Search PubMed⌕ Search

Biomedical subjects

G Sachs

Publications and source records attributed to G Sachs.

At least 235 records · Page 13Linked to original sources
PubMed1987

Three patients with concomitant panic attacks and seizure disorder: possible clues to the neurology of anxiety.

The authors present the cases of three patients in whom panic attacks and epilepsy appeared together. These cases illustrate various possible relationships between panic attacks and epilepsy. These relationships include panic attacks representing the aura of a complex partial seizure, panic attacks representing a manifestation of interictal behavior change, and panic attacks and seizure coexisting independently. The authors conclude that exploration of the mechanisms operating in unusual cases like these may provide a vehicle for clarifying the neurobiological basis of anxiety.

Adult↗
PubMed1987

Triazolam-induced brief episodes of secondary mania in a depressed patient.

Large doses of triazolam repeatedly induced brief episodes of mania in a depressed elderly woman. Features of organic mental disorder (delirium) were not present. Manic excitement was coincident with the duration of action of triazolam. The possible contribution of the triazolo group to changes in affective status is discussed.

Aged↗
PubMed1986

Identification of a vanadate-sensitive potassium-dependent proton pump from rabbit colon.

Membrane vesicles prepared from rabbit distal colon were used to study colonic transport mechanisms. Differential and sucrose-Ficoll density gradient centrifugation of the mucosal homogenate yielded fractions which supported ATP-dependent proton transport, as measured with the fluorescent weak base acridine orange. Quenching of acridine orange absorbance in light microsomes and microsome-derived density gradient fractions was MgATP-dependent and was reversed with nigericin; these characteristics suggest the presence of one or more ATP-driven proton pumps. Proton transport in the microsomal fraction was inhibited by N-ethylmaleimide more than by orthovanadate, and was dependent on extravesicular chloride. Vesicles in a microsome-derived gradient fraction were inhibited by orthovanadate more than by N-ethylmaleimide. N-ethylmaleimide pretreatment of this gradient fraction uncovered a vesicle population with characteristics similar to the gastric H+,K+ATPase: proton transport was abolished by orthovanadate and the experimental anti-ulcer drug SCH 28080, was enhanced by potassium, and was not affected by chloride. ATP-generated proton gradients in this fraction were not dissipated by the proton ionophore 3,3',4',5-tetrachlorosalicylanilide. We conclude that two ATP-driven proton pumps are present in mucosa from distal rabbit colon; one with characteristics of N-ethylmaleimide-sensitive organelle associated proton pumps, and one similar to the gastric proton-potassium exchanger.

Adenosine Triphosphatases↗
PubMed1986

Regulation of free cytosolic Ca2+ in the peptic and parietal cells of the rabbit gastric gland.

Quin 2-loaded isolated rabbit gastric glands and purified peptic cells were used to measure free cytosolic Ca2+ ([Ca2+]i) during hormone stimulation. Rabbit gastric glands are composed of peptic and parietal cells with less than 1% endocrine cells. Although both cell types responded to the same hormones, they may be distinguished in terms of the source of Ca2+ bringing about the change in [Ca2+]i. Experiments were designed to assign changes in [Ca2+]i to either the peptic or parietal cells and to attempt to maintain these distinctions in the mixed cell population of gastric glands. It was shown that the peptide cholecystokinin octapeptide induced a rapid and transient increase in [Ca2+]i of isolated peptic cells. This signal was independent of medium Ca2+ and insensitive to the Ca2+ channel blockers La3+ and nifedipine. In gastric glands, the Ca2+ outdependent increase in (Ca2+)i (the secondary transient) was slower and dose dependently blocked by La3+ and nifedipine. This allowed [Ca2+]i levels in the physiologically more intact rabbit gastric glands to be dissected and correlated with fluorescence changes of quin 2 in either cell type. The transient increase in [Ca2+]i coincided with a burst of pepsin but not acid secretion. A subsequent slower phase of pepsin secretion took place while the cells restored near resting [Ca2+]i. Using a combination of the Ca2+ ionophore A23187 and the protein kinase C activating phorbol ester 12-O-tetra-decanoylphorbol 13-acetate, the hormone response pattern of pepsin secretion could be mimicked. The intracellular Ca2+ stores of the peptic cells in the gastric gland remained depleted of Ca2+ until specific antagonists were added. The reloading of intracellular stores required medium Ca2+ although [Ca2+]i was maintained at resting level during the entire reloading period. Hence, a specialized pathway of Ca2+ reloading is postulated.

Aminopyrine↗
PubMed1986

Crystallization of the gastric H,K-ATPase.

Crystalline arrays of the gastric H,K-ATPase were obtained in membrane preparations from hog and rabbit gastric mucosa. The lattice was formed rapidly in a medium containing K+, vanadate, Mg2+, and dimethyl sulfoxide at pH 6.0-6.9 in imidazole buffer from 4 to 22 degrees C. The crystal lattice exhibited P2 symmetry, and the unit cell dimension (a = 5.6, b = 11, and c = 10 nm) could accommodate 2 polypeptides of mass 116-129 kDa. In addition, the isolated preparation contained previously undescribed long cylindrical structures 16 nm thick. These structures consisted of a central core 6-7 nm wide from which particles spaced 5.5 nm apart protruded symmetrically.

Adenosine Triphosphatases↗
PubMed1986

The parietal cell as a therapeutic target.

Inhibition of acid secretion or an improvement in mucosal resistance is central to treatment of upper gastrointestinal tract ulcers. Initiation of secretion is largely brought about by activation of the H2-histamine receptor, though other receptors are also involved to a lesser extent. Activation of the parietal cell by histamine is dependent on adenylate cyclase, and is a result of direct stimulation of the enzyme by histamine, Cyclic AMP can mimic the effect of H2-receptor activation. Mechanisms of cholinergic and gastrinergic stimulation involve different receptors and second messengers. These three systems can be used to construct a model of the parietal cell and its activation. On activation, changes in metabolism, structure and H+ pump function occur in the parietal cell, and these suggest the possibility of several sites of action for the phosphokinases activated by the second messengers cyclic AMP and Ca2+. Detailed studies have been carried out on the H+K+ATPase of hog gastric mucosa and a reaction sequence has been proposed, which can be correlated to the transport functions of the enzyme. The molecular weight of the enzyme is 94,000 and a part of its amino acid sequence has been determined. As knowledge about the enzyme becomes more precise, it should be possible to design a specific inhibitor. Such a terminal step inhibitor should be able to completely inhibit acid secretion in therapeutic doses.

Adenosine Triphosphatases↗
PubMed1985

Characterization of an electrogenic ATP and chloride-dependent proton translocating pump from rat renal medulla.

To study acidification mechanisms in the distal nephron, microsomes were prepared from rat renal medulla by differential centrifugation. Microsomes were enriched in the enzyme marker gamma-glutamyl transferase and contained an ATP-dependent proton pump, as evidenced by ATP-dependent, 3,3',4',5-tetrachlorosalicylanilide-reversible quenching of acridine orange fluorescence. Acidification was vanadate-insensitive, but was completely inhibited by micromolar N-ethylmaleimide. Maximal acidification was achieved in the presence of halide (Cl-, Br-) only and was not attainable with potassium-valinomycin diffusion potentials without halide ion. Microsomal ATPase activity was neither chloride- nor N-ethylmaleimide-sensitive. A chloride conductance was observed only with vesicles which had undergone ATP-dependent acidification. An ATP-dependent, N-ethylmaleimide-inhibitable, 3,3',4',5-tetrachlorosalicylanilide-reversible, and chloride-attenuated quench of bis(1,3-dibutylbarbituric acid-(5] pentamethinoxonol fluorescence was seen, consistent with net transfer of positive charge into the vesicles. Nonetheless, positive intravesicular potentials increased the ATP-dependent initial acidification rate, perhaps by increasing availability of chloride ion to the transport site. Our results are consistent with an electrogenic, ATP-dependent proton pump regulated by a voltage-sensitive chloride site.

Adenosine Triphosphatases↗
PubMed1985

Role of free cytosolic calcium in secretagogue-stimulated amylase release from dispersed acini from guinea pig pancreas.

To determine the role of free cytosolic calcium ([Ca+2]i) in stimulated enzyme secretion from exocrine pancreas, we determined the effects of various pancreatic secretagogues on [Ca+2]i and amylase release in dispersed acini from the guinea pig pancreas. Cholecystokinin-octapeptide (CCK-OP), carbachol, and bombesin, but not vasoactive intestinal peptide, stimulated rapid increases in [Ca+2]i from 100 to 600-800 nM that were independent of extracellular calcium. The increases in [Ca+2]i were transient (lasting less than 5 min) and correlated with an initial rapid phase of amylase release. After 5 min, secretagogue-stimulated amylase release occurred at basal [Ca+2]i. Carbachol pretreatment of the acini abolished the effects of CCK-OP and bombesin on [Ca+2]i and the initial rapid phase of amylase release. 4 beta-phorbol 12-myristate 13-acetate (PMA) had no effect on [Ca+2]i but stimulated an increase in amylase release. The addition of CCK-OP or A23187 to PMA-stimulated acini caused an increase in [Ca+2]i and PMA-stimulated amylase release only during the first 5 min after addition of these agents. These results indicate that CCK-OP, carbachol, and bombesin release calcium from an intracellular pool, resulting in a transient increase in [Ca+2]i and that this increase in [Ca+2]i mediates enzyme secretion during the first few minutes of incubation. The results with PMA suggest that secretagogue-stimulated secretion not mediated by increased [Ca+2]i (sustained secretion) is mediated by 1,2-diacylglycerol.

Amylases↗
PubMed1985

Solubilization and reconstitution of the gastric H,K-ATPase.

Proteoliposomes containing the hog gastric H+,K+-ATPase were prepared from cholate and n-octyl glucoside extracts of native microsomes. Experiments were presented which show reconstitution-dependent selective purification of a 94-kDa peptide capable of Rb+/Rb+ exchange and active H+ transport. The absence of selective enrichment of residual protein contamination in this material suggests but does not prove that those transport reactions are attributable only to the 94-kDa peptide. Transport demonstrated inhibitor sensitivity and cation specificity comparable to the microsomal gastric ATPase. In K2SO4 media the H+ transport reaction was protonophore insensitive and correlated with MgATP-dependent 86Rb+ extrusion. This and other evidence suggested that active transport occurs via electroneutral H+in for K+out exchange. 86Rb+ exchange (uptake) in the proteoliposomes demonstrated both saturable and nonsaturable components. At a K0.5 = 1.5 mM, saturable 86Rb+ uptake accounted for about 90% of Rb+ influx. The vanadate-sensitive cation exchange indicated that the ATPase was reconstituted asymmetrically into the proteoliposomes (70% cis-/30% trans-vanadate site). 86Rb+ exchange was inhibited by ATP and stimulated about 2-fold by low Mg2+ and 5 mM phosphate. These ligand effects and the demonstration of comparable rates of passive exchange and active Rb+ efflux suggest that passive K+ exchange is not severely limited by a K+-occluded enzyme form in the H,K-ATPase. A model compatible with this hypothesis is suggested.

Adenosine Triphosphatases↗
PubMed1985

Electrolyte transport across the basolateral membrane of the parietal cells.

The ion-transport properties of the basal lateral membranes of intact isolated parietal cells were studied at the cellular and subcellular level. The presence of an amiloride-sensitive Na+:H+ exchange was demonstrated in cells by proton gradient-driven Na+ uptake and by changes in cell pH as monitored by dimethylcarboxylfluorescein fluorescence both in a fluorimeter and on single isolated cells using a fluorescence microscope and an attached intensified photodiode array spectrophotometer. The presence of the Na+:H+ antiport in vesicles was shown both by intravesicular acidification monitored by acridine orange fluorescent quenching and by proton gradient-dependent Na+ uptake. The presence of Cl-:HCO-3 exchange was determined in intact cells by monitoring changes in cell pH due to Cl- uptake and was shown to be 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid- and 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonic acid-sensitive. In vesicles, Cl-:HCO-3 exchange was demonstrated by Cl- flux measurement. The apparent affinities for both Cl- and HCO-3 on either side of the membrane were determined to be Km Cli = 20 mM, Km Clout = 17.5 mM, Km HCO-3in = 2.5 mM, and Km HCO-3out = 7.5 mM. A K+ conductance in cells and vesicles was demonstrated by monitoring K+ gradient-dependent 86Rb uptake. No evidence was found for the presence of a Cl- conductance in either cells or vesicles but a H+ conductance was found to be present in vesicles but not in intact cells. In the latter, by determining the effect of either Na+ or Cl- gradients on cell pH and by flux calculations it was concluded that the Cl-:HCO-3 exchange was the major passive flux mechanism for pH regulation in this cell type.

Amiloride↗
PubMed1985

Reversal of antisecretory activity of omeprazole by sulfhydryl compounds in isolated rabbit gastric glands.

We have examined the interaction of omeprazole, a gastric antisecretory agent, with endogenous or exogenous sulfhydryl compounds in isolated rabbit gastric glands. The glands exposed to omeprazole (2 microM for 50 min) could recover acid secretory response to dibutyryl-cAMP upon addition of dithiothreitol, cysteine or glutathione. Washing the omeprazole-exposed glands free of the extracellular drug also led to a similar recovery of the acid secretory response. Depletion of cellular glutathione with 2-cyclohexen-1-one had no considerable effect on the secretory response of the glands to dibutyryl-cAMP, but prevented the reversal of the antisecretory effect of omeprazole upon washing or adding exogenous cysteine. Also, the antisecretory potency of omeprazole increased several fold in the glutathione-depleted glands. These observations indicate that cellular glutathione is essential to reactivate the omeprazole-modified enzyme(s), possibly (H+ + K+)-ATPase, in acid secretory process and led us to propose that omeprazole is an agent reacting with sulfhydryl groups.

Animals↗
PubMed1985

Emotional problems during weight reduction: advantages of a combined behavior therapy and antidepressive drug therapy for obesity.

Depressive symptoms may increase in a subgroup of obese individuals shortly after beginning a weight-reducing diet. Therefore an additional antidepressive medication should have a positive effect on the course and results of therapy. This hypothesis was tested in three different institutional settings, with identical therapeutic programs. In this study there were 23 obese women. Therapeutic strategies were concerned with an increase of self-control over eating behavior, the improvement of social skills, and the establishment of new problem-solving abilities. Doxepin was used as the anti-depressant in a double blind procedure. Our results seem to support the hypothesis of this study: depressive symptoms markedly increased soon after the beginning of weight-reduction; additional antidepressive medication helped to improve the symptoms and in the long term had a positive effect on the rate of weight loss.

Adult↗
PubMed1985

Inositol trisphosphate modification of ion transport in rough endoplasmic reticulum.

The ion transport properties of the rough endoplasmic reticulum (RER) from liver have been defined by using measurements of active and potential gradient-driven transport. The Ca2+ pump is shown to be electrogenic, and both ATP and potential difference is able to drive vanadate-inhibitable Ca2+ uptake into the RER. ATP-dependent Ca2+ transport into the RER depends on the presence of tetraethylammonium-sensitive cation conductance and a furosemide-inhibited cation/chloride cotransport pathway. Inositol trisphosphate does not affect either of the monovalent ion translocation systems but activates a Ca2+ conductance in the RER, allowing efflux of RER Ca2+ stores into the cytosol in exchange for K+ uptake.

Adenosine Triphosphate↗
PubMed1985

Ca2+ metabolism during cholinergic stimulation of acid secretion.

Carbachol-induced changes in 45Ca fluxes and cytosolic free Ca2+ were characterized in rabbit gastric glands and isolated dog parietal cells. Cholinergic stimulation was expressed as changes in the membrane permeability of the parietal cell to Ca2+ without Ca2+ release from intracellular stores. The changes in the membrane permeability to Ca2+ were sustained as long as the cells were exposed to carbachol, independent of extracellular Ca2+, and had the properties of a passive pathway across which Ca2+ distributed according to its chemical gradient. As a consequence of the changes in membrane permeability to Ca2+, carbachol caused a sustained increase in free cytosolic Ca2+ from a resting level of 134 +/- 11 to 533 +/- 81 nM (n = 14). After carbachol stimulation, calcium ions were sequestered in mitochondrial and probably nonmitochondrial compartments. When cell stimulation was terminated by atropine or La3+, the cells restored the resting level of the intracellular Ca2+ activity ([Ca2+]in), independent of uncoupling of mitochondrial oxidation phosphorylation. Reduction in [Ca2+]in was mainly through Ca2+ efflux across the plasma membrane of the parietal cell. Manipulation of intracellular Na+ ion activity in intact cells and studies with basal-lateral membrane vesicles from gastric mucosa indicated the absence of extracellular Na+-intracellular Ca2+ exchange activity in the plasma membrane of the parietal cell. A calmodulin-regulated, ATP-dependent Ca2+ pump that could maintain active Ca2+ extrusion from parietal cells was found in the basal-lateral membrane of the parietal cells.

Animals↗
PubMed1985

Acid secretion by frog gastric mucosa is electroneutral.

The action of a newly developed, specific inhibitor of the gastric proton pump, omeprazole, was investigated using intact frog gastric mucosa. Omeprazole was found to inhibit acid secretion, and the inhibition could be reversed with glutathione or 2-mercaptoethanol. Inhibition was not stimulus specific, occurring with histamine, carbachol, and forskolin. With hypertonic solutions bathing the mucosal surface, omeprazole inhibition of acid secretion did not change the tissue conductance, whereas inhibition by thiocyanate or cimetidine resulted in a significant decrease in conductance. With high-K+ (greater than 80 mM) sulfate solutions bathing both surfaces, omeprazole inhibition of acid secretion resulted in no change in transtissue potential difference. In chloride solutions, omeprazole caused an increase in potential difference and short-circuit current. These results provide evidence that the proton pump in frog gastric mucosa is electroneutral.

Animals↗
PubMed1985

Role of calcium in cholecystokinin-stimulated phosphoinositide breakdown in exocrine pancreas.

In dispersed acini from guinea pig pancreas cholecystokinin octapeptide (CCK-OP) stimulated breakdown of the phosphoinositides phosphatidylinositol (PI) and its phosphorylated derivative, phosphatidylinositol 4,5-bisphosphate (PI-P2), as measured by a decrease in the mass of PI and decreases in the content of [3H]PI and [32P]PI-P2 in acini prelabeled with myo-[2-3H]inositol or H3(32)PO4. The breakdown occurred in the absence of extracellular Ca2+ and when the CCK-OP-induced rise in free intracellular Ca2+ ([Ca2+]i) was ablated by loading the acini with the Ca2+-selective indicator and chelator quin-2 in the absence of extracellular Ca2+. In contrast to CCK-OP, the calcium ionophore A23187 caused breakdown of PI and PI-P2 in the presence but not in the absence of extracellular Ca2+, although like CCK-OP A23187 stimulated 45Ca outflux, a measure of cellular Ca2+ mobilization, and amylase release during the first 5-10 min of incubation independent of extracellular Ca2+. In the absence of extracellular Ca2+ A23187 did not inhibit the ability of CCK-OP to cause PI breakdown. These results indicate that CCK-OP stimulates breakdown of PI and PI-P2 and that this breakdown is independent of extracellular Ca2+, mobilization of intracellular Ca2+, and the CCK-OP-induced rise in [Ca2+]i. These findings suggest that one of the initial events resulting from CCK-OP interaction with its receptor is phosphoinositide breakdown.

Aminoquinolines↗
PubMed1985

Emerging strategies in ulcer therapy: pumps and receptors.

The treatment of gastric and duodenal ulcers has recently been revolutionised. The reason for this is the increased knowledge of the physiology and biochemistry of the mucosae at the cellular and subcellular levels. In this article, we try to explain how the gastric parietal cell works, and how, based on that knowledge, we might be able to devise increasingly sophisticated tools for inhibition of acid secretion.

Animals↗