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

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Query: EC:3.6.1.3 (ATPase)
65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Na+,K(+)-ATPase and Ca(2+)-ATPase in testis were inhibited with an oral administration of cimetidine and ranitidine. Cimetidine at dose level of 100 and 30 mg while ranitidine at 70 and 10 mg per kg body wt inhibited the enzyme activities, 24 hr after single administration or daily administration for 15-days. Mg(2+)-ATPase activity was increased with cimetidine while ranitidine inhibited the enzyme. Michaelis-Menten kinetic characteristics revealed mixed type of inhibition for Na+,K(+)-ATPase with cimetidine, whereas it was noncompetitive for Ca(2+)-ATPase with cimetidine as well as ranitidine administration. Inhibition of Na+,K(+)-ATPase with ranitidine was also of noncompetitive type. Mg(2+)-ATPase behaved differently with administration of ranitidine at both the time points used i.e. noncompetitive type of inhibition after 24 hr and mixed type after 15-days. Histologically, signs of degeneration of testicular elements appeared after administration of cimetidine with a significant decrease in tubular diameter and germinal epithelial cell height. Ranitidine administration did not produce any change in the seminiferous tubules of testis. Scanning electron microscopy of spermatozoa from cimetidine-treated mice exhibited distinct departure from the normal morphology such as, (i) breaks at various places along distal portion of the tail, (ii) roughening, wrinkling and disorganization of plasma membrane of the head region, (iii) decapitation of the head and (iv) changes in shape of cytoplasmic droplet. Ranitidine administration showed normal morphology of the spermatozoa.
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PMID:Effect of H2-receptor antagonists, cimetidine and ranitidine on reproductive functions in male mice. 166 45

Oral administration of the antiulcerogenic drug, cimetidine, was studied on kidney-bound hydrolytic enzymes at three different dose levels (30 mg, 100 mg, and 2000 mg/kg body weight) and for single administration for 2 and 24 h, and daily administration for 15 days in mice. It significantly inhibited Na+, K(+)-ATPase, Mg(2+)-ATPase, and Ca2+, Mg(2+)-ATPase in the isolated basolateral membrane (BLM). Brush-border-membrane-(BBM)-associated enzymes, sucrase, lactase, maltase, leucine aminopeptidase, and alkaline phosphatase also showed a marked reduction. Substrate saturation kinetics revealed the nature of inhibition was of mixed type in the case of sucrase, lactase, maltase, and alkaline phosphatase (Km was increased, while Vmax decreased), whereas it was of non-competitive type for leucine aminopeptidase (Km was unchanged, while Vmax decreased). In vitro addition of cimetidine (5-20 mM) to the BBM also inhibited the enzyme activity. Dixon plot produced the inhibition constant (Ki) for cimetidine in the case of maltase, alkaline phosphatase, and leucine aminopeptidase in the order of 14.83, 32.83 and 11.5 mM, respectively. Analysis of lipids revealed a significant reduction in BBM-associated phospholipid and phospholipid/cholesterol molar ratio, while the neutral lipid fraction, i.e., cholesterol and triglycerides were not altered. Free fatty acid exhibited an increase after drug treatment, which was significant at higher dose after 24 h of single and 15 days of daily treatment. BLM-associated lipids did not exhibit any significant change. Cimetidine-induced depression in renal BLM- and BBM-associated disaccharidases and ATPases, at least at the higher dose level, may have serious consequences in the absorption of end-product nutrients.
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PMID:Depression of membrane-bound hydrolases by cimetidine in mouse renal basolateral and brush border. 183 34

The effects of pure ethanol and some alcoholic beverages on acid secretion and metabolism were examined in the isolated toad gastric mucosa. Pure ethanol applied to the luminal side or to the submucosal side at low concentrations (2%-10%) was a potent stimulant of acid secretion, whereas high concentrations (greater than or equal to 20%) were inhibitory. Cimetidine and calcium-free solutions did not abolish the secretory effect of ethanol. Beer and wine, but not rum and whisky, caused a significant stimulation of acid secretion. Respiration was progressively increased by ethanol at concentrations between 2% and 20%. This effect was not affected by cimetidine or by SCH 28080, an inhibitor of the gastric hydrogen-potassium-stimulated adenosine triphosphatase. Ethanol (10%) significantly increased by 46% the tissue lactate-pyruvate ratio. The oxidations of glucose, butyrate, and acetate were progressively reduced by low concentrations of ethanol (5% and 10%). The results indicate that (a) low concentrations of ethanol and alcoholic beverages with low ethanol content are direct stimulants of acid secretion and (b) the secretory and metabolic effects of low concentrations of ethanol seem to be mediated via its oxidation.
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PMID:Secretory and metabolic effects of ethanol in the isolated amphibian gastric mucosa. 190 55

There are two means of reducing acid secretion. The best studied is inhibition of stimulation of the parietal cell. There are three major types of receptors that activate secretion by this cell and two classes of receptor antagonists, as well as at least two intracellular messenger pathways. The receptors are for histamine (H2 subtype), acetyl choline (M2 subtype) and gastrin. Antagonists of these receptors include the H2-antagonist class (Tagamet, Zantac and Pepcid), the M1 muscarinic antagonists (pirenzepine, telenzepine) and the gastrin antagonist, proglumide. The major pathway for stimulation appears to be the H2-receptor, since this is the only receptor that stimulates adenylate cyclase, and both acetyl choline and gastrin release histamine locally within the gastric mucosa. However, these agonists elevate intracellular calcium, which has a partially independent action on acid secretion. Accordingly, the most efficacious type of receptor antagonist will be of the H2 class, which is borne out by clinical experience. Prostaglandins of the E type prevent adenylate cyclase stimulation by histamine and are also effective antisecretory agents. It will be difficult to abolish acid secretion entirely by a single receptor antagonist, although longer-acting H2-antagonists should show clinical superiority to short-acting antagonists of this type. An alternative approach to acid suppression is to block the terminal step of acid secretion, the gastric proton pump (H+, K(+)-ATPase). This enzyme is virtually unique to the parietal cell and, when active, forms a very acidic space within the parietal cell called the secretory canaliculus. Activation of acid secretion involves several steps. The enzyme is present in cytosolic membranes when the cell is at rest and moves to the membrane of the secretory canaliculus when stimulated. Simultaneously, there is an increased permeability of potassium chloride (KCl), which allows presentation of K+ to the luminal surface of the pump and H+ for K+ exchange. The result is the secretion of HCl into the canaliculus, and hence into the gland lumen and then the stomach. There are two classes of pump inhibitors. One class is K+ competitive and relatively selective for the H+, K(+)-ATPase, as exemplified by SCH28080. This class has not yet been used in man. The other class is specific to the functioning H+, K(+)-ATPase in the stomach. It is exemplified by omeprazole (Losec). This compound is a weak base with a pKa of 4. In the unprotonated, uncharged form it will penetrate cell membranes and, at pH less than 4, it becomes protonated and therefore charged.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Biological basis of omeprazole therapy. 256 65

Over the past ten years there have been major advances in the physician's ability to treat patients with peptic ulcer disease. Cimetidine continues to be the standard against which newer therapies are generally compared, although ranitidine is equally effective for short-term therapy, more effective for maintenance therapy, and has a superior safety profile. Famotidine is an even more potent H2 receptor antagonist, and initial clinical studies are promising. The initial concern for the development of gastric carcinoid lesions in rodents, maintained for long periods on high doses of omeprazole, defused the initial enthusiasm for this hydrogen-potassium ATPase "proton pump" inhibitor, but recent studies continue to show a marked efficacy of this agent for the short-term care of patients with gastric or duodenal ulcers and for the management of patients with the Zollinger-Ellison syndrome. Sulcrate continues to enjoy wide popularity for acute and chronic care of acid peptic disorders because of its local action and minimal adverse effects. Pirenzepine is effective in achieving and maintaining healing, but prevalence of anticholinergic side-effects has hampered enthusiasm for its widespread use. The 2 forerunners in the prostaglandin analogues arena, misoprostol and enprostil, are antisecretory agents when given in sufficiently high doses. These orally administered prostaglandins have a favourable safety profile, and their only adverse effect is that of the development of transient mild diarrhea. Finally, while antacids continue to be used in large amounts because of their over-the-counter availability, their clinical usefulness is limited by their unpalatable taste and the relatively large amounts usually required to achieve ulcer healing.
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PMID:Pharmacological management of patients with peptic ulcer disease: prospects for the late 1980's. 288 21

The mechanism of stimulatory action of histamine on gastric alkaline secretion was investigated in anesthetized rats. Intravenous infusion of histamine (2-8 mg/kg/hr) dose-dependently stimulated acid secretion and in the presence of omeprazole (60 mg/kg), an H+/K+-adenosine triphosphatase inhibitor, produced an increase of gastric but not duodenal alkaline secretion; the degree of gastric alkalinization was also dependent on the dose of histamine, reaching the maximal values of approximately 1.0 microEq/10 min. Cimetidine (100 mg/kg s.c.) significantly inhibited both acid and alkaline secretory responses caused by histamine, whereas indomethacin (5 mg/kg s.c.) significantly prevented the increased alkaline secretion caused by histamine as well as mucosal acidification (100 mM HCl for 10 min). Tripelennamine (10 mg/kg s.c.) had no effect on either acid or alkaline secretion. Histamine (8 mg/kg/hr) reduced the arterial blood pressure (25.3%) and increased the mucosal vascular permeability in the stomach as determined by Evans blue (160%), but these vascular responses were significantly prevented only by tripelennamine, excluding the possible contribution of the vascular effects to the increased gastric alkaline secretion. These results suggest that histamine may stimulate gastric alkaline secretion as well as acid secretion, and the mechanism of histamine-induced alkaline secretion may involve both endogenous prostaglandins and stimulation of H2-receptors.
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PMID:Stimulation of gastric alkaline secretion by histamine in rats: possible involvement of histamine H2-receptors and endogenous prostaglandins. 291 81

Gastrin levels, in the peripheral venous blood of conscious dogs treated with apomorphine (0.05 mg/kg IV), were analysed with a radioimmunoassay. Pretreatment (30 min) with the gastric acid inhibitors cimetidine, ranitidine (H2 receptor antagonists, 4 mg/kg and 1 mg/kg respectively) or omeprazole (H+-K+ ATPase inhibitor, 1.6 mg/kg) prolonged the elevation of gastrin levels occurring in response to an administration of apomorphine. Haloperidol (0.1 mg/kg), but not the peripheral dopamine receptor antagonist domperidone (0.2 mg/kg), abolished the enhanced gastrin response to apomorphine occurring after pretreatment with cimetidine. Cimetidine did not increase the gastrin response to apomorphine in vagotomized dogs. The results are interpreted in terms of an additive gastrin response to apomorphine (different from the short lasting initial peak previously described) which is vagally mediated and inhibited by the gastric acid.
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PMID:A long lasting gastrin response to apomorphine revealed by inhibitors of gastric acid secretion. 362 88

Effects of SCH 32651, a novel antisecretory and cytoprotective agent, on resting and stimulated acid secretion by the guinea-pig isolated fundic mucosa were studied. SCH 32651 inhibited resting acid secretion in proportion to concentrations in serosal solution (0.1-10 microM), the IC50 being 4.4 microM. Cimetidine and atropine at concentrations up to 100 microM were inactive. Serosal application of SCH 32651 inhibited acid secretory responses to histamine (10 microM), methacholine (1 microM) or dibutyryl cyclic AMP (0.5 mM) plus theophylline (1 mM) in a concentration-dependent manner. The IC50S against histamine, methacholine and db cyclic AMP plus theophylline were 4.2 microM, 0.71 microM and 2.9 microM, respectively. In contrast, atropine and cimetidine each at 100 microM, a concentration that entirely abolished responses to methacholine and histamine, respectively, did not affect acid responses to db cyclic AMP plus theophylline. The inhibitory effects of SCH 32651 on resting and histamine-stimulated acid secretion were readily reversible upon washing. SCH 32651 0.1 mM in the mucosal solution also greatly suppressed the resting and stimulated acid secretion. In the presence of histamine treatment, SCH 32651 concomitantly caused a marked rise in K+ entry into the mucosal solution in parallel to a decline in the appearance of H+ in the same solution. The various events demonstrated by SCH 32651 in the present study are shared by omeprazole, a potent antisecretory agent working through inhibition of gastric H+/K+-ATPase. We conclude that SCH 32651 as a potent antisecretory agent seems to act directly on the parietal cell, near or at the site of H+/K+-ATPase which is a final step in the acid secretory process triggered by various stimuli.
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PMID:Effects of SCH 32651 on resting and stimulated acid secretion in guinea-pig isolated fundic mucosa. 609 29

We have examined histamine- or carbachol-induced changes in rat gastric membranes enriched in K+-stimulated ATPase. Stimulation of secretion by both secretagogues in vivo produced a class of microsomal membranes which exhibited valinomycin-independent, KCl-dependent H+ transport. In contrast, membrane vesicles isolated from cimetidine inhibited resting mucosa exhibited largely the ionophore-dependent H+ transport. In addition, only in the carbachol-stimulated membranes a portion of the ionophore-independent H+ transport was refractory to cimetidine pretreatment. The gastric microsomal membranes were resolved into light and heavy fractions by centrifugation over isotonic 2H2O media. The ionophore-independent H+ transport was almost exclusively associated with the heavy microsomal fraction while the ionophore-dependent H+ transport was detected in the light fraction. Also, these fractions were considerably different from each other in their appearance in electron micrographs and SDS gel electrophoresis patterns. Secretagogue stimulation increased the population of the heavy microsomal membrane vesicles exhibiting the valinomycin-independent, K+-dependent H+ transport and their overall content of K+-stimulated ATPase. Cimetidine treatment, on the other hand, increased the ATPase activity associated with the light microsomes, and produced the heavy microsomal membranes showing only a marginal degree of the ionophore independent H+ accumulation, even though they were very similar to the carbachol-stimulated heavy membranes in the specific activity of K+-stimulated ATPase. SDS gel patterns and appearance in electron micrograph. These observations suggest that activation of secretion involves at least two distinctive events; transformation of the light to the heavy gastric membranes containing a K+-dependent H+ pump and an increased KCl permeability in the latter.
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PMID:Effect of carbachol or histamine stimulation on rat gastric membranes enriched in (H+-K+)-ATPase. 632 23

The mechanism of action of gastrin was investigated using cytochemical quantitation of hydroxyl ion production (HIP) in guinea pig gastric oxyntic mucosa. The reaction depends upon the trapping of OH ions produced during gastric stimulation and is blocked by the benzimidazole, Hassle 149/94, which inhibits the K+ + H+-ATPase and by acetazolamide, an inhibitor of carbonic anhydrase activity. It is thus a measure of hydroxyl ions produced during stimulation of the oxyntic cell and reflects upon hydrogen ion production. Gastrin (2.5 X 10(-16) -2.5 X 10(-12) M) caused a linear dose-dependent stimulation of HIP in the oxyntic cells. The response was biphasic, with an early peak at 90 s and a secondary rise at 240 s, which persisted for 10 min. Natural human gastrin (sulfated and nonsulfated) and the active COOH-terminal octapeptide fragment of gastrin stimulated HIP, whereas the biologically inert NH2-terminal (1-13) fragment of gastrin had no effect. The activation of oxyntic cell HIP by gastrin was neutralized by an antiserum directed towards the COOH-terminus of gastrin and not by nonimmune serum. Cimetidine (10(-5) M) blocked 25% and atropine (10(-5) M) had no effect on gastrin-stimulated HIP. EGTA (10(-3) M) and LaCl3 (10(-3) M) inhibited the action of gastrin by 67 and 52%, respectively. The calmodulin antagonists, trifluoperazine (10(-5) M), pimozide (10(-5) M), and the naphthalene sulfonamides, W-7 and W-13 (10(-5) M), inhibited gastrin-stimulated HIP by 45.6 38.5, 42.3, and 37.2%, respectively. Higher doses of W-7 and W-13 (10(-4) M) inhibited gastrin-stimulated HIP by 83 and 67%. The Ca2+ ionophore, A23187 (10(-4) M), stimulated HIP. Thus, it appears that gastrin stimulation of HIP is complex. 25% of its action is via a histamine-dependent pathway. 45% of its action is dependent upon extracellular Ca2+. Its action is also in part dependent upon a Ca2+/calmodulin mechanism.
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PMID:Action of gastrin in guinea pig oxyntic cells. Studies using quantitative cytochemistry. 633 Jan 72


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