Omeprazole has a dual mechanism of action: it inhibits both H(+)K(+)ATPase and gastric mucosa carbonic anhydrase enzyme in humans (in vitro and in vivo experiments).
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In this study our experiments followed in vitro and in vivo the effect of omeprazole on purified and erythrocyte carbonic anhydrase (CA) I and II isozymes, as well as on gastric mucosa CA IV in humans. Our in vitro results show that omeprazole-induced inhibition of purified CA I and CA II and gastric mucosa CA IV is dose- and pH-dependent. In vivo, the i.v. administration of omeprazole in humans in therapeutic doses produced a decrease in erythrocyte CA I and CA II activity, as well as in gastric mucosa CA I, II, and IV. Regarding CA IV, the results lead to the conclusion that omeprazole selectively inhibits gastric mucosa CA IV and does not modify the activity of the same isozyme from the kidney and lung, indicating organ specificity. Our results strongly suggest that omeprazole has a dual mechanism of action: H(+)K(+)ATPase inhibition and gastric mucosa CA inhibition, and that these enzymes may be functionally coupled. This 2-fold mechanism of action could explain the greater effectiveness of substituted benzimidazoles as compared with other therapies. (+info)
Association of heparin with basic fibroblast growth factor, epidermal growth factor, and constitutive nitric oxide synthase on healing of gastric ulcer in rats.
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The healing effect of heparin on gastric ulcer and its underlying mechanisms were studied. The influences of protamine on these effects were also investigated. Gastric ulcer was induced by acetic acid in rats. Heparin (100-1000 U/kg i.v.) was given once daily for 4 or 7 days. Ulcer area was measured; gastric mucosal regeneration, proliferation, and angiogenesis were determined by histological or immunohistochemical methods. Gastric mucosal basic fibroblast growth factor (bFGF) level was assessed by an enzyme-linked immunosorbent assay, and the mucosal epidermal growth factor (EGF) level and nitric oxide synthase (NOS) activity were measured by radioimmunoassay. The anticoagulant action of heparin was determined by the duration of bleeding time. The results showed that heparin given for 4 or 7 days significantly accelerated gastric ulcer healing in a dose-dependent manner. The three doses of heparin significantly stimulated mucosal regeneration and proliferation as well as angiogenesis but not the contraction of ulcer base. Similar effects were observed in gastric mucosal bFGF and EGF levels and constitutive NOS activity. Protamine not only abolished the anticoagulant action of heparin but also significantly potentiated its effects on ulcer healing, gastric mucosal proliferation, angiogenesis, and constitutive NOS activity. These findings indicate that heparin can accelerate gastric ulcer healing, which is associated with mucosal regeneration, proliferation, and angiogenesis. These actions are likely to be stimulated by bFGF, EGF, and constitutive NOS activity in the gastric mucosa. Protamine potentiates the ulcer-healing effect of heparin, which is probably acting through constitutive NOS activation. (+info)
Drug interactions of H2-receptor antagonists involving cytochrome P450 (CYPs) enzymes: from the laboratory to the clinic.
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This paper reviews the main steps in the research of the interactions of H2-receptor antagonist drugs with cytochrome P450 (CYP) enzymes. Cimetidine, ranitidine, and related compounds are used as examples. The results from in vitro studies are related to the observed clinically significant in vivo drug-drug and drug-chemical interactions. Uses of the in vitro results are discussed for the interpretation and possible prediction of drug-drug interactions, which may be important in developing new drugs. Other approach in the use of the in vitro data is to prevent undesirable and toxic actions of drugs related to the catalytic activity of CYP enzymes. In the case of H2-receptor antagonists, the inhibition of the metabolic reactions due to the binding of the drugs with the enzymes was used to avoid side effects of co-administered drugs. The in vitro metabolic studies using recombinant human as well as animal CYP enzymes are now widely used as model syste ms for designing new drugs with improved therapeutic properties. (+info)
Cytological transformations associated with parietal cell stimulation: critical steps in the activation cascade.
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Cultured rabbit parietal cells were used to evaluate morphological responses to activators and inhibitors of HCl secretion. Immunofluorescence was used to localize the proton pump protein, H, K-ATPase, and the apical membrane-cytoskeletal linker protein, ezrin; fluorescent-labeled phalloidin was used as a marker of F-actin. Treatment of healthy control parietal cells with secretagogues resulted in exaggerated swelling of apical membrane vacuoles, presumably with the accumulation of HCl and water. Thus stimulation-associated swelling of apical vacuoles was blocked by inhibitors that work at various steps in the secretion-activation cascade. When secretion was blocked by agents that prevent the translocation of H,K-ATPase-rich tubulovesicles to apical membrane vacuoles (such as H2-receptor antagonists and protein kinase A inhibitors), the general resting morphology was maintained. ME-3407 (a functional analogue of wortmannin) was unique in preventing H, K-ATPase redistribution and effecting the delocalization of ezrin from apical membrane vacuoles. When secretion was blocked by agents that inhibit the H+ pump or induce H+ backflux, the translocation of H,K-ATPase to apical membrane vacuoles occurred but the large vacuolar swelling associated with HCl and H2O accumulation was greatly diminished. These data support the membrane recycling/recruitment hypothesis of HCl secretion in which H, K-ATPase-rich tubulovesicles are recruited from a cytoplasmic domain to the apical surface, and they are inconsistent with models proposing that the tubulovesicles, regardless of shape, are contiguous with the apical plasma membrane. These studies also demonstrate the utility of the parietal cell culture model in distinguishing a general site of action for various inhibitors and antisecretory agents. (+info)
Roles of prostaglandin E receptors in mesangial cells under high-glucose conditions.
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BACKGROUND: High glucose reportedly stimulates prostaglandin (PG) E2 production and DNA synthesis in mesangial cells (MCs). However, the pathophysiological significance of PGE2 in MCs has remained unclear. METHODS: The effects of prostanoids on [3H]-thymidine uptake and cAMP production in rat MCs cultured with 5.6 mM glucose, 25 mM glucose, or 5.6 mM glucose supplemented with 19.4 mM mannitol were examined. The gene expression of PGE2 receptor (EP) subtypes in MCs was analyzed with Northern blotting techniques. RESULTS: Northern blotting indicated EP1 and EP4 gene expression in MCs. EP1 agonists and PGE2 stimulated [3H]-thymidine uptake in MCs. EP1 antagonists dose dependently attenuated high-glucose-induced [3H]-thymidine uptake, which suggests EP1 involvement, by an increase in intracellular Ca2+, in DNA synthesis of MCs. On the other hand, forskolin, db-cAMP, and 11-deoxy-PGE1, an EP4/EP3/EP2 agonist, significantly decreased DNA synthesis in MCs. These inhibitory effects are thought to be mediated via EP4 as a result of an increase in cAMP synthesis. The effects via EP4 seem to be particularly important because PGE2-induced cAMP synthesis was significantly attenuated in the high-glucose group compared with the mannitol group, in which [3H]-thymidine uptake did not increase in spite of augmented PGE2 production. CONCLUSION: The increase in DNA synthesis in MCs under high-glucose conditions can be explained, at least in part, by the high-glucose-induced inhibition of cAMP production via EP4, which augments EP1 function in conjunction with the overproduction of PGE2. (+info)
Antiulcer effect of lafutidine on indomethacin-induced gastric antral ulcers in refed rats.
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Lafutidine is a new type antiulcer agent with antisecretory and gastroprotective activities. We investigated the effect of lafutidine on indomethacin-induced antral ulcer in refed rats. Subcutaneous indomethacin injection resulted in the formation of gastric antral ulcer. Lafutidine (1-10 mg/kg, p.o.) reduced the area of ulcer in a dose-dependent manner when administered immediately after the indomethacin injection. Capsaicin at 3 mg/kg, p.o. and 16,16-dimethyl prostaglandin E2 at 3 microg/kg, p.o. also reduced the ulcer area. Chemical deafferentation of capsaicin-sensitive neurons or N(G)-nitro-L-arginine treatment aggravated the ulcer formation and abolished the preventive effect of lafutidine and capsaicin. After the induction of gastric ulcer, lafutidine given twice daily for 2.5 days reduced the area of ulcer in a dose-dependent manner with a significant effect at 10 mg/kg, p.o., as compared with that of the control group. In chemically-deafferentated rats, lafutidine did not show any healing effect. Cimetidine (30 mg/kg, p.o.) and famotidine (1 mg/kg, p.o.) had no significant effect on indomethacin-induced antral ulcer. These results may suggest that lafutidine, unlike cimetidine and famotidine, can prevent the indomethacin-induced antral ulcer formation and accelerate the healing of the ulcer in refed rats through mechanisms involving the capsaicin-sensitive afferent neurons and nitric oxide. (+info)
Heartburn treatment in primary care: randomised, double blind study for 8 weeks.
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OBJECTIVE: To compare the effects and tolerability of omeprazole and cisapride with that of placebo for control of heartburn in primary care patients. DESIGN: Randomised, double blind, placebo controlled study. SETTING: 65 primary care practices in Norway. PARTICIPANTS: 483 untreated patients with complaints of heartburn >/=3 days a week, with at most grade 1 reflux oesophagitis. INTERVENTIONS: Omeprazole 20 mg once daily, cisapride 20 mg twice daily, or placebo for 8 weeks. MAIN OUTCOME MEASURES: Adequate control of heartburn, defined as +info)
The effect of omeprazole on gastro-oesophageal reflux and symptoms during strenuous exercise.
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BACKGROUND: Strenuous exercise exacerbates gastro-oesophageal reflux and symptoms and this may be diminished by antisecretory medication with omeprazole. METHODS: Fourteen well-trained athletes (13 men, one woman), who indicated suffering from either heartburn, regurgitation or chest pain during competition running, performed two experimental trials at 2-week intervals using a randomized, double-blind, placebo-controlled crossover design. During the 6 days preceding the trial and on the trial day itself either 20 mg of omeprazole or a placebo was administered. Two hours after a low-fat breakfast and 1 h after the last study dose, the trial started with five successive 50-min periods: rest, three running periods on a treadmill, and recovery. Reflux (percentage time and number of periods oesophageal pH <4) was measured with an ambulant pH system during these periods. RESULTS: Compared to rest, reflux lasted significantly longer and occurred more frequently during the first running period, irrespective of the intervention, whereas during the second running period this effect was only observed with the placebo. Reflux occurred for longer and more frequently with the placebo than with omeprazole, but this was significant during the first two running periods only. Seven subjects reported heartburn, regurgitation and/or chest pain during exercise, irrespective of the intervention. Only a minority of the symptom periods was actually associated with acid reflux and in all cases this concerned periods with heartburn. CONCLUSIONS: Running-induced acid reflux, but not symptoms, were decreased by omeprazole, probably because most symptoms were not related to acid reflux. (+info)