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PubMed1975

The influence of metiamide on ouabain cardiotoxicity.

The effect of metiamide on the cardiotoxicity produced by ouabain was studied in pentobarbital-anesthetized cats. The onset of ouabain-induced ventricular tachycardia and fibrillation was significantly delayed in cats treated with metiamide as compared with cats that did not receive metiamide. Although the mechanism by which metiamide inhibits ouabain toxicity is speculative, the data suggest that histamine H2-receptor blocking agents may be useful as anti-arrhythmic drugs in digitalis cardiotoxicity.

Animals↗
PubMedDate not supplied

Influence of atropine, metiamide and vagotomy on cAMP of resting and stimulated gastric mucosa.

In normal rats the effect of atropine and metiamide was studied on cAMP levels of resting and histamine-, pentagastrin-, carbachol- and insulin-stimulated gastric mucosa. In vagotomized rats gastric mucosal cAMP levels were investigated under basal conditions and after insulin. Atropine and metiamide did not alter cAMP levels of resting gastric mucosa. Truncal vagotomy caused an increase in gastric mucosal cAMP, which was not affected by insulin. All gastric secretagogues caused a significant rise in gastric mucosal cAMP levels, which was not antagonized by atropine. Metiamide effectively blocked the rise in cAMP concentration after histamine and pentagastrin, but not that evoked by cholinergic stimulation. The results are consistent with the view that the in vivo rise of gastric mucosal cAMP after carbachol or insulin is not due to a direct cholinergic action. From the spectrum of inhibitory actions of metiamide it looks as if the increase in rat gastric mucosal cAMP concentration after histamine and pentagastrin administration is mediated by H2-receptor stimulation.

Animals↗
PubMed1976

Effect of metiamide, a histamine H2 - receptor antagonist, on the development of gastric stress ulcers and acid secretion.

In normal and stressed rats with chronic gastric fistula small doses of metiamide (0.001-0.01 muM/kg) increased and doses of over 20 muM/kg decreased gastric acid secretion. In both these dose ranges of dosage metiamide suppressed the development of stress ulcers, most markedly in doses of 0.005 and 100 muM/kg. Intermediate doses had no such action. Only the anti-ulcer action of large doses of metiamide ran parallel to a reduction in acid secretion. Small doses of metiamide increased gastric secretion, but like larger doses, had a weak adrenergic action.

Animals↗
PubMed1981

Centrally mediated pressor response to metiamide as a result of GABA-receptor antagonism.

The mechanism of the pressor response to metiamide was examined in anesthetized cats. Intravenous administration of metiamide had no effect on blood pressure. Infusion into the lateral ventricle (10 mg/kg/min for 10 min), caused a marked pressor response which was due to an increase in sympathetic outflow since pretreatment of cats with guanethidine completely prevented it. In a rat brain synaptosome preparation, both metiamide and cimetidine displaced [3H] CABA. These data strongly suggest that metiamide increases blood pressure in the cat through a central mechanism involving GABA-receptor antagonism.

Animals↗
PubMed1980

Histamine 2-receptor-mediated immunomodulation in the mouse. II. Immunomodulation by the H2 antagonist metiamide.

Modulation of delayed hypersensitivity and antibody formation to sheep red cells by metiamide were studied in the mouse system. Depending on the time and dose of antigen and metiamide administration suppression or enhancement of the delayed hypersensitivity response was observed. The effects in this system did not differ from those reported for the H2 agonist tolazoline, which were most probably mediated by suppressor cells. As far as the humoral response was concerned metiamide tended to stimulate the IgM response. Optimal stimulation was reached if 50 mg metiamide/kg was administered 3 days before immunization with 2 x 10(8) SRBC. Under all conditions tested the IgG response was unaffected. These results suggest antagonistic effects of metiamide for tolazoline and adduce further evidence for the presence of H2 receptors on B cells. The IgM production per plasmacell was enhanced suggesting different H2 receptors to be involved in differentiative and proliferative B cell responses. The possible consequences of H2 antagonist application in human therapy are discussed.

Animals↗
PubMed1975

Displacement by metiamide of the dose-response curves to pentagastrin and methacholine in the conscious rat.

1. The effect of a specific histamine H2-receptor antagonist, metiamide, on the acid dose-response curves for pentagastrin or methacholine was studied in rats provided with Heidenhain pouches. 2. Metiamide induced a shift to the right of the dose-response curve to pentagastrin and lowered the maximal secretion. 3. In contrast, metiamide only increased the ED50 for methacholine but did not alter the calculated maximal response. 4. The effect of metiamide on pentagastrin and methacholine-induced secretion is in agreement with the previously suggested difference in the part played by mucosal histamine in the mode of action of the two stimulatory agents.

Animals↗
PubMed1977

The effects of metiamide on cell-mediated immune reactions in the guinea-pig.

1 The effects of the H2-receptor antagonist, metiamide, on two types of cell-mediated immune response in vivo was investigated in the guinea-pig, in a test of the hypothesis that H2-receptor antagonists would result in 'runaway' unregulated hypersensitivity reactions. 2 Metiamide in doses of 5 mg-125 mg/kg given by 6-hourly injection during sensitization and challenge did not modify the delayed hypersensitivity reaction to tuberculin. 3 Metiamide in doses of 25-125 mg/kg given by injection, 6-hourly throughout sensitization to dinitrofluorobenzene (DNFB) and subsequent challenge six days later, did not modify the contact sensitivity reaction to DNFB. 4 It is concluded that metiamide, given during these cell-mediated immune reactions in the guinea-pig, does not enhance cell-mediated hypersensitivity responses.

Animals↗
PubMed1976

A quantitative study of metiamide, a histamine H2-antagonist, on the isolated whole rat stomach.

1. An isolated whole stomach preparation from immature rats is described. The lumen of the stomach was perfused and the hydrogen ion activity of the perfusate recorded continuously. 2. The mean basal acid secretion before stimulation was 4-19 +/- 0-31 X 10 (-8) mol min-1. Metiamide did not significantly reduce this spontaneous secretion. 3. The preparation gave dose-dependent responses to histomine (10(-5)-10(-4)M) which were readily reversed on washing. 4. The effect of metiamide on histamine-stimulated acid secretion was investigated. Metamide, at doses of 3 X 10(-6)M, and 3 X 10(-5)M, caused a parallel displacement of the histamine dose-response curve, indicating competitive antagonism. These dose-response curves were used to calculate dose ratios (DR) for metiamide. 5. A plot of log10 (DR - 1) against log 10 [antagonist] gave a pA2 value for metiamide of 5-91.

Animals↗
PubMed1975

Effects of metiamide on distribution of 14C-histamine in aortic smooth muscle.

The effects of metiamide on 14C-histamine movements and on contractions induced by histamine were studied in rabbit aortic smooth muscle. Low temperature (0 degrees C) and pretreatment with aminoguanidine or chloroquine markedly reduced the uptake of 14C. Component analysis of 14C efflux curves indicated that this decrease occurred mainly within the slower of two washout components. Addition of metiamide (but not pyrilamine) to the bathing solution decreased 14C-histamine uptake, and exposure to metiamide during the washout of 14C-histamine decreased the rate of efflux. These effects of metiamide on 14C-histamine movements can be explained in terms of an altered ability of rabbit aortic smooth muscle to accumulate histamine at some cellular site or store.

Animals↗
PubMed1975

Effect of the H2-receptor antagonists (burimamide and metiamide) on gastric secretion stimulated by histamine and its methyl derivatives.

This study was done to determine the comparative effectiveness of burimamide and metiamide as antagonists of gastric secretion stimulated by histamine and its methyl derivatives, Nalpha-methylhistamine, N-alpha,N-alpha-dimethylhistamine and 4-methylhistamine, in dogs with vagally denervated (Heidenhain pouches) and vagally innervated gastric mucosal septal pouches (Pavlov-type pouches). The secretagogues were always given by continuous i.v. infusion to produce steady states of secretory activity in the fasted conscious dogs; the antagonists were given by either rapid "bolus" i.v. injection or continuous i.v. infusion. With bolus injections, both antagonists promptly inhibited the secretion produced by histamine and its methyl derivatives. When control secretory rates were similar, 40 mumol of burimamide per kg and 4 mumol of metiamide per kg produced the same degree of inhibition. When the antagonists were also given by continuous i.v. infusion, the difference between them was greater, metiamide being 15 to 17 times more potent than burimamide. The effectiveness of the antagonists was not changed by vagal denervation. Symptoms of toxicity to burimamide developed at doses in excess of 30 mumol/kg/hr; none occurred with doses of metiamide ranging from 1.8 to 7.5 mumol/kg/hr.

Animals↗
PubMed1977

Effect of histamine H2 antagonism by metiamide on the response of the canine gastric mucosa to acid and bile salt.

Prevention of acute gastric erosions with histamine H2-receptor blocking agents suggests that these drugs may improve the ability of the gastric mucosa to maintain electrical, ionic, and protein concentration gradients. In 5 awake mongrel dogs, transmural potential difference, ion fluxes, and protein loss were measured across Heidenhain pouches topically exposed to isotonic solutions containing either 80 mM HCl or 80 mM HCl plus 20 mM sodium taurocholate (BS). The dogs received an intravenous infusion of either saline (as a control) or the H2 antagonist metiamide, 10 mumoles per kg-hr. Metiamide increased the H+ clearance rate found after acid test solution exposure but had no significant effect on potential difference or ion fluxes. H2 antagonism decreased the protein loss but not the increase in cation permeability due to BS. Net H+ loss actually increased, which, along with a decrease in Cl- gain, suggests inhibition of acid secretion by metiamide in BS-exposed gastric mucosa. These effects of metiamide point to histamine as a likely mediator of the gastric mucosal damage due to BS.

Animals↗
PubMed1975

Effect of metiamide on the response to secretin and cholecystokinin in man.

The effects of intravenous metiamide on the pancreatic exocrine response to intravenous infusion of secretin plus cholecystokinin has been studied in eight patients with duodenal ulceration. The secretion of bicarbonate and water was not altered by metiamide. The secretion of enzymes was significantly less than control during infusion of metiamide. The differences between the pancreatic and gastric responses to metiamide are discussed.

Bicarbonates↗
PubMed1980

Influence of the H2-receptor blocking agent metiamide on the clonidine-induced changes in the brain catecholamine turnover.

Metiamide (800 micrograms intracerebroventricularly to rats) enhanced the DOPA accumulation in noradrenaline-predominant brain areas following DOPA decarboxylase inhibition and it accelerated the alpha-methyltyrosine-induced disappearance of noradrenaline in the brain, both normally and after clonidine (0.1 mg/kg i.p.). These findings indicate that metiamide stimulates the release of noradrenaline. They can explain why metiamide antagonizes the clonidine-induced hypotension.

Animals↗
PubMed1977

Rat gastric secretion and mucosal blood flow during restraint stress--effect of a low dose metiamide.

In rats under either mild stress (= controls) or severe stress (= restraint) gastric secretion (acid; pepsin, volume), mucosal blood flow, serum gastrin and ulcer formation were evaluated without and with additional infusion of a low dose (0.25 mg/kg.h) metiamide over an 8 h experimental period. Calculated constants of dose-response characteristics for acid output in this species are: Km = 1.41 +/- 0.36 mg/kg.h; Vmax = 94.4 +/- 11.0 per cent. Restraint depresses markedly secretion and microcirculation, but stimulates ulcer formation and raises serum gastrin. In controls, metiamide inhibits secretion and ulcer index significantly, but leaves mucosal blood flow and gastrin unaltered. In contrast, with restraint and metiamide, ulcer index was not improved, whereas mucosal blood flow was restored to almost control levels. Therefore, H2-receptor blockers, in addition to inhibition of secretion, may interfere with microcirculation either directly or by secondary release of yet unknown mediator substance(s), depending on the prevailing tissue environment.

Acids↗
PubMed1980

The effect of atropine and metiamide on pepsin secretion of the rat.

The inhibition of pepsin secretion by metiamide and atropine was studied by perfusing the stomach lumen of anaesthetized rats. Atropine was more effective than metiamide in the inhibition of pepsin secretion induced by pentagastrin or carbachol. Perfusion of the stomach with a weak acid solution stimulated pepsin secretion, which was only abolished by atropine. Metiamide was ineffective. It is postulated that (1) hydrogen ions probably stimulate pepsin secretion, (2) a cholinergic-like reflex may be involved in this stimulation, (3) anticholinergics are direct and strong inhibitors of pepsin secretion, (4) histamine H2-receptor antagonists probably inhibit pepsin secretion indirectly via reduction of acid output.

Animals↗
PubMed1977

The effect of metiamide in in vitro and in vivo canine models of type I hypersensitivity reactions.

The histamine H2-receptor antagonist metiamide was evaluated in in vitro and in vivo canine models of immediate-type hypersensitivity reactions. At concentrations of 2 and 4 X 10(-4) M, the antagonist significantly increased the amount of histamine present in the medium surrounding passively sensitized canine lung fragments which had been challenged with ascaris antigen. In contrast, the compound was without effect on the release of a slow reacting substance of anaphylaxis. On the basis of these observations metiamide was investigated in an in vivo canine model of allergic asthma. At doses of 10, 30 and 50 mu moles/kg, the antagonist did not enhance the ascaris antigen-induced pulmonary pathophysiology. Similarly, at 10 and 50 mu moles/kg metiamide did not alter histamine-induced increases in pulmonary resistance or decreases in dynamic lung compliance. Insofar as the canine model of allergic asthma may be predictive of the human disease, it could be anticipated that the use of histamine H2-receptor antagonists may not be deleterious to allergic asthmatics.

Airway Resistance↗
PubMed1975

Metiamide: an antagonist of histamine-stimulated gastric acid secretion.

Metiamide, 25 mg, antagonized the action of histamine on acid and pepsin secretion from both denervated pouches and innervated stomachs in dogs. In the same preparations its action on pepsin following food, pentagastrin or 2 deoxy-d-glucose was nonsignificant. Following pilocarpine or secretin, metiamide augmented pouch pepsin. The action of every acid stimulant was depressed by metiamide including the direct vagal action of deoxy-d-glucose on the innervated stomach. H2 receptors seem, therefore, to be involved in some form in acid stimulated by the vagi, histamine, pentagastrin and pilocarpine. Pepsin stimulation does not seem to be via H2 receptors with the esception of stimulation by histamine itself.

Animals↗
PubMed1977

The effects of somatostatin and metiamide on tachyphylaxis of pentagastrin stimulated gastric acid and pepsin secretion in the conscious cat.

1. Pentagastrin stimulated gastric acid and pepsin secretions show parallel rates of tachyphylaxis in the conscious cat. The responses to histamine show only slight tachyphylaxis. 2. Somatostatin 10 microng.kg(-1).hr(-1) inhibits pentagastrin but not histamine stimulated acid secretion and inhibits pentagastrin stimulated pepsin secretion. 3. The inhibition of pentagastrin stimulated acid and pepsin secretion by Somatostatin delays the tachyphylaxis of these responses, but the rates of tachyphylaxis when they do subsequently occur are identical. 4. Metiamide 10 mg-kg(-1)-hr(-1) equally inhibits histamine and pentagastrin stimulated acid secretion but does not inhibit pentagastrin stimulated pepsin secretion. 5. Inhibiton of acid secretion during metiamide infusion neither prevents nor delays acid nor pepsin tachyphylaxis. 6. It is suggested that tachyphylaxis of acid and pepsin secretion is a gastrin receptor phenomenon and that Somatostatin occupies or modifies the behaviour of these receptors, preventing tachyphylaxis. Metiamide, however, exerts its action only on the histmine H2-receptor and not the gastrin receptor mechanism, and this apparently does not prevent or delay acid tachyphylaxis.

Animals↗