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PubMed1985

Electrogenic calcium transport in plasma membrane of rat pancreatic acinar cells.

ATP-dependent 45Ca2+ uptake was investigated in purified plasma membranes from rat pancreatic acinar cells. Plasma membranes were purified by four subsequent precipitations with MgCl2 and characterized by marker enzyme distribution. When compared to the total homogenate, typical marker enzymes for the plasma membrane, (Na+,K+)-ATPase, basal adenylate cyclase and CCK-OP-stimulated adenylate cyclase were enriched by 43-fold, 44-fold, and 45-fold, respectively. The marker for the rough endoplasmic reticulum was decreased by fourfold compared to the total homogenate. Comparing plasma membranes with rough endoplasmic reticulum, Ca2+ uptake was maximal with 10 and 2 mumol/liter free Ca2+, and half-maximal with 0.9 and 0.5 mumol/liter free Ca2+. It was maximal at 3 and 0.2 mmol/liter free Mg2+ concentration, at an ATP concentration of 5 and 1 mmol/liter, respectively, and at pH 7 for both preparations. When Mg2+ was replaced by Mn2+ or Zn2+ ATP-dependent Ca2+ uptake was 63 and 11%, respectively, in plasma membranes; in rough endoplasmic reticulum only Mn2+ could replace Mg2+ for Ca2+ uptake by 20%. Other divalent cations such as Ba2+ and Sr2+ could not replace Mg2+ in Ca2+ uptake. Ca2+ uptake into plasma membranes was not enhanced by oxalate in contrast to Ca2+ uptake in rough endoplasmic reticulum which was stimulated by 7.3-fold. Both plasma membranes and rough endoplasmic reticulum showed cation and anion dependencies of Ca2+ uptake. The sequence was K+ greater than Rb+ greater than Na+ greater than Li+ greater than choline+ in plasma membranes and Rb+ greater than or equal to K+ greater than or equal to Na+ greater than Li+ greater than choline+ for rough endoplasmic reticulum. The anion sequence was Cl greater than or equal to Br greater than or equal to 1 greater than SCN greater than NO3 greater than isethionate greater than cyclamate greater than gluconate greater than SO2(4) greater than or equal to glutarate and Cl- greater than Br greater than gluconate greater than SO2(4) greater than NO3 greater than 1 greater than cyclamate greater than or equal to SCN, respectively. Ca2+ uptake into plasma membranes appeared to be electrogenic since it was stimulated by an inside-negative K+ and SCN diffusion potential and inhibited by an inside-positive diffusion potential. Ca2+ uptake into rough endoplasmic reticulum was not affected by diffusion potentials. We assume that the Ca2+ transport mechanism in plasma membranes as characterized in this study represents the extrusion system for Ca2+ from the cell that might be involved in the regulation of the cytosolic Ca2+ level.

Adenosine Triphosphate↗
PubMed1973

Anion conductance of frog muscle membranes: one channel, two kinds of pH dependence.

Anion conductance and permeability sequences were obtained for frog skeletal muscle membranes from the changes in characteristic resistance and transmembrane potential after the replacement of one anion by another in the bathing solution. Permeability and conductance sequences are the same. The conductance sequence at pH = 7.4 is Cl(-) Br(-) > NO(3) (-) > I(-) > trichloroacetate >/= benzoate > valerate > butyrate > proprionate > formate > acetate >/= lactate > benzenesulfonate >/= isethionate > methylsulfonate > glutamate >/= cysteate. The anions are divided into two classes: (a) Chloride-like anions (Cl(-) through trichloroacetate) have membrane conductances that decrease as pH decreases. The last six members of the complete sequence are also chloride like. (b) Benzoate-like anions (benzoate through acetate) have conductances that increase as pH decreases. At pH = 6.7 zinc ions block Cl(-) and benzoate conductances with inhibitory dissociation constants of 0.12 and 0.16 mM, respectively. Chloride-like and benzoate-like anions probably use the same channels. The minimum size of the channel aperture is estimated as 5.5 x 6.5 A from the dimensions of the largest permeating anions. A simple model of the channel qualitatively explains chloride-like and benzoate-like conductance sequences and their dependence on pH.

Acetates↗
PubMed1972

Origin of the after-hyperpolarization that follows removal of depolarizing agents from the isolated superior cervical ganglion of the rat.

1. Potential changes in isolated rat superior cervical ganglia following addition and removal of depolarizing agents were recorded using a moving-fluid extracellular electrode system.2. Ganglionic negativity produced by carbachol was followed by a pronounced ganglionic positivity on washing. This after-positivity was attributed to hyperpolarization of the ganglion cells since it was unaffected by crushing the postganglionic trunk.3. The after-hyperpolarization was selectively depressed by (a) cooling (Q(10) 2.3), (b) metabolic inhibitors (cyanide, azide, 2,4-dinitrophenol), (c) reducing [K(+)](o) or substituting Cs(+) for K(+), (d) ouabain, and (e) substituting Li(+) for Na(+). This suggested a close dependence on active Na(+) transport.4. When K(+) was restored to K(+)-free solution, or the preparation was warmed rapidly, or when metabolic inhibitors were washed away, the hyperpolarization was rapidly regenerated. The effect of restoring K(+) indicated that the hyperpolarization was generated directly by the Na(+) pump.5. The hyperpolarization was not altered by replacing Cl(-) with isethionate, indicating that the voltage change produced by the Na(+) current was not modified by passive Cl(-) movements.6. Hexamethonium added to the washout fluid augmented the after-hyperpolarization, suggesting that there was a high (cationic) leak current due to continued receptor-activation on washing with normal Krebs solution.7. The hyperpolarization was reduced by omission of Ca(2+) and restored by addition of Mg(2+). This was considered to result from changes in passive membrane permeability.8. The time-course of post-carbachol hyperpolarization accorded with a Na(+) extrusion process whose rate was directly proportional to [Na(+)](i) with a rate constant of 0.38+/-0.02 min(-1) at 23-27 degrees C.9. With increasing concentrations of carbachol, the amplitude of the hyperpolarization increased in proportion to the preceding depolarization, but the rate constant of the hyperpolarization was unchanged.

Acetylcholine↗
PubMed1973

Effects of anions and cations on the resting membrane potential of internally perfused barnacle muscle fibres.

1. Single barnacle muscle fibres from Megabalanus psittacus (Darwin) were internally perfused with a number of K salt solutions (200 mM) which were made isotonic to the barnacle saline with sucrose.2. 200 mM-K acetate solution, in general, was found to be more effective than other solutions of K salts in generating and maintaining stable resting membrane potential of -56.0 +/- 0.7 mV (all potentials are referred to the external solutions as ground). The various K salts, on the basis of the magnitude of the resting potential they generated in the muscle fibres, followed the sequence, acetate > isethionate > aspartate > glutamate > fluoride > monohydrogen phosphate > succinate > citrate > sulphate > oxalate > iodobenzoate > ferrocyanide > chlorate > nitrate > chloride > thiocyanate > iodide > bromide > cyanide.3. The resting potential in muscle fibres perfused with solutions of acetate, aspartate and glutamate increased linearly with the logarithm of the K concentration (slope = 30.4 mV for K acetate and 27.4 for K aspartate and glutamate) when the ionic strength of the solutions was progressively increased from 50 to 650 mM. On the other hand, similar increase of ionic strength beyond 200 mM of solutions of K isethionate, fluoride, monohydrogen phosphate, succinate and citrate depolarized the muscle fibres.4. Perfusion of acetate solutions of other alkali metal ions gave low values for the resting potential and followed the sequence K > Na > Rb > Li > Cs. Also NH(4) and Tris ions gave low values for the resting potential which underwent oscillations associated with the twitching of the fibre and occasionally became positive in value (action potential).5. Addition of tetraethyl ammonium chloride (TEA-Cl), 20-100 mM, to K acetate solutions (200 mM) depolarized the fibre membrane and the consequent reduction of resting potential varied linearly with the logarithm of TEA concentration.6. Replacement of chloride ion by acetate or isethionate in the external solution did not change significantly the resting potential although the values were consistently lower by about 2 mV.7. Complete elimination of K in the external solution and reduction of its ionic strength using sucrose depolarized the muscle fibres by about 27 mV when Na was changed from 475 to 1 mM. Under these conditions, external solutions completely in acetate form gave resting potentials which were more positive than those observed in completely chloride solutions by 6-8 mV.8. Replacement of Na by Li, Tris, choline, tetramethyl or tetraethyl ammonium ion in the external solution made the values of the resting potential more positive (depolarization). Similarly increasing the concentration of K (or Cs or Rb in place of K) by correspondingly decreasing the concentration of Na in the outside solution depolarized the fibres and the resting potential became zero at a concentration of 280 mM (or 308 or 1500 mM for Rb or Cs, respectively) on extrapolation.

Acetates↗
PubMed1991

Treatment of psoriasis with piritrexim, a lipid-soluble folate antagonist.

Methotrexate is an effective and convenient treatment for severe psoriasis whose use is limited by the development of hepatic fibrosis and cirrhosis in a small number of patients. The mechanism of hepatotoxicity is unknown, but it is believed to be the result of intracellular polyglutamation and prolonged retention of methotrexate within the cell. Piritrexim isethionate is a lipid-soluble antifolate that has a mechanism of action similar to that of methotrexate. Since it is not polyglutamated, piritrexim could be effective in the treatment of psoriasis without the associated long-term hepatotoxicity. A 12-week phase I/II clinical trial of severe chronic plaque psoriasis assessed the safety and efficacy of oral piritrexim therapy. Based on experience gained from oncologic trials, each patient received a twice-daily dosage for 5 consecutive days every 2 weeks. Dosages ranged from 25 to 100 mg twice a day. Improvement in both lesion scores and percentage of body involvement was significant at a dose of 50 mg or more twice daily. Fifteen of 19 patients who completed 12 weeks of therapy demonstrated greater than 50% improvement in lesion scores. Improvement was limited by recrudescence of lesions over the 9-day rest period. Adverse experiences were minimal and dose related. Piritrexim is efficacious in the treatment of psoriasis.

Adult↗
PubMed1979

Fluid movements across rabbit ileum coupled to passive paracellular ion movements.

1. Theophylline (10 mM) and choleragen (1 x 10(-6) g ml.-1) abolish net fluid absorption by everted sacs of rabbit ileum. Triaminopyrimidine (20 mM) and ethacrynate (0.1 mM) prevent this inhibition of net fluid movement. Replacing Ringer Cl- with isethionate prevents the theophylline-dependent decrease in fluid absorption also. 2. Ouabain (0.1 mM) abolishes net fluid movements in both control and theophylline-treated tissue. 3. With ouabain present, hypertonic NaCl (200 mM) in the mucosal solution causes net fluid secretion (serosal-mucosal flux). With theophylline added to both the mucosal and serosal solution, net fluid absorption (mucosal-serosal flux) is observed (P less than 0.001). Triaminopyrimidine (20 mM), or ethacrynate (0.1 mM), or replacement of Ringer Na+ with choline, or Ringer Cl- with isethionate all prevent the theophylline-induced reversal of osmotic flow. 4. Theophylline increases passive net flux of Na+ and Cl- from mucosal solution containing hypertonic (200 mM) NaCl+ ouabain (0.1 mM) across sheets of ileum into serosal solution containing mannitol Ringer + ouabain. The increased passive Na+ flux is blocked by triaminopyrimidine and the increased Na+ and Cl- fluxes are blocked by ethacrynate (0.1 mM). 5. The suggested route of increased NaCl leakage is via the paracellular pathway as it is inhibited by triaminopyrimidine. The increase, itself, is a consequence of the increased passive permeability of the mucosal border to Cl-, induced by theophylline or choleragen. Water is apparently electro-osmotically coupled to the paracellular Na+ leakage (100 mole water mole-1 Na+), hence increased passive leakage reverses osmotic flow. In active tissue the lateral intercellular space contains hypertonic NaCl, and hence increased leakage of NaCl across the tight-junction in theophylline or choleragen-treated tissue gives rise to net fluid secretion.

Animals↗
PubMed1989

Hypoxic changes in hippocampal neurons.

1. Reversible effects of brief periods of anoxia (replacing 95% O2-5% CO2 with 95% N2-5% CO2 for 2-4 min) were studied in CA1 neurons in hippocampal slices (from Sprague-Dawley rats), kept in an interface-type chamber at 33.5 degree. 2. The predominant voltage change during anoxia (N2) was a hyperpolarization, accompanied by a marked fall in resistance and excitability; synaptic potentials were also depressed, especially inhibitory postsynaptic potentials (IPSPs). 3. In voltage-current (V-I) plots, the N2-evoked hypolarization had a reversal potential below -90mV, even when recording with 2 M KCl electrodes and after substituting 90% of medium Cl- with isethionate. The accompanying fall in input resistance (RN) is therefore probably caused by an increase in K conductance (in agreement with previous reports). There was evidence that anomalous rectification enhances the fall in RN but limits the hyperpolarization. 4. These effects of anoxia were not fully blocked by any of the K-channel antagonists tested, including Cs, TEA, 4-AP, quinine and apamin. 5. Intracellular injections of Ca chelators caused a variable depression of N2-evoked reductions in RN. 6. It is unlikely that N2 activates ATP-sensitive K channels as tolbutamide enhanced rather than depressed the hyperpolarization and fall in RN. 7. When early depletion of cellular ATP was prevented by incubation in creatine (25 mM for greater than 1 h), even longer anoxic periods produced only minor changes in potential, RN, and synaptic transmission. 8. It was concluded that activation of K conductance by a rise in cytosolic-free Ca2+ is the most plausible of several possible underlying mechanisms.

4-Aminopyridine↗
PubMed1987

Trimetrexate for the treatment of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome.

Preclinical studies have demonstrated that trimetrexate is a potent inhibitor of dihydrofolate reductase from Pneumocystis carinii. On the basis of this evidence, this lipid-soluble antifolate was used as an antipneumocystis agent in 49 patients with the acquired immunodeficiency syndrome (AIDS) and pneumocystis pneumonia. Simultaneous treatment with the reduced folate leucovorin was used as a specific antidote to protect host tissues from the toxic effects of the antifolate without affecting the antipneumocystis action of trimetrexate. Patients were assigned to three groups and treated for 21 days: in Group I, trimetrexate with leucovorin was used as salvage therapy in patients in whom standard treatments (both pentamidine isethionate and trimethoprim-sulfamethoxazole) could not be tolerated or had failed (16 patients); in Group II, trimetrexate with leucovorin was used as initial therapy in patients with a history of sulfonamide inefficacy or intolerance (16 patients); and in Group III, trimetrexate with leucovorin plus sulfadiazine was used as initial therapy (17 patients). The response and survival rates were, respectively, 69 percent and 69 percent in Group I; 63 percent and 88 percent in Group II; and 71 percent and 77 percent in Group III. Trimetrexate therapy had minimal toxicity; transient neutropenia or thrombocytopenia occurred in 12 patients and mild elevation of serum aminotransferases in 4. We conclude that the combination of trimetrexate and leucovorin is safe and effective for the initial treatment of pneumocystis pneumonia in patients with AIDS and for the treatment of patients with intolerance or lack of response to standard therapies.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Low-molecular-weight sulfonates, a major substrate for sulfate reducers in marine microbial mats.

Several low-molecular-weight sulfonates were added to microbial mat slurries to investigate their effects on sulfate reduction. Instantaneous production of sulfide occurred after taurine and cysteate were added to all of the microbial mats tested. The rates of production in the presence of taurine and cysteate were 35 and 24 microM HS(-) h(-1) in a stromatolite mat, 38 and 36 microM HS(-) h(-1) in a salt pond mat, and 27 and 18 microM HS(-) h(-1) in a salt marsh mat, respectively. The traditionally used substrates lactate and acetate stimulated the rate of sulfide production 3 to 10 times more than taurine and cysteate stimulated the rate of sulfide production in all mats, but when ethanol, glycolate, and glutamate were added to stromatolite mat slurries, the resulting increases were similar to the increases observed with taurine and cysteate. Isethionate, sulfosuccinate, and sulfobenzoate were tested only with the stromatolite mat slurry, and these compounds had much smaller effects on sulfide production. Addition of molybdate resulted in a greater inhibitory effect on acetate and lactate utilization than on sulfonate use, suggesting that different metabolic pathways were involved. In all of the mats tested taurine and cysteate were present in the pore water at nanomolar to micromolar concentrations. An enrichment culture from the stromatolite mat was obtained on cysteate in a medium lacking sulfate and incubated anaerobically. The rate of cysteate consumption by this enrichment culture was 1.6 pmol cell(-1) h(-1). Compared to the results of slurry studies, this rate suggests that organisms with properties similar to the properties of this enrichment culture are a major constituent of the sulfidogenic population. In addition, taurine was consumed at some of highest dilutions obtained from most-probable-number enrichment cultures obtained from stromatolite samples. Based on our comparison of the sulfide production rates found in various mats, low-molecular-weight sulfonates are important sources of C and S in these ecosystems.

Cysteic Acid↗
PubMed1989

GABA and glycine channels in isolated ganglion cells from the goldfish retina.

1. Adult goldfish retinas were enzymatically dissociated and ganglion cells were maintained in culture for periods of 1-5 days. Ganglion cells could be identified by their morphology, and this identification was confirmed by retrograde transport of the fluorescent dye Fast Blue injected into the optic nerve stub. 2. All the ganglion cells tested responded to 30 microM-GABA or 100 microM-glycine between 2 and 30 h after enzymatic dissociation of the retina. 3. Whole-cell responses to 30 microM-GABA or glycine declined over a period of seconds during sustained applications of the agonists, probably as a result of desensitization. There was an irreversible decline in the peak whole-cell response to repeated applications of 30 microM-GABA unless the pipette-filling solution contained 2 mM-ATP, 4 mM-Mg2+, 10 mM-EGTA and no added Ca2+. Both GABA and glycine responses also showed an irreversible decline in outside-out patches but, in this case, Mg2+, ATP, and very low Ca2+ failed to stabilize the response. 4. Whole-cell currents activated by both GABA and glycine were demonstrated to be chloride-selective by investigating the dependence of reversal potential (Vr) on internal chloride concentration ([Cl-]i). For GABA responses, the dependence of Vr on [Cl-]i could not be distinguished from that predicted by the Nernst relation. For glycine, deviations from Nernstian dependence were observed, but the permeability to Cl- was at least 20 times greater than to isethionate, SO4(2-), or monovalent cations (Na+ and Cs+). 5. Bicuculline methochloride (10 microM) selectively blocked responses to 3-30 microM-GABA without affecting responses to 30 microM-glycine. Bicuculline itself was not as selective. At agonist concentrations of 30 microM, 3 microM-bicuculline partially blocked the response to GABA but not that to glycine, but bicuculline at 10 microM blocked responses to both GABA and glycine. Strychnine (0.3-1 microM) blocked responses to 30 microM-glycine but also competitively antagonized GABA responses. Picrotoxinin (10 microM) blocked responses to 3 microM-GABA in some cells but also partially antagonized responses to 30 microM-glycine. 6. GABA channels had at least two conductance states at 10-12 degrees C in nearly symmetrical (141 mM in, 142 mM out) chloride. The slope conductance of the most frequently observed (main) state was 16 +/- 2 pS. The reversal potential for the main state was not significantly different from the chloride equilibrium potential (0 mV).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1996

Brodimoprim synergy against Enterococcus faecalis evaluated in vitro.

Combinations of either brodimoprim or trimethoprim plus either carbenicillin, gentamicin, ciprofloxacin or rifampicin showed synergy at sub-inhibitory concentrations against both Enterococcus faecalis NCTC 5957 and 775. Brodimoprim alone and in combination showed greater antibacterial activity against both strains of E. faecalis than trimethoprim. MBCs of brodimoprim and trimethoprim were 14.4 and 25.6 mg/L for E. faecalis NCTC 5957 and 7.2 and 12.8 mg/L for E. faecalis NCTC 775. Combinations of either brodimoprim or trimethoprim plus the other antibacterial agents, except gentamicin and dibromopropamidine isethionate, were bactericidal at achievable plasma concentrations. Viable count determinations of cultures of both test organisms in the presence of 3/4 of the MIC of each of the four antibiotics and the two antifolates alone and combinations of each antibiotic with either brodimoprim or trimethoprim indicated that only the combinations prevented recovery and regrowth of the cultures over 24 h. The ATP released from cultures of both strains of E. faecalis treated with brodimoprim and trimethoprim at the same concentrations was approximately 1.5 times greater with brodimoprim than with trimethoprim. Combinations of 3/4 of the MIC of each of the antibiotics in combination with 3/4 of the MIC of brodimoprim against cultures of both strains of E. faecalis resulted in greater release of ATP than occurred with equivalent trimethoprim combinations. It is postulated that the increased activities observed with the brodimoprim combinations resulted from an effect of brodimoprim on the bacterial cell permeability control. These results indicate that both brodimoprim and trimethoprim offer potential benefits for use with either carbenicillin, gentamicin, ciprofloxacin or rifampicin for the treatment of E. faecalis infections.

Anti-Bacterial Agents↗
PubMed1993

A multicentre 12-week open study of a lipid-soluble folate antagonist, piritrexim in severe psoriasis.

An open, 12-week, multicentre study was conducted to assess the efficacy of piritrexim isethionate in the treatment of severe psoriasis. Piritrexim isethionate is a lipid-soluble dihydrofolate reductase inhibitor which cannot form polyglutamates, and may be as effective as methotrexate in the treatment of psoriasis. If, as is suspected, but as yet unproven, methotrexate polyglutamates are responsible for the hepatotoxicity of methotrexate, piritrexim should be less hepatotoxic, and may offer an alternative to methotrexate therapy. Fifty-five patients were enrolled, of whom 41 completed the study. Patients were allocated to receive either 150, 225, 300, or 450 mg of piritrexim weekly, in divided doses over 72 h (low-dose groups, 150 and 225 mg), or over 36 h (300 and 450 mg groups). Twenty-four of the 41 patients who completed the study had a greater than 50% improvement in the severity of their psoriasis, as demonstrated by a reduction in the Psoriasis Severity Score, a measure analogous to the PASI scoring system. Adverse events were common, but mild, and were controlled by dose reduction. Piritrexim appears to be an effective therapy for severe psoriasis at doses of 300 and 450 mg weekly, in three divided doses over 36 h.

Drug Administration Schedule↗
PubMed2005

Pentamidine is an antiparasitic and apoptotic drug that selectively modifies ubiquitin.

We have determined the cytotoxic properties of pentamidine isethionate (2) towards the promastigotes of the protozoan parasite Leishmania infantum. The leishmanicidal activity of 2 was 60 times higher after 72 h of incubation than that of cisplatin (4). The pentamidine salt 2 induced a higher amount of programmed cell death (PCD) than cisplatin, which is associated with inhibition of DNA synthesis and cell-cycle arrest in the G2/M phase. Circular dichroism (CD) data indicate that binding of 2 to calf-thymus DNA (CT-DNA) induces conformational changes in the DNA double helix, consistent with a B-->A transition. Moreover, the interaction of 2 with ubiquitin led to a 6% increase in the beta-sheet content of the protein as observed by CD spectroscopy. Fluorescence-spectroscopy studies agreed with the CD data, showing that the pentamidine portion of 2 induces a significant decrease in the fluorescence of the Ub residues Phe4 and Phe45 located on the beta-cluster of the molecule, but not of Tyr59 on the alpha-cluster. These data indicate that pentamidine specifically modifies the beta-cluster, i.e., the 'basic face' of ubiquitin. Our results suggest that the biochemical mechanism of action of pentamidine may be a consequence of its dual binding to DNA and proteins.

Amino Acid Sequence↗
PubMed1986

Two independent anion transport systems in rabbit mandibular salivary glands.

Cholinergically stimulated Cl and HCO3 transport in perfused rabbit mandibular glands has been studied with extracellular anion substitution and administration of transport inhibitors. In glands perfused with HCO3-free solutions, replacement of Cl with other anions supported secretion in the following sequence: Br = greater than Cl greater than I = greater than NO3 greater than isethionate. Furosemide, 1.0 and 0.1 mmol/l, inhibited Cl-supported secretion by 97-99% and 70-78%, respectively. SITS, 0.1 mmol/l, had no effect and amiloride, 1.0 mmol/l, caused a 55-65% inhibition. Addition of SITS to amiloride-treated glands produced no further effect. In glands perfused with Cl-free solutions, but containing 25 mM HCO3, amiloride, 1.0 mmol/l, inhibited secretion by 95% and methazolamide, 0.1 mmol/l, by 55%. In glands perfused with solutions containing both HCO3 and Cl, furosemide had smaller effects than in glands perfused with solutions containing only Cl - a dose of 1.0 mmol/l inhibited 60% of the initial fast phase of secretion, and 90% of the later plateau phase, while a dose of 0.1 mmol/l inhibited 30% of the initial phase, but had no effect on the plateau. SITS, 0.1 mmol/l, actually stimulated secretion by about 30%, but when infused in addition to furosemide (0.1 mmol/l), it inhibited by about 20%. Amiloride (1.0 mmol/l) caused no inhibition. The results suggest that there are at least three distinct carriers in the rabbit mandibular gland. One is a furosemide-sensitive Na-coupled Cl (probably Na-K-2Cl) symport, responsible for the bulk of normal secretion. The others are an amiloride-sensitive Na-H antiport and a SITS-sensitive Cl-HCO3 antiport.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed1972

Changes in axon light scattering that accompany the action potential: current-dependent components.

1. When light scattering was measured during hyperpolarizing and depolarizing voltage-clamp steps, relatively large scattering changes were found during the depolarizing steps. These large changes were found to depend on the time integral of the ionic current and not on the changes in conductance or potential.2. The current-dependent changes were examined at several scattering angles, and three distinct time courses were found. At 30-120 degrees , the main change occurred after the current when steps of 2-5 msec duration were used. This change was called I-90 degrees . At 15-30 degrees , the change occurred with the same time course as the time integral of the current. This change was called I-25 degrees . At 5-15 degrees the scattering change occurred with a time course intermediate between that of I-90 degrees and I-25 degrees . This change was called I-10 degrees .3. In all experiments, outward potassium and outward sodium currents led to similar light scattering changes indicating that specific effects of the cation carrying the current across the membrane were not involved.4. The size of I-90 degrees was reduced by 29% when an isethionate artificial sea water was substituted for the normal chloride artificial sea water. This reduction equalled the reduction predicted for a transport number effect at the membrane-solution interface. The time course of I-90 degrees was similar to the predicted time course for a volume change in the periaxonal space, and such volume changes were tentatively identified as the origin of I-90 degrees .5. Because of difficulties in measuring the time course of I-25 degrees , it was not possible to distinguish between a water of hydration effect and a transport number effect as the cause of this change. Similarly, the origins of I-10 degrees were not identified. Only I-10 degrees was altered in size and time course when the external refractive index was increased with bovine albumin.6. When the scattering changes during the action potential were examined in light of the voltage-clamp experiments, we concluded that the forward-angle change was potential-dependent and that the long-lasting change at right angles probably represented a swelling of the periaxonal space resulting from the fact that chloride carried a significant fraction of the outward current during the action potential.

Action Potentials↗
PubMed1995

Cerebroprotective effect of lamotrigine after focal ischemia in rats.

BACKGROUND AND PURPOSE: Glutamate receptor antagonists are protective in animal models of focal cerebral ischemia. Lamotrigine (3,5-diamino-6-[2,3-dichlorophenyl]-1,2,4-triazine) is an anticonvulsant drug that blocks voltage-gated sodium channels and inhibits the ischemia-induced release of glutamate. We describe the cerebroprotective effect of lamotrigine (as the isethionate salt) after middle cerebral artery occlusion in rats. METHODS: Neurological deficit and infarct volume (visualized by the lack of reduction of 2,3,5-triphenyltetrazolium chloride) 24 hours after permanent left middle cerebral artery occlusion were studied in Fischer rats (n = 8 per group per dose). RESULTS: Lamotrigine at 20 mg/kg i.v. over 10 minutes administered immediately after middle cerebral artery occlusion reduced total infarct volume by 31% and cortical infarct volume by 52%. Lamotrigine at 8 mg/kg i.v. over 10 minutes reduced cortical infarct volume by 38%. Lamotrigine at 50 mg/kg i.v. for 10 minutes was not cerebroprotective and induced a decrease of 29 +/- 15 mm Hg in mean arterial blood pressure (P < .05, n = 8). The optimum dose of lamotrigine (20 mg/kg i.v. over 10 minutes) when administered with a 1-hour delay after middle cerebral artery occlusion reduced cortical infarct volume by 41%. Lamotrigine (20 mg/kg i.v. over 10 minutes) with a 2-hour delay after middle cerebral artery occlusion was ineffective. Neurological deficits after 24 hours were improved after immediate treatment with lamotrigine at 20 mg/kg i.v. over 10 minutes. CONCLUSIONS: The cerebroprotective effect of lamotrigine in rats is limited to a narrow dose range between 8 and 20 mg/kg. Lamotrigine or analogous compounds may be useful when given shortly after the onset of stroke.

Animals↗
PubMed2006

Chloride-dependency of amyloid beta protein-induced enhancement of glutamate neurotoxicity in cultured rat hippocampal neurons.

In our previous studies, pathophysiological concentrations of amyloid-beta (Abeta) proteins increased intracellular Cl(-) concentration ([Cl(-)]i) and enhanced glutamate neurotoxicity in primary cultured neurons, suggesting Cl(-)-dependent changes in glutamate signaling. To test this possibility, we examined the effects of isethionate-replaced low Cl(-) medium on the Abeta-induced enhancement of glutamate neurotoxicity in the primary cultured rat hippocampal neurons. In a normal Cl(-) (135 mM) medium, treatment with 10 nM Abeta25-35 for 2 days increased neuronal [Cl(-)]i to a level three times higher than that of control as assayed using a Cl(-)-sensitive fluorescent dye, while in a low Cl(-) (16 mM) medium such an Abeta25-35-induced increase in [Cl(-)]i was not observed. The Abeta treatment aggravated glutamate neurotoxicity in a normal Cl(-) medium as measured by mitochondrial reducing activity and lactate dehydrogenase (LDH) release, while in a low Cl(-) medium the Abeta treatment did not enhance glutamate toxicity. Upon such Abeta plus glutamate treatment under a normal Cl(-) condition, activated anti-apoptotic molecule Akt (Akt-pS473) level monitored by Western blot significantly decreased to 74% of control. Under a low Cl(-) condition, a resting Akt-pS473 level was higher than that under a normal Cl(-) condition and did not significantly change upon Abeta plus glutamate treatment. Tyrosine phosphorylation levels of 110 and 60 kDa proteins (pp110 and pp60) increased upon Abeta plus glutamate treatment under a normal Cl(-), but not low Cl(-), condition. These findings indicated that Abeta-induced enhancement of glutamate neurotoxicity is Cl(-)-dependent. Chloride-sensitive Akt pathway and tyrosine phosphorylation of proteins (pp110 and pp60) may be involved in this process.

Amyloid beta-Peptides↗
PubMed1968

On the electrogenic sodium pump in mammalian non-myelinated nerve fibres and its activation by various external cations.

1. A study has been made of the hyperpolarization that follows a period of electrical activity (the post-tetanic hyperpolarization) in mammalian non-myelinated nerve fibres.2. Evidence is presented that under certain circumstances this postetanic hyperpolarization is a result of activity of an electrogenic sodium pump that normally is absolutely dependent on the external presence of potassium.3. When the external chloride is replaced by sulphate or by isethionate the post-tetanic hyperpolarization, which in normal Locke solution is only a few millivolts in amplitude, is increased usually to about 20 mV, and on occasion to 35 mV.4. This effect of removing the chloride takes several minutes to develop and is consistent with the idea that the increase in the post-tetanic response is the result of removing the short-circuiting effect of internal chloride ions (by their being washed out into the chloride-free bathing medium).5. Small anions, such as chloride, nitrate, iodide, bromide, and thiocyanate can short-circuit the electrogenic pump, whereas larger anions such as sulphate and isethionate cannot. The bicarbonate ion, which is larger than chloride, short-circuits the pump but less effectively.6. In Locke solution containing 5 mM potassium the post-tetanic hyperpolarization declines exponentially, with a time constant of about 1-3 min. The time constant is inversely related to the external potassium concentration.7. However, when the external potassium concentration is zero the hyperpolarization declines rapidly to a very small value. Subsequent addition of potassium to the bathing medium causes a marked redevelopment of the hyperpolarization.8. This potassium-activated response declines exponentially with a time constant that is inversely related to the potassium concentration. When the added potassium concentration is 5 mM, the time constant is 1.9 min.9. The amplitude of the potassium-activated response increases with increasing concentrations of potassium.10. Other cations can produce this activated response. Thus, thallium is more effective than, rubidium as effective as, caesium and ammonium about 1/10 as effective as, and lithium ions about 1/30 as effective as potassium in producing the activated response. Choline is quite ineffective.11. The size of the post-tetanic response is little affected by changes in the duration of the period of stimulation. However, increasing the duration definitely increases the time constant of recovery.12. Reducing the external sodium concentration increases the size of the post-tetanic hyperpolarization (by about 25%), but the effect is complex and requires further study.13. Reducing the calcium of the Locke-solution from 2.2 to 0.2 mM has no appreciable effect on the post-tetanic response, nor has increasing the pH of the Locke from 7.2 to 9.2.14. When the membrane potential is increased or decreased, by externally applied currents, there is relatively little change in the post-tetanic response.15. A mathematical model of the electrogenic pump, devised to mimic the experimental results, was analysed with an analogue computer. A satisfactory agreement between model and experiment was achieved by a model in which: (1) the rate of extrusion of sodium ions depends on the degree to which a pool of carrier molecules on the inside surface of the membrane is combined with sodium; (2) each carrier molecule transfers three sodium ions at a time; (3) the rate constant for extrusion of sodium ions also depends on the presence externally of potassium ions, which combine with some sites on the external surface of the membrane that are half-saturated when the external concentration of potassium is 2.8 mM.

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