Effects of substituted benzimidazole (H 149/94) on gastric acid secretion in humans.
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2-Pyridinylmethylsulfinylbenzimidazoles↗
Biomedical subjects
E Fellenius
Publications and source records attributed to E Fellenius.
Acid secreting gastric heterotopia in the duodenum.
Heterotopic gastric mucosa was found in the duodenum of a female patient with duodenitis and acid hyposecretion. The heterotopic isolated fundic glands were shown to accumulate 14C-aminopyrine in basal state and on stimulation with histamine suggesting that the heterotopic mucosa secreted acid. The ectopic acid secretion in the duodenal bulb suppressed gastric acid secretion, and might have caused the duodenitis and at least partly the clinical symptoms. The heterotopic gastric mucosa could be removed surgically by local excision. This procedure, combined with a Nissen fundoplication for suspected reflux oesophagitis, was followed by total symptomatic relief and normalization of gastric acid secretion.
Choristoma↗
Substituted benzimidazoles inhibit gastric acid secretion by blocking (H+ + K+)ATPase.
Studies both in vivo and in vitro have shown that substituted benzimidazoles inhibit the stimulation of acid secretion produced by dibutyryl cyclic AMP and histamine. Furthermore, the results differ from those produced by H2 antagonists and anticholinergic agents in that the inhibition is not competitive, and the site of action is intracellular and peripheral to that of dibutyryl cyclic AMP. To investigate the biochemical mechanism of action of substituted benzimidazoles, one such compound, H 149/94 (2-([2-(3-methyl)pyridyl-methyl]-sulphinyl)-5-methoxycarbonyl-6-methylbenzimidazol), has been tested either directly on an (H+ + K+)ATPase isolated from pig and human gastric mucosa or on the function of this enzyme in gastric glands isolated from rabbit and human gastric mucosa. (H+ + K+)ATPase, which has only been found at the secretory surface of the parietal cell, catalyses a one-to-one exchange of protons and potassium ions. It is possibly the proton pump within the gastric mucosa, and may thus be the terminal or one of the terminal steps of the acid secretory process. We show here that H 149/94 inhibits (H+ + K+)ATPase, which may explain its inhibitory action on acid secretion in vitro and in vivo. Because of the unique distribution and properties of the (H+ + K+)ATPase, the inhibitory action of H 149/94 on this enzyme may be a highly selective clinical means of suppressing the acid secretory process.
2-Pyridinylmethylsulfinylbenzimidazoles↗
Effect of beta-adrenoceptor blockade on exercise performance and metabolism.
1. Carbohydrate and lipid metabolism and the capacity to perform prolonged submaximal physical exercise were studied in six young healthy subjects treated in a randomized double-blind fashion for 2 days with either placebo, the non-selective beta-adrenoceptor antagonist propranolol (80 mg b.i.d.) or the cardioselective agent metoprolol (100 mg b.i.d.). On day 3, 1 h after the last dose, the subjects exercised for 30 min periods followed up 10 min rest up to the point of exhaustion. 2. The capacity to perform exercise was decreased with both beta-adrenoceptor antagonists. However, at an equal degree of beta 1-adrenoceptor blockade, all subjects could exercise for a longer period of time on the cardioselective agent as compared with the non-selective drug. 3. Blood glucose levels decreased during exercise irrespective of the type of treatment, but the attenuation occurred most rapidly on propranolol. At exhaustion the average non-esterified fatty acid levels had increased 256% on placebo, 148% on metoprolol and 65% on propranolol. A significant positive correlation was found between changes in non-esterified fatty acid levels during exercise and total working time. It is concluded that beta-adrenoceptor blockade diminishes the capacity for prolonged sub-maximal exercise at least in part by reducing the availability of substrates to the working muscles.
Adult↗
Metabolic and haemodynamic effects and pharmacokinetics of a new selective beta 1-adrenoceptor agonist, prenalterol, in man.
The metabolic and haemodynamic effects of three intravenous doses (0.5, 1.0 and 4.0 mg) of prenalterol, a selective beta 1-adrenoceptor agonist, were studied in 10 healthy male subjects. Plasma levels of prenalterol during the experiments were related to the haemodynamic effects. Prenalterol induced a dose-dependent increase in systolic blood pressure and heart rate. The maximal effects amounted to about 30 mm Hg and 15 beats/min, respectively, after the highest dose (4.0 mg). The diastolic blood pressure fell by a maximum of about 15 mm Hg. The effect of prenalterol on systolic blood pressure and heart rate persisted for about 3 h after the end of the last infusion, whereas that on diastolic blood pressure only lasted for 60 min. Compared with placebo, there was a moderate increase in plasma FFA and glycerol. A small rise in insulin level was also recorded, but no significant change was seen in other metabolic variables--triglycerides, glucose, lactate pyruvate. Serum potassium tended to decrease and serum sodium was unchanged. The initial distribution of prenalterol was rapid (half-life 7 min) and the overall elimination rate corresponded to a plasma half-life of 2 h. A linear relationship was found between the plasma level of prenalterol and its effects on systolic blood pressure and heart rate.
Adrenergic beta-Agonists↗
Functional and metabolic effects of terbutaline and propranolol in fast- and slow-contracting skeletal muscle in vitro.
The soleus, a slow-contracting, and the extensor digitorum longus (EDL), a fast-contracting skeletal muscle from guinea-pig were prepared for isometric recording of sub-tetanic contractions in vitro. The contents of adenosine-triphosphate (ATP) and creatinephosphate (CP) together with their metabolites and the contents of lactate, pyruvate and cyclic adenosine-monophosphate (c-AMP) in the muscles were determined. It was found that the energy and redox state of the isolated soleus and EDL muscles is very stable and does not significantly differ from the normal state in vivo. Moreover, there were no consistent changes in these variables after treatment with terbutaline (a beta 2-adrenoceptor agonist) or propranolol or both. Thus, effects on energy metabolism do not seem to cause the changes in muscle contraction, characteristic for beta-adrenoceptor stimulation. On the other hand, the functional effects were accompanied by elevation of the c-AMP level of the muscles.
Adenosine Diphosphate↗
The effect of beta-receptor blockade on adrenaline-induced changes in redox and energy state in m. vastus lateralis and m. soleus of the rat in vivo.
The metabolic changes in blood, red (m. soleus) and white (m. vastus lateralis) skeletal muscle fibres were investigated after short-term (3 min) infusion of adrenaline with or without prior treatment with propranolol or metoprolol. The adrenaline-induced increase in plasma lactate levels was totally prevented by prior treatment with metoprolol or propranolol, whilst the beta-blockers had no effect on blood glucose levels. Similar effects on lactate levels were found in the m. soleus, while metoprolol was less effective than propranolol in m. vastus lateralis. Adrenaline decreased the level of muscle creatinine phosphate and ADP, causing the equilibrium of the creatinine kinase reaction to change in the direction of ATP synthesis, although the level of ATP usually decreased. This effect was more pronounced in m. vastus lateralis compared with m. soleus. The [ATP]/[ADP] [Pi]-ratio tended to increase during infusion of adrenaline. This effect was counteracted by metroprolol but not by propranolol. The effects on the "phosphate potential" ([ATP]/[ADP] [Pi]) and the equilibrium within the creatine kinase were more pronounced in m. vastus lateralis than in m. soleus. The results demonstrate the possible role of receptors other than beta-receptors, i.e. alpha-receptors, in mediating changes in plasma glucose levels, while plasma lactate levels are regulated by the beta-adrenergic system. The role of beta-receptors in mediating changes in muscle lactate levels may differ in m. soleus and m. vastus lateralis, with a relative predominance of beta 2-receptors in m. vastus lateralis. Quantitative and qualitative differences in the adrenergic control of the energy state in the two types of muscle fibre were obvious, although it was not possible to distinguish clearly between the relative importance of alpha, beta 1 and beta 2-receptors.
Adenine Nucleotides↗
Differences in metabolic responses to beta-adrenergic stimulation after propranolol or metoprolol administration.
Isoprenaline, or the beta 2-agonist terbutaline, was infused in healthy male volunteers and the plasma levels of insulin, glucose and free fatty acids (FFA) were determined. Saline, propranolol, or the selective beta 1-receptor antagonist, metoprolol, was administered i.v. prior to the infusion of the beta-stimulants. The two beta-receptor blockers inhibited isoprenaline-induced increase in chronotropy to about the same extent, while the effects on systolic and diastolic blood pressure were in accordance with a selective beta1-blocking effect of metoprolol and a non-selective beta-blocking action of propranolol. Quantitative differences were found between metoprolol and propranolol on the metabolic parameters. The effects can best be described in terms of beta 1- or beta 2-receptors, where effects on plasma FFA and glycerol levels seem to be mainly beta1-mediated. An apparent beta 2-mediated effect was found for insulin release and hepatic glucose output.
Adult↗
Kinetic studies of dose-dependent metabolism of alprenolol: in vitro and in vivo studies in different species.
Kinetic studies of the metabolism of alprenolol were performed with isolated microsomes from the rat, guinea-pig, dog and man at an initial substrate concentration of 0.17--150 micrometer. In all species the rate of aromatic hydroxylation reached a plateu above 50 micrometer of alprenolol in contrast to the rate of desisopropylation, where consistent saturation level was not obtained. The Km-values for the aromatic hydroxylation in the guinea-pig and man, 2,7 micrometer and 1.3 micrometer respectively, showed no concentration dependency in contrast to the rat (Km1 = 0.20 micrometer, Km2 = 26 micrometer) and the dog (Km1 = 0.78 micrometer, Km2 = 66 micrometer). The apparent Km-value of 0.20 micrometer for aromatic hydroxylation in the rat seemed to be of the same order of magnitude as reported spectral dissociation constant (Ks = 0.34 micrometer). In vivo experiments in the rat by oral administration of 7--700 mu mol/kg demonstrated a dose-dependent presystemic elimination of alprenolol. The urinary excretion of hydroxy-alprenolol was significantly lower after the highest dose. It is proposed, that the saturation of the aromatic hydroxylation, catalyzed by a high affinity site or subspecies of cytochrome P-450 with a low capacity, contributes to the dose-dependent kinetics in vivo.
Administration, Oral↗
Properties of a new class of gastric acid inhibitors.
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Animals↗
beta-Adrenoceptor blockers, plasma-potassium, and exercise.
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Clinical Trials as Topic↗
Acute hypotensive effect of combined beta1-adrenoceptor blockade and beta2-adrenoceptor stimulation in spontaneously hypertensive rats (SHR).
The effect on heart rate (HR) and blood pressure (BP) of metoprolol, propranolol and terbutaline, applied alone or in combinations was studied in spontaneously hypertensive rats. Terbutaline had little effect on BP and HR. Propranolol combined with terbutaline had no effect while metoprolol combined with terbutaline decreased BP by 48 mm Hg without affecting HR. Thus the beta2-mediated increase in peripheral vascular resistance after terbutaline was revealed by a drop in BP after beta1-blockade by metoprolol, but not when both beta1-and beta2-receptors were blocked by propranolol.
Adrenergic beta-Agonists↗
Influence of acetate on the metabolism of beta-hydroxybutyrate in the perfused hind-quarter of the rat.
The effect of acetate, at concentrations normally found during ethanol combustion in intact animals and man in vivo, on the uptake and oxidation of beta-hydroxybutyrate by the perfused rat hind-quarter was studied. The addition of acetate did not significantly affect the total uptake of beta-hydroxybutyrate, but caused a 40% decrease in the oxidation of beta-hydroxybutyrate to CO2. The oxidation of 14C-beta-hydroxybutyrate to 14CO2 accounted for about 10% of the total oxygen consumption by the perfused muscle in the absence of acetate. In the presence of acetate this figure was reduced to about 5%. The addition of beta-hydroxybutyrate did not significantly affect the metabolic fate of 14C-acetate. It is concluded that acetate is preferred as oxidative substrate to beta-hydroxybutyrate. The inhibited oxidation of beta-hydroxybutyrate by acetate did not affect the concentration ratio between beta-hydroxybutyrate and acetoacetate in the medium at the end of the perfusion, indicating that the ability of the muscle tissue to restore an increased redoxlevel, "exported" from the liver during ethanol combustion to extrahepatic tissues, was not impaired by acetate.
Acetates↗
Influence of acetate on the metabolism of palmitate in the perfused hind-quarter of the rat.
The metabolism of 1-14C-palmitate and its metabolic interaction with U-14C-acetate were studied in the perfused hind-quarter of the rat. 9% of 1-14C-palmitate taken up was oxidized to 14CO2 accounting for 7% of total oxygen consumption by the perfused tissue. Most label from 1-14C-palmitate was found in the lipid fraction of the muscle tissue. In spite of a 40% inhibition of palmitate oxidation, acetate only caused minor changes in the overall metabolism of palmitate. U-14C-acetate was mainly oxidized to 14CO2 and the oxygen consumption due to oxidation of acetate accounted for 20-30% of the total oxygen uptake. Minor amounts of 14C-acetate were found in muscle lipids. The addition of palmitate did not alter the metabolism of acetate. It is concluded that the presence of palmitate did not affect 14C-acetate metabolism, while the presence of acetate inhibited 14C-palmitate oxidation. The possible sites of interaction are discussed. The found interaction will probably not contribute to any major extent to the disturbed lipid metabolism found in animals and man during ethanol intake. No major changes in the tissue content of high-energy phosphate compounds were found in the presence of palmitate or acetate or both.
Acetates↗
Anti-hypertensive effect of metoprolol in spontaneously hypertensive rats.
1. Oral and intravenous administration of metoprolol to adult spontaneously hypertensive rats (SHR) with established hypertension lowered arterial blood pressure within 4 days of treatment. 2. Steady state plasma concentrations of metoprolol were similar to those of patients during anti-hypertensive treatment with this drug. 3. The neuroeffector function of portal veins of SHR treated orally for 14 days or intravenously for 4 days was not impaired when studied in vitro. This is in contrast to previous findings after long-term treatment. 4. It is concluded that the anti-hypertensive effect of metoprolol in SHR in many respects resembles that observed in patients. It is suggested that impairment of vasomotor nerve control may contribute to the anti-hypertensive effect of beta-adrenoreceptor antagonists.
Animals↗
Metabolic effects of pentobarbital narcosis in the rat.
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Animals↗
Towards a valid technique of sampling fish muscle to determine redox substrates.
The redox substrates--lactate, malate, alpha-glycerophosphate, dihydroxy acetonephosphate and pyruvate--have been determined in liver and muscle tissue from young salmon. The redox quotients have also been calculated. The freeze clamping technique was used and reliable samples of fish muscle for the determination of lactate were obtained with the aid of a pair of pliers with a gear mechanism. It was established that the lactate content in the body muscle is in close agreement with that in the blood from rested salmon parr. The concentrations of redox substrates are in good agreement with those found in mammalian tissue. The determination of the content of glycogen in fish muscle is discussed in the light of the results obtained in this study.
Animals↗
Influence of acetate on glucose metabolism in the perfused hind-quarter of the rat.
The metabolism of U-14C-glucose and U-14C-acetate and the interaction between the two substrates in the perfused hind-quarter of the rat was studied. 5% of glucose taken up was oxidized to CO2, accounting for 15% of total oxygen consumption. Glucose was mainly incorporated into glycogen, while incorporation into lipids was negligible. Acetate did not significantly alter glucose uptake, 14C-glucose oxidation or the incorporation of 14C-glucose into glycogen and lipids. 45% of acetate taken up was oxidized to CO2, accounting for 20-25% of total oxygen consumption. Insulin did not affect acetate uptake but increased 14C-acetate oxidation. Oxygen consumption was slightly increased by simultaneous oxidation of glucose and acetate and in this situation the tissue content.of high-energy phosphate compounds was slightly elevated. It is concluded that only minor effects by acetate on glucose metabolism in the perfused skeletal muscle were found. The insignificant effects compared to previously reported studies on heart tissue (Neely and Morgan 1974) can be explained by differences in acetate metabolism between the two tissues.
Acetates↗