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Biomedical subjects

W Kromer

Publications and source records attributed to W Kromer.

At least 37 records · Page 2Linked to original sources
PubMed1990

Reflex peristalsis in the guinea pig isolated ileum is endogenously controlled by kappa opioid receptors.

(1) Reflex peristalsis in the circular muscle of the guinea pig ileum was elicited in vitro by sustained luminal distension of the intestinal wall according to 2 cm H2O and evaluated in terms of the number of peristaltic waves within 15 min intervals. (2) The poorly mu-selective opioid antagonist naloxone at concentrations of 10(-7) and 10(-6) mol/l increased the frequency of peristaltic contractions within the first 15 min interval, and thereafter in a declining fashion, by 68 and 88%, respectively. The highly kappa-selective opioid antagonist nor-binaltorphimine behaved similarly. It was, by one order of magnitude, more potent but a little less effective than naloxone, i.e., the maximum effect was 57% increase in peristaltic frequency at 10(-8) mol/l. Concentrations of 10(-7) and 10(-6) mol/l had the same effect as 10(-8) mol/l, and 10(-9) mol/l were ineffective. The highly mu-selective antagonist CTOP-NH2 and the highly delta-selective antagonist ICI 174,864 were ineffective up to 10(-6) mol/l. (3) It is concluded that predominantly kappa opioid receptors are used by endogenous opioids under the present conditions to inhibit reflex peristalsis.

Animals↗
PubMed1990

Direct comparison between the ulcer-healing effects of two H(+)-K(+)-ATPase inhibitors, one M1-selective antimuscarinic and one H2 receptor antagonist in the rat.

A direct comparison of the ulcer-healing effects of two H(+)-K(+)-ATPase inhibitors (pantoprazole and omeprazole), one M1 antimuscarinic (telenzepine) and one H2 receptor antagonist (cimetidine) was performed in the rat. Gastric and duodenal ulcers were induced by local application of acetic acid and thereafter treated over 10 days by the test drugs. Overall and on a molar basis, ulcer healing was comparably accelerated by pantoprazole, omeprazole and telenzepine and less so by cimetidine. The same rank order was found with respect to the inhibition of gastric acid secretion in the modified Shay rat.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1990

Endogenous opioids, the enteric nervous system and gut motility.

Opium alkaloids have been used for centuries as potent antidiarrheals and analgesics, their constipating action in the latter instance taken as an unwanted effect. It was only during the last decade that the physiological role of opioid peptides present in both neurons and endocrine cells of the gastrointestinal (GI) tract has been defined. The recognition of distinct opioid receptor types which may be differentially involved in the control of motility, acid and electrolyte secretion in the GI tract presently focuses the attention of researchers in this field on the identification of receptor-type-selective opioid agonists in order to free these clinically extremely useful drugs from side effects. The present review provides a survey of mostly physiological data on the functional role of intestinal opioids.

Animals↗
PubMed1990

BY 1023/SK&F 96022 INN pantoprazole, a novel gastric proton pump inhibitor, potently inhibits acid secretion but lacks relevant cytochrome P450 interactions.

The novel H+/K(+)-adenosine triphosphatase inhibitor (gastric proton pump inhibitor), BY 1023/SK&F 96022, was found to be more potent than omeprazole in some rat models and slightly less potent in a dog model. Overall, both compounds are of a similar potency and efficacy. BY 1023/SK&F 96022 exhibited a somewhat longer duration of the antisecretory action than omeprazole in the Ghosh-Schild rat. In the modified Shay rat, on the basis of equieffective doses in terms of the initial effect, both compounds had a comparable duration of action. However, the p.o./i.v. dose ratio upon acute administration was larger for omeprazole, possibly reflecting its lower stability in the acidic environment of the secreting stomach, compared to BY 1023/SK&F 96022. As in vivo, both compounds were equipotent to inhibit acid production in rabbit isolated fundic glands. However, omeprazole interacted with the 7-ethoxycoumarin dealkylase in vitro with high affinity (Ki = 38.5 mumol/l), in contrast to BY 1023/SK&F 96022 (Ki = 135 mumol/l). Compared to omeprazole, BY 1023/SK&F 96022 also showed less interaction with the cytochrome P450 enzyme hydroxylating ionazolac. Moreover, this difference between the two compounds was also found in the rat in vivo with respect to their interaction with diazepam. Thus, both compounds displayed a comparable antisecretory potency in vivo and in vitro but showed a different interference with cytochrome P450 in favor of less interaction by BY 1023/SK&F 96022.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1989

Stimulation by McN-A-343 and blockade by telenzepine of acid secretion in the mouse isolated stomach at histamine-liberating cells.

(1) In the lumen-perfused mouse stomach in vitro, potential sites of gastric antisecretory action of the muscarine M1-receptor antagonist telenzepine were investigated. Acid secretion was stimulated by the muscarinic agonist McN-A-343 (1-1000 mumol/l). Neither basal nor McN-A-343-stimulated acid secretion was affected by 1 mumol/l TTX indicating that neuronal structures were probably not involved. (2) Acid secretion stimulated by 10 mumol/l McN-A-343 was inhibited by telenzepine (0.1-1.4 mumol/l) and cimetidine (10-140 mumol/l). Neither of the antagonists affected basal acid secretion. TTX had no inhibitory influence on the antagonist effect of telenzepine and cimetidine. (3) Compound 48/80 (100 mumol/l), which depletes histamine stores, initially mimicked but subsequently prevented the effect of McN-A-343. Prenylamine (50 mumol/l), which prevents histamine release, also abolished the secretagogue effect of subsequently administered McN-A-343. (4) Up to concentrations greater than 100 mumol/l, McN-A-343 did not stimulate acid production in rabbit isolated fundic glands and guinea-pig isolated parietal cells. Thus, parietal cells are not directly stimulated by McN-A-343. (5) Based on the site of action of the agonist McN-A-343 in the mouse isolated stomach and its failure to stimulate parietal cells from different species directly, it is concluded that telenzepine blocks, in the mouse isolated stomach, muscarine receptors located on paracrine cells to reduce endogenous histamine release.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1989

The current status of opioid research on gastrointestinal motility.

Apparently conflicting data on opioid effects on gastrointestinal motility have been reported in the literature. The current status is reviewed and an attempt is made to find a common denominator to discrepant results by suggesting functionally contrasting opioid systems modulating the same physiological functions. Upon superimposition, these contrasting systems might result in opposite opioid effects dependent on the actual functional balance between the systems at the time of drug administration. Inhibitory neuromodulation at multiple sites leading to either inhibition or disinhibition by opioids may serve as a common basis of their contrasting effects. This interpretation, though consistent with most of the currently available data, is still a working hypothesis.

Animals↗
PubMed1989

Comparison of telenzepine, pirenzepine and atropine on gastric acid and pepsin secretion in response to histamine, pentagastrin, bethanechol, sham-feeding and feeding.

This study was designed to compare gastric antisecretory effects of telenzepine, a new antimuscarinic agent, with those of pirenzepine and atropine in dogs. None of these antimuscarinics affected gastric acid secretion induced by histamine but all of them caused a dose-dependent inhibition of acid secretion from the gastric fistula (GF) and Heidenhain pouches (HP) stimulated by pentagastrin and bethanechol, telenzepine being 5-9 times more potent than pirenzepine and equipotent with atropine. All antimuscarinics were also effective inhibitors of acid responses to sham feeding and ordinary feeding. The inhibitory effect of telenzepine and pirenzepine were not accompanied by any major alterations in plasma gastrin or somatostatin but those of atropine were related to significant increase in plasma gastrin and to significant decrease in plasma somatostatin levels, suggesting the involvement of M2 receptors in the cholinergic control of these hormones. All three antimuscarinics were effective inhibitors of pepsin secretion induced both from the GF and HP by all secretagogues used. Neither telenzepine nor pirenzepine administered in various doses affected the heart rate while atropine caused a significant increase in heart rate confirming that the former agents are selective M1 receptor antagonists. This study provides evidence that telenzepine is more potent than pirenzepine in the inhibition of gastric secretion induced by pentagastrin, bethanechol, sham-feeding and ordinary feeding and that, unlike atropine, it does not increase plasma gastrin responses to meat feeding. In fact, telenzepine and pirenzepine alike reduced plasma gastrin concentrations under these conditions. No influence of these antimuscarinics on plasma somatostatin levels was observed.

Animals↗
PubMed1988

An acid-independent antiulcer effect of M1 antimuscarinics in the rat.

In the rat, the antiulcer potencies of the M1 antimuscarinics telenzepine and pirenzepine, the H2 receptor blocker cimetidine, and the H+/K+-ATPase inhibitor omeprazole were compared with their antisecretory potencies. On a molar basis and with regard to inhibition of cysteamine-induced acid secretion, telenzepine ranked first, followed by omeprazole, cimetidine, and pirenzepine; cysteamine-induced duodenal ulcers were best inhibited by telenzepine, with pirenzepine, omeprazole and cimetidine ranking 2nd, 3rd and 4th. Up to the highest dose tested, cimetidine and omeprazole caused inhibition by 26 and 37%, respectively. While, with the antimuscarinics, lesion inhibition runs parallel with inhibition of acid secretion, the H2 receptor blocker and the H+/K+-ATPase inhibitor markedly impair acid secretion, but do not or merely negligibly inhibit cysteamine-induced formation of duodenal ulcers. This suggests that in this animal model the antiulcer effect cannot be attributed exclusively to the antisecretory action.

Animals↗
PubMed1988

Comparison of the gastric antisecretory and antiulcer potencies of telenzepine, pirenzepine, ranitidine and cimetidine in the rat.

In different rat models, the antisecretory and antiulcer effects of the M1-antimuscarinics telenzepine and pirenzepine, the nonselective antimuscarinic atropine, and the H2-blockers ranitidine and cimetidine were compared to each other. Intravenous telenzepine proved to be more potent in inhibiting gastric acid secretion in the Ghosh-Schild rat (carbachol-stimulated), the chronic fistula rat (basal secretion), or, both intravenously and orally, in the modified Shay rat, as compared to pirenzepine, cimetidine or ranitidine. After intravenous administration, only atropine was equally potent to telenzepine in all three models, but it was less potent than telenzepine after oral administration in the modified Shay rat. Gastric mucosal lesions induced by pylorus ligation plus acetylsalicyclic acid or acetylsalicyclic acid plus HCl were best inhibited by telenzepine and atropine, with pirenzepine, ranitidine and cimetidine being less potent, their relative potencies depending on the particular experimental model used. Thus, among the antiulcer drugs tested, telenzepine was the most potent one with respect to both antisecretory and antiulcer activity. Moreover, the duration of the antiulcer effect of telenzepine proved to be significantly longer than that of pirenzepine in the modified Shay rat.

Animals↗
PubMed1987

Specificity of the substituted benzimidazole B 823-08: a prodrug for gastric proton pump inhibition.

Substituted benzimidazoles are potent inhibitors of the parietal cell proton pump, the H+/K+-ATPase. One member of this group, the sulfide B 823-08 (2-[(4-methoxy-3-methyl-2-pyridylmethyl)-thio]-5-trifluoromethyl-(1H)- benzimidazole) inhibits gastric acid secretion in various in vivo models, but fails to affect acid secretion in the isolated, lumen perfused mouse stomach. In contrast, the corresponding sulfoxide (B 823-10) is active under both in vivo and in vitro conditions. Since the sulfide is metabolically transformed to sulfoxide in vivo, the sulfide behaves as a prodrug of the sulfoxide. No effects of biological significance are found on organ functions which critically depend on Na+/K+-ATPase activity. This is in line with observations that the sulfoxide needs activation in an acidic environment, which constitutes the basis of its specificity for inhibiting stimulated parietal cells.

2-Pyridinylmethylsulfinylbenzimidazoles↗
PubMed1985

Binding of 3H-iloprost to rat gastric mucosa: a pitfall in performing radioligand binding assays.

Binding of 3H-iloprost was studied in a 20,000 x g sediment of the rat gastric mucosa. When pH in both test tubes for total and non-specific binding was kept identical, no displaceable binding of iloprost could be detected. When no care was taken to keep the pH identical in corresponding test tubes of the binding assay, changes in pH simulated specific and displaceable binding of iloprost. Therefore it is concluded that - in contrast to earlier reports - it is not possible to demonstrate specific iloprost binding using the given method.

Animals↗
PubMed1984

Stereospecific inhibition by naloxone of histamine-stimulated acid secretion in isolated guinea pig parietal cells.

Acid secretion from isolated and enriched guinea-pig parietal cells stimulated by histamine and measured by the 14C-aminopyrine accumulation technique was enhanced by nanomolar concentrations of D-ala2-D-leu5-enkephalin (DADLE). This effect was blocked by naloxone. Naloxone inhibited histamine-stimulated acid secretion even in the absence of exogenous opioids. The effect of naloxone was stereospecific, i.e. (+)-naloxone was ineffective. The DADLE effect varied between different cell preparations and changed from stimulation to inhibition as the inhibitory effect of naloxone alone increased. Thus, an inverse relationship between the magnitude of inhibition by naloxone and enhancement by DADLE was observed. The data suggest that endogenous opioids modulate acid secretion in gastric mucosal cells.

Animals↗
PubMed1983

Modulation of acid secretion from enriched guinea pig parietal cells by opioid receptors.

Membrane fragments of isolated cells from guinea pig gastric mucosa, enriched to 65% parietal cells, bind with high affinity the opioid peptide 3H-D-Ala2-D-Leu5-enkephalin (3H-DADLE). Binding was saturable and reversible. Scatchard analysis revealed a second binding site with low affinity but high capacity. Acid secretion by isolated, enriched parietal cells was determined by means of 14C-aminopyrine uptake. Basal acid secretion was not influenced by DADLE but that stimulated by histamine was further augmented by the enkephalin analog. This potentiating effect was prevented by the opioid antagonist naloxone. The present data provide for the first time evidence that gastric acid secretion is modulated by an opioid mechanism probably located on the parietal cell.

Animals↗