UMLS:C0344329 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Target Concepts:

Query: UMLS:C0344329 (collapse)
28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

SK&F 101926 is a synthetic octapeptide which was designed to promote free water excretion by antagonizing the action of antidiuretic hormone. The clinical and pathologic changes in rats resulting from lethal doses of SK&F 101926 have suggested that death is associated with respiratory failure and/or cardiovascular collapse. To define the relationships between respiratory failure, cardiovascular collapse, and death, respiratory and cardiovascular parameters were monitored in anesthetized rats following the intravenous administration of SK&F 101926 at a dosage (3 mg/kg) which resulted in 70% mortality. Within 5 min after receiving this dosage, mean arterial blood pressure was reduced to values between 30 and 40 mm Hg in all rats. This degree of hypotension was well tolerated by some rats and, consequently, was not considered to be the cause of death. Deaths occurred between 9 and 58 min after dosing and were preceded by respiratory depression involving marked reductions in respiratory rate and the lack of compensatory increases in tidal volume. At the time of respiratory arrest, heart rates remained above 200 beats/min, mean arterial blood pressure remained between 30 and 40 mm Hg, and there were no consistent changes in dynamic lung compliance or total pulmonary resistance. Pretreatment of rats with a mast cell stabilizing agent (disodium cromoglycate), a mast cell degranulating agent (compound 48/80), or a histamine/5-hydroxytryptamine blocking agent (cyproheptadine) prevented the reductions in respiratory rate and death caused by SK&F 101926. These pretreatments also reduced the effect of SK&F 101926 on blood pressure, but were not able to completely prevent the hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Respiratory and cardiovascular changes associated with toxic doses of a peptide antagonist of vasopressin in the rat. 160 Dec 32

The current study was done to test the hypotheses that parafollicular granules contain a vacuolar ATPase (V-ATPase) similar to that found in chromaffin granules, that the transport of H+ into granules mediated by this enzyme drives the granular uptake of 5-hydroxytryptamine (5-HT, serotonin), and that secretagogues stimulate both the acidification of parafollicular granules and their ability to take up 5-HT by opening an anion channel in the granular membrane. Our studies indicate that parafollicular granules contain a V-ATPase that is antigenically similar to that of the V-ATPase of adrenal chromaffin granules; however, the parafollicular granular membrane differs from that of chromaffin granules in permeability to Cl- and K+. The membranes of granules derived from resting parafollicular cells appear to be relatively impermeable to Cl- but permeable to K+. Parafollicular granules (and ghosts derived from them) manifest ATP-dependent transmembrane transport of 5-HT. This transport is more dependent on the pH difference (delta pH) than on the membrane potential component of the proton electrochemical gradient across the granular membrane. Transport of 5-HT is thus inhibited more by exposure of parafollicular granules to agents, such as nigericin, that collapse delta pH than by those, such as valinomycin, that decrease transmembrane difference in potential. ATP-dependent uptake of 5-HT by granules isolated from secretagogue-stimulated parafollicular cells is greater than that into granules isolated from unstimulated cells. Since secretagogues open a Cl- channel in parafollicular granule membranes, which enhances acidification of the granules, the facilitation of 5-HT uptake by secretagogues is probably due to an increase in delta pH.
...
PMID:ATP-dependent uptake of 5-hydroxytryptamine by secretory granules isolated from thyroid parafollicular cells. 182 54

The action of activated 27,000 Mr toxin from Bacillus thuringiensis var. israelensis (Bti toxin) on Malpighian tubules of Rhodnius prolixus has been investigated. Its binding to the tubules is slowed by low temperature but is not prevented even at 0 degree C. The binding is less effective at pH 10 than at pH7. Pretreatment of the tubules with 0.1 mmol l-1 ouabain or bumetanide or 1 mumol l-1 5-hydroxytryptamine did not affect the toxicity of the toxin. The toxin causes very large changes in the trans-epithelial potential difference; it changes from 40 mV, lumen negative, often to more than 100 mV, lumen positive. This reflects an initial collapse of the potential of the basal cell membrane, followed by a large positive-going potential change at the luminal cell membrane. Just prior to the effects of the toxin on rapid fluid secretion, the basal cell membrane becomes permeable to sucrose molecules. Raffinose at 170 mmol l-1 in the bathing solution does not protect the tubules from Bti toxin action but dextran, Mr5000, at 60 mmol l-1 significantly delayed failure of fluid secretion and, even more, the onset of staining of the tubule cells with Trypan Blue. Exposing tubules to saline that is calcium-free and/or magnesium-free, or has a composition adjusted to be similar to that of the intracellular milieu, does not affect the time course of failure of fluid secretion induced by the toxin. There is no evidence that effective aggregates of Bti toxin molecules are formed in concentrated solutions.(ABSTRACT TRUNCATED AT 250 WORDS)
...
PMID:Action of activated 27,000 Mr toxin from Bacillus thuringiensis var. israelensis on Malpighian tubules of the insect, Rhodnius prolixus. 263 87

1. The potential of the potassium channel activator, cromakalim (BRL 34915), as a bronchodilator has been evaluated in guinea-pig models in comparison with nifedipine. Some effects of the compounds on guinea-pig tracheal spirals have been studied in an attempt to elucidate their different efficacies in vivo. 2. When given by the intraduodenal route to anaesthetized guinea-pigs, cromakalim (3 and 10 mg kg-1) inhibited 5-hydroxytryptamine (5-HT)-induced bronchospasm for at least 60 min. When given by the i.v. route, the dose of cromakalim producing 50% inhibition of the 5-HT response was 84 micrograms kg-1. Nifedipine failed to show any protective effect up to 100 micrograms kg-1, i.v. and was lethal at higher dose levels. 3. Cromakalim protected conscious guinea-pigs from asphyxic collapse in response to histamine aerosol. The maximal effect occurred 60 min following oral dosing, with 2.5 mg kg-1 providing complete protection for almost half of the animals. Nifedipine had only a weak protective effect even at a high dose level of 50 mg kg-1, p.o. 4. Cromakalim prolonged the time before convulsive cough in response to an antigen challenge in actively sensitized guinea-pigs. Its minimum protective dose was 1 mg kg-1, p.o. Nifedipine (50 mg kg-1, p.o.) was ineffective. 5. Cromakalim inhibited both spontaneous and prostaglandin E2-induced tone in guinea-pig isolated tracheal spirals with IC50 values, relative to the maximum inhibition achieved by isoprenaline (10(-3)M), of 1.1 x 10(-6)M and 8.9 x 10(-7)M, respectively. Its maximal effect was 89% of that produced by isoprenaline. Removal of the epithelium did not influence its activity. Studies using the two enantiomers showed that the activity of cromakalim resided almost entirely in the (-)-enantiomer. 6. Nifedipine (2 x 10-SM) achieved only 49% of the relaxant effect of 10 -3M isoprenaline in isolated tracheal spirals. Addition of cromakalim (10- 5 M) at the end of the nifedipine concentrationresponse experiment caused further relaxation to 94% of the effect of isoprenaline. 7. It is concluded that cromakalim has greater potential than nifedipine as a bronchodilator. It appears that opening of potassium channels, with consequent hyperpolarization and stabilization of the membrane potential, prevents calcium entering the cytosol through routes that are unaffected by calcium entry blockers.
...
PMID:Evaluation of the potassium channel activator cromakalim (BRL 34915) as a bronchodilator in the guinea-pig: comparison with nifedipine. 320 91

Storage of 5-hydroxytryptamine (5HT) in membrane-bound vesicles (dense bodies) of platelets has been proposed to occur as a result of the formation of macromolecular complexes between nucleotides and 5HT, or because of the existence of an electrochemical proton gradient (delta mu H+) across the vesicle membrane. Tests of the applicability of these hypotheses to 5HT storage in the dense bodies of human platelets have been made by examining the disposition of quinacrine and 5HT in these organelles following varying treatments. Binding seems unlikely, since solid analogues of the dense body core (calcium, adenine nucleotides, and pyrophosphate) do not significantly bind 5HT or quinacrine. Incubation of platelets with substances which disrupt delta mu H+ releases a large percentage of the intra-platelet quinacrine. A much smaller fraction of the total platelet 5HT is released by similar treatment, suggesting that the delta mu H+ may not be required for 5HT storage. Because inhibition of the de novo uptake of 5HT into dense bodies fails to cause the significant loss of the 5HT stored in this compartment, 5HT stores do not appear to be maintained by active 5HT uptake. Several substances which enter the dense bodies equally well at 0 degrees C and 37 degrees C cause release of 5HT at 37 degrees C but not at 0 degrees C. The release observed at 37 degrees C thus cannot be attributable to collapse of delta mu H+ or to the displacement of 5HT from intra-granular binding sites, but may be related to increased membrane permeability to 5HT at 37 degrees C. Based on these observations, it appears as if 5HT taken up into the dense bodies of human platelets is retained because the dense body membrane has a very low passive permeability for 5HT, and that many compounds which cause 5HT release at 37 degrees C may act by increasing this permeability.
...
PMID:Exploration of mechanisms of amine storage in the dense bodies of human platelets. 609 85

1. Highly purified resealed chromaffin-granule ;ghosts' were assayed for ATPase and ATP-driven H(+)-translocation and 5-hydroxytryptamine-uptake activities, and for 5-hydroxytryptamine uptake driven by an imposed transmembrane H(+)-gradient. The effects of several inhibitors on these activities were studied. 2. Dicyclohexylcarbodi-imide inhibits all of these activities, but not in parallel; at low concentrations it decreases the permeability of the membrane to protons. 3. 4-Chloro-7-nitrobenzofuran (Nbf-Cl) and silicotungstate inhibit ATP-dependent activities, without effect on 5-hydroxytryptamine uptake driven by an imposed H(+)-gradient. 4. Tributyltin chloride inhibits all of the activities. 5. Treatment of the ;ghosts' with low concentrations of urea inhibits 5-hydroxytryptamine uptake and ATP-dependent generation of a transmembrane H(+)-gradient, without inhibiting ATPase activity. 6. Nbf-Cl and silicotungstate are without effect on the rate of leakage of 5-hydroxytryptamine from preloaded ;ghosts', whereas dicyclohexylcarbodi-imide and tributyltin chloride accelerate the rate of leakage. 7. Treatment of the membranes with (14)C-labelled Nbf-Cl labels several proteins; membranes treated with dicyclohexyl[(14)C]carbodi-imide are labelled predominantly in a protein of low molecular weight, which may be analogous to the mitochondrial H(+)-conducting proteolipid. 8. It is concluded that Nbf-Cl and silicotungstate inhibit the H(+)-translocating ATPase of the granule membrane; that dicyclohexylcarbodi-imide inhibits the ATPase, and inhibits 5-hydroxytryptamine accumulation by accelerating leakage of the amine; and that the effects of tributyltin chloride are due to inhibition of the ATPase, and collapse of the transmembrane H(+)-gradient through OH(-)-anion exchange.
...
PMID:Inhibition of adenosine triphosphatase, 5-hydroxytryptamine transport and proton-translocation activities of resealed chromaffin-granule 'ghosts'. 625 64

The actions of ionophores with different ion specificities and of thrombin on the release of 14C-labeled 5-hydroxytryptamine, [3H]noradrenaline, and endogenous ATP were measured in human platelets suspended in media with various K+ and Na+ concentrations. Besides thrombin, those ionophores [monensin, nigericin, and the combination of carbonylcyanide-p-trifluoromethoxyphenyl hydrazone (FCCP) with nonactin and/or valinomycin] which cause a rapid collapse of H+ gradients induced a fast and virtually total release of 14C-labeled 5-hydroxytryptamine and [3H]noradrenaline into the various media. FCCP alone, which causes an inversion of the membrane potential to inside negative values, induced a considerably slower amine release. Changes in the K+ and Na+ gradients did not lead to amine release, nor did interference with energy transduction by antimycin A with or without glycolysis inhibitors. Monensin and FCCP did not release ATP, whereas thrombin, added before or after incubation of platelets with FCCP and monensin, caused a marked liberation of the nucleotide. It is concluded that in intact human platelets (a) the intragranular storage of 5-hydroxytryptamine and noradrenaline mainly depends on the proton gradient across the granular membrane, and (b) ionophores causing a collapse of H+ gradients induce non-exocytotic release of 5-hydroxytryptamine and noradrenaline from intracellular storage granules.
...
PMID:Storage of biogenic amines in intact blood platelets of man. Dependence on a proton gradient. 628 76

The effect of the transmembrane proton gradient (delta pH) and potential gradient (delta psi) upon the rate and extent of amine accumulation was investigated in intact 5-hydroxytryptamine (serotonin) containing dense granules. The granules were isolated and purified from other subcellular organelles under isotonic conditions utilizing a newly developed continuous density gradient of Percoll. As measured by [14C]methylamine distribution, isolated granules suspended in a highly buffered medium at pH 7.0 had an intragranular pH of 5.40, independent of the pH of the external medium. This pH gradient could be collapsed by the addition of 60 mM ammonia. In the presence of Mg-ATP, a transmembrane potential (delta psi) of 30-40 mV, inside positive, was generated and sustained for over 30 min, as measured by [14C]thiocyanate distribution. The addition of carbonyl cyanide p-trifluoromethoxyphenylhydrazone, a proton translocator, resulted in the reversal of the potential to negative values. The Mg-ATP-dependent generation of the delta psi was prevented by addition of dicyclohexylcarbodiimide and trimethyltin, inhibitors of proton-translocating ATPases in this and other subcellular organelles. Ammonia (1-50 mM) addition to highly buffered suspensions of serotonin granules caused a dose-dependent decrease in the delta pH, while thiocyanate added at varying concentrations produced a dose-related collapse of the delta psi and had no effect upon the delta pH. Both the delta pH and delta psi were found to independently drive accumulation of [14C]serotonin into the granules; stepwise collapse of each gradient resulted in a corresponding diminution of [14C]serotonin accumulation. The maximum rate and extent of [14C]serotonin uptake, however, were observed in the presence of both the delta pH and delta psi. The conclusions provide support for the existence of a proton-translocating ATPase in the serotonin granule membrane responsible for the generation of the delta pH and delta psi. Moreover, the results demonstrate a primary role for the electrochemical proton gradient (delta mu H+) in the carrier-mediated active transport of 5-hydroxytryptamine into the platelet granule.
...
PMID:Serotonin transport in isolated platelet granules. Coupling to the electrochemical proton gradient. 645 50

Human platelets appear to accumulate quinacrine both in a thrombin-releasable compartment (dense bodies or amine storage vesicles) and in another compartment from which it is released by agents known to collapse pH gradients (possibly lysosomes with an acidic interior). Approximately 61% of the total amount of quinacrine present in human platelets resides in dense bodies and 14+ in lysosomes, with the remainder probably present in the cytoplasm. Other basic amines are accumulated in the three compartments to widely varying extents, suggesting that several factors besides the existence of pH gradients act to determine the distribution of these substances within the cell. The fluorescence emission of quinacrine excited with 420 nm light is completely quenched for quinacrine inside both dense bodies and lysosomes, and the absorption of 440 nm light is decreased by approximately 25%. Quinacrine added to dense bodies at 37 degrees C induces the efflux of 5-hydroxytryptamine (5HT) from the bodies. There is, however, no 5HT loss following quinacrine entry at 0 degree C, and the relationship between the two types of amine movement varies according to incubation time at 0 degree C and 37 degrees C. This action of quinacrine therefore does not appear to be associated with stoichiometric exchange of 5HT and quinacrine, but rather to modulation of the passive permeability of the dense body membrane for 5HT.
...
PMID:Quinacrine and basic amines in human platelets: subcellular compartmentation and effects on serotonin. 670 2

The relationship between the electrochemical proton gradient (delta mu-H+) and the electrochemical gradient for biogenic amines (delta mu-A) was investigated in isolated chromaffin ghosts free of endogenous components and gradients. The addition of ATP to a ghost suspension resulted in the generation of a large proton concentration gradient (delta pH), acidic inside (measured by [14C]-methylamine distribution), and a large proton electrical gradient (delta psi), positive inside (measured by [14C]-thiocyanate distribution). In the presence of this large electrochemical proton gradient, the accumulation of [14C]5-hydroxytryptamine (serotonin) and other biogenic amines rapidly reached an apparent steady state level. Collapse of the proton gradients after steady state levels were achieved resulted in the efflux of the accumulated amines. Uptake in the presence of a delta psi alone produced an amine gradient equal to the magnitude of the delta psi, while in the presence of a delta pH alone biogenic amine distribution was equal to twice the magnitude of the delta pH. Using additions of ammonia or thiocyanate, it was possible to vary the magnitude of the electrochemical proton gradient over a wide range of values; the driving force for amine accumulation under these conditions was found to be equal to delta psi--2Z delta pH (where Z = 2.3 RT/F). The results, which provide unequivocal evidence for the primary role of the electrochemical proton gradient in the active transport of biogenic amines, are consistent with a model based on the chemiosmotic hypothesis, of an obligatory coupling of amine influx and proton efflux, mediated via a putative reserpine-sensitive translocator. Measurement of the stoichiometry of this coupling of H+ and amines permits conclusions concerning the molecular mechanism of amino accumulation.
...
PMID:Proton: substrate stoichiometries during active transport of biogenic amines in chromaffin ghosts. 724 Jan 71

1 2 Next >>