductivity across the sarcolemmal membranes of cardiocytes.

Animals↗
PubMed1969

The distribution of dopamine in the brain of a tortoise, Geochelone chilensis (Gray).

1. Dopamine was found in the tortoise brain; the highest concentration (3.7 mug/g) occurred in a region of the telencephalon containing the nucleus basalis and cortex olfactoria. This region may be considered similar to the mammalian and avian corpus striatum with respect to dopamine.2. The administration of reserpine or prenylamine substantially decreased the concentration of dopamine in the tortoise brain. This effect appeared later and lasted longer than in birds or mammals. When these drugs were given in doses which nearly depleted brain dopamine the characteristic signs observed in birds or mammals were not present.

Animals↗
PubMed1970

Extent of possible rehabilitation of service personnel with ischaemic heart disease.

Sixty unselected survivors from ischaemic heart disease, all male service personnel, were treated, within 1 to 6 months of recovery from the acute episode, by promotion of physical activity, correction of coronary risk factors, and routine use of nicoumalone and prenylamine lactate. The results showed that this approach was conducive to more rewarding rehabilitation than was obtained in 89 patients who, in the past, were on conventional treatment based on advice regarding weight, diet, and physical and mental activity. Thus within 1 to 30 months of treatment by this approach, out of 60 patients, 12 were fit for medical category A active service duties in operational areas in any part of the world in any terrain, including altitudes between 10,000 and 18,000 feet, 30 were fit for medical category B service duties in non-operational communication zones in any part of the world including altitudes below 10,000 feet, and 17 were fit for medical category C sedentary duties in non-operational areas in India only. One patient, who initially recovered from congestive heart failure, died while in a state of temporary unfitness for service. No patient was released from service on account of ischaemic heart disease. Against this, by the conventional approach, out of 89 patients, 81 were fit for medical category C sedentary duties in non-operational areas in India only, 4 were released from service, and 4 died.

Acenocoumarol↗
PubMed1983

Effect of calcium antagonism on contractile behavior of canine hearts.

The cardiovascular effects of prenylamine (P), verapamil (V), and nifedipine (N) were studied in open-chest, anesthetized dogs and in isolated, isovolumic dog hearts perfused at constant coronary blood flow (CBF). These drugs significantly decreased left ventricular pressure (LVP) and its maximal rates of rise (+P) and fall (-P). The tension developed by an isometric segment of the left ventricle and its maximal rates of rise (+T) and fall (-T) also decreased, whereas heart rate (HR) did not show statistically significant differences. Maximal rates of fall (-P and -T) were proportionally more depressed than maximal rates of rise (+P and +T), producing significant increments in the ratios between both maximal velocities (+P/-P and +T/-T). The time constant of LVP isovolumic decay tau was significantly prolonged, either in the whole animal or in isolated perfused hearts. The afterload reduction produced by the compounds can account in part for the increase in +P/-P but not for the increase in +T/-T or for the prolongation of tau. These relaxation indices remained unchanged after comparable myocardial depressions elicited by d,l-propranolol or pentobarbital sodium. It is concluded that calcium antagonist compounds are characterized by an "antirelaxant" effect, not explained by changes in HR, CBF, or loading conditions, and independent from their negative inotropic action.

Animals↗
PubMed1978

Pathogenesis of isoproterenol-induced myocardial lesions: its reation to human 'coagulative myocytolysis'.

Animals develop 'infarct-like' lesions when injected with isoproterenol (ISP), a potent synthetic catecholamine. These lesions are morphologically similar to those of 'coagulative myocytolysis' (COAM) or myofibrillar degeneration, one of the findings described in acute myocardial infarction and sudden death in man. Wistar rats were divided into 8 groups: some were injected with 10 mg/kg ISP i.p. plus 5 muCi of tritiated ISP, while others served as control. Animals were sacrified at 5 and 30 min and 24 and 72 h. The ISP-induced lesions were studied by means of light microscopy, histochemistry, autoradiography and electron microscopy. Myofibrillar degeneration, positive tests for ischemia, increase of succinic dehydrogenase enzymes, hypercontraction and widening of Z bands of sarcomers were correlated with the rapid distribution of ISP. These lesions were minimized by prenylamine, a drug which inhibits catecholamine effects by slowing down Ca transport. It is concluded that myocardial necrosis induced by ISP is probably due to a primary act on the sarcolemmal membrane, followed by stimulation of adenylate cyclase, activation of Ca and Na channels, exaggreated Ca inflow, excess of excitation-contraction coupling mechanism, energy consumption and cellular death. The close resemblance of human COAM to ISP-induced lesions suggests that similar mechanisms may be involved.

Animals↗
PubMed1983

Early reports on drug interactions.

Letters in correspondence columns or brief reports in medical journals are an essential part of an early warning system, and they are invaluable in alerting clinicians and clinical pharmacists to associations between drugs and their reactions. A survey of the literature during the first half of 1982 has identified a number of these early reports; some are purely anecdotal, others may be coincidental, but all serve to warn the practitioner of potential hazard. Brief information on the following reports of drug-drug interactions is given in this article with the intention of giving these reports wider publicity and, possibly, encouraging further observation and research to establish or disprove their validity in a larger and wider range of patients or volunteer subjects. The following interactions are reviewed: amiodarone-quinidine, lidocaine-prenylamine, erythromycin-carbamazepine, azapropazone-phenytoin, chlordiazepoxide-levodopa, gentamicin-furosemide, ethanol-aspirin, acetaminophen-coumarin anticoagulant, and cimetidine-lidocaine.

Acetaminophen↗
PubMed1976

Effect of coronary vasodilators on cardiac dynamics of the normal dog and the dog with experimental coronary sclerosis.

Observations are presented about the effects of four kinds of coronary vasodilators (dipyridamole, oxyfedrine, prenylamine and trimetazidine) on coronary circulation in the heart with coronary sclerosis which has been induced by intravenous injection of allylamine in the dog. Following results are obtained: 1) All of the drugs examined increase coronary blood flow and decrease coronary vascular resistance in the dogs with coronary sclerosis as well as in normal dogs. 2) An amplitude of response of coronary circulation to the coronary vasodilators is significantly less in the dogs with coronary sclerosis than in the normal dogs. 3) The clinical value of coronary vasodilator has been discussed.

Allylamine↗
PubMed1987

The inhibitory effects of calmodulin antagonists on TSH-stimulated thyroid hormone release by mouse thyroid lobes.

Calcium ions have been shown to play a mojor regulatory role in the release of various hormones from a wide variety of endocrine organs. More recently, in vitro evidence suggests that a calcium-binding protein, calmodulin, is also involved in the release of many hormones. So we examined the effects of several types of calmodulin antagonists on TSH-stimulated thyroid hormone release in vitro. Mouse thyroid lobes (one thyro-tracheal unit/tube) were incubated in Krebs-Ringer bicarbonate buffer at 37 degrees C for 4h. Free thyroxine (fT4) released in the incubation medium, thyroidal cAMP and calmodulin content were measured by RIA. TSH (5 mU/ml) and dibutyryl cAMP (DBC) (200 micrograms/ml) caused a 2-4 fold increase in thyroidal release of fT4. The stimulatory effects of TSH on fT4 release were significantly inhibited by trifluoprazine and prenylamine lactate at the concentration of 5 X 10(-5) M. More specific calmodulin antagonists, W-7 and W-13, were also shown to inhibit TSH stimulation of fT4 release at the concentration of 5 X 10(-5) M. In contrast, TSH stimulation of fT4 release was not depressed by non-specific antagonists, W-5 or W-12, at the same concentration as 5 X 10(-5) M. Further, W-13 also markedly inhibited DBC-stimulated fT4 release. Neither TSH nor PGI2 altered the thyroidal calmodulin content, dissociating with a marked increase in the cAMP concentration. These results suggest that calmodulin plays an important role in TSH-stimulated thyroid hormone release and further that this mechanism exists, at least in part, at the site subsequent to the generation of cAMP.

Animals↗
PubMed1975

Prevention of hereditary cardiomyopathy in the hamster by verapamil and other agents.

Verapamil, Prenylamine and, to a lesser extent, Cinnarizine were highly efficient in preventing the development or reducing the severity of heart lesions in cardiomyopathic hamster of the UM-X7.1 line. The calcium antagonistic compounds did not protect against the skeletal muscle changes already present at the time when treatment was initiated. The cardiac lesions were also significantly diminished in frequency and severity by a low calcium diet and in apparent contradiction, by parenteral administration of calcium gluconate. The relation of these electrolytes and creatine phosphokinase is not yet fully understood but suggests that a primary defect in muscles cell membranes may be responsible for hereditary cardiomyopathy in hamsters.

Animals↗
PubMed1975

[Key-role of intracellular calcium overload in acute necrosis of the myocardium. Cardioprotection with verapamil].

Ca ions are highly cardiotoxic if their influx into the myocardial fibres becomes abundant. The intracellular Ca overload initiates a deleterious high-energy phosphate deficiency by excessive activation of Ca-dependent intracellular ATPases and by impairing the phosphorylating capacity of mitochondria. This Ca-induced high-energy phosphate exhaustion is a crucial point in the etiology of the myocardial fibre necroses produced in rats by large doses of beta-adrenergic catecholamines, particularly isoproterenol, or by a number of other cardiotoxic agents. Accordinly, the myocardium is sensitized to necrotization by factors which favour Ca overload (dihydrotachysterol, 9alpha-flourocortisol acetate, NaH2PO4). Conversely, the structural integrity of the hearts can be protected by any substance or procedure which prevents an excessive intracellular Ca accumulation, particularly by inhibitors of the transmembrane Ca influx, such as verapamil, D 600 or prenylamine.

Adenosine Triphosphate↗
PubMed1989

Identification of receptors for platelet-activating factor in rat Kupffer cells.

Ligand binding studies demonstrated that isolated rat Kupffer cells possess high affinity binding sites for platelet-activating factor (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine, AGEPC). AGEPC binding reached saturation within 10 min at 25 degrees C and was reversible. A Scatchard analysis revealed a single class of AGEPC receptors numbering about 10,600 sites/cell and possessing a dissociation constant of 0.45 nM. Similar values for the dissociation constant for AGEPC (0.12 and 0.34 nM) were obtained independently by kinetic analysis of specific AGEPC binding. AGEPC binding was stereospecific and was inhibited by Zn2+ and AGEPC receptor antagonists including BN52021 and U66985. The AGEPC receptor was functionally active since it was shown to mediate arachidonic acid release and eicosanoid production in Kupffer cells, and these events were inhibited by AGEPC receptor antagonist BN52021. The receptor-mediated arachidonic acid release was extracellular calcium-dependent and was abolished by calcium channel blocker prenylamine and by [ethylenebis(oxyethylenenitrilo)]tetraacetic acid, indicating that calcium influx through a receptor-regulated calcium channel in the plasma membrane is involved in the AGEPC-induced arachidonic acid release. It is suggested that rat Kupffer cells have specific and functionally active AGEPC receptors which are involved in signaling mechanisms which govern the production of several other autacoid-type mediators in the liver.

Animals↗