Biomedical subjects

W Kromer

Publications and source records attributed to W Kromer.

At least 19 recordsLinked to original sources

PubMed1995

Unexpected prosecretory action component of loperamide at mu-opioid receptors in the guinea-pig colonic mucosa in vitro.

1. In a voltage clamp setting (Ussing chamber), the antidiarrhoeal drug, loperamide (Lop) slightly augmented prostaglandin E1 (PGE1) plus theophylline-stimulated net chloride secretion above control values at low concentrations (10(-10) and 10(-9) M) but inhibited it at higher concentrations (10(-6) and 10(-5) M). The apparently weak prosecretory action component of Lop was turned into a clear cut antisecretory effect by pretreatment with 2 x 10(-7) M naloxonazine plus 10(-7) M CTOP-NH2 (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2), two selective mu opioid receptor antagonists. This indicates a prosecretory effect of loperamide at mu opioid receptors. The antisecretory effect of low Lop concentrations, uncovered by mu opioid receptor blockade, was prevented by additional blockade of kappa opioid receptors by 5 x 10(-9) M nor-binaltorphimine (nor-BNI). 2. The nonselective opioid antagonist, naloxone, at 10(-6) M did not significantly reduce either PGE1 plus theophylline-stimulated net chloride secretion in Lop-free controls or the antisecretory action of Lop. By contrast, the partial agonist ethylketocyclazocine (EKC), which activates kappa but blocks mu opioid receptors, concentration-dependently inhibited PGE1 plus theophylline-stimulated net chloride secretion without any consistent prosecretory action component. Nor-BNI at 5 x 10(-8) M significantly blocked the antisecretory action of EKC. 3. It is concluded that, in the guinea-pig colonic mucosa under the present conditions, mu opioid receptors mediate enhancement and kappa opioid receptors inhibition of PGE1-stimulated net chloride secretion by low Lop concentrations. The two opposite actions are largely masked by superimposition. An opioid receptor-independent mechanism of action contributes to the antisecretory effect of Lop at high concentrations.

Alprostadil↗

PubMed1995

Similarities and differences in the properties of substituted benzimidazoles: a comparison between pantoprazole and related compounds.

The novel antiulcer drugs omeprazole, lansoprazole, and pantoprazole are members of the class of substituted benzimidazoles. They potently inhibit the gastric proton pump by a common mechanism which depends on the acid-induced conversion of the parent compounds to the pharmacologically active principles: thiophilic cyclic sulfenamides. This transformation takes place in the luminal compartment of the secreting parietal cell. However, while the three proton pump inhibitors belong to the same chemical class, their two ring systems bear different functional substituents. This leads to essential modification of the physiochemical, metabolic, and pharmacokinetic properties of these drugs, possibly resulting in differences in tissue selectivity and thereby, in the long term, drug safety. Both preclinical and clinical data have accumulated that point to advantages of pantoprazole related to the above parameters: pantoprazole shows a higher stability at moderately acidic pH values and less inhibitory potential against cytochrome P450 than the other two drugs. In addition, pantoprazole displays linear pharmacokinetics with a high bioavailability.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1993

Synergistic opioid inhibition of colonic Cl- secretion by kappa-opioid receptor agonism plus mu-opioid receptor antagonism.

On the basis of the novel concept of a dual prosecretory/antisecretory intestinal opioid system, a voltage-clamp experiment was performed with guinea-pig colonic mucosa, and net anion (Cl-) secretion was measured after stimulation with prostaglandin E1 (PGE1) plus theophylline. Synergism between kappa-opioid receptor agonism by U69593 and mu-opioid receptor antagonism by CTOP-NH2 (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2) was observed.

Amiloride↗

PubMed1993

Mu opioid receptors modulate net chloride secretion in the guinea pig colonic mucosa in a dual fashion.

The present voltage-clamp data from guinea pig colonic mucosa indicate that mu opioid receptors both enhance and inhibit net chloride secretion stimulated by PGE1 plus theophylline. Actually, enhancement by the mu opioid agonist DAGO (0.2 nmol/l) declines and finally turns into inhibition with increasing net chloride secretion observed in control preparations taken from the same animals. Moreover, inhibition by the mu opioid antagonist CTOP-NH2 (100 nmol/l) increases with increasing inhibition (or decreasing enhancement) by the mu opioid agonist DAGO. Thus, the mu opioid agonist DAGO and the mu opioid antagonist CTOP-NH2 display opposite effects on net chloride secretion only to a limited degree but otherwise show parallel, either stimulatory or inhibitory, effects. To explain this complex function of mu opioid receptors in the control of net chloride secretion, a working hypothesis is being proposed.

Alprostadil↗

PubMed1992

Effect of acute and chronic acid suppression on plasma gastrin release in the rat.

The mechanisms by which administration of the H+,K(+)-ATPase inhibitor B 831-78 or intragastric perfusion with NaHCO3 induces plasma gastrin release were studied in the rat. Experiments were performed after a washout of residual intragastric contents in fasted animals provided with chronic gastric fistulae. Acute and chronic administration of B 831-78 elevated plasma gastrin dose-dependently up to 5-6 times above control levels, while the increase was only twofold with intragastric NaHCO3 infusion despite similar neutralization of gastric acidity. The profound hypergastrinaemia induced by the H+,K(+)-ATPase inhibitor, after both acute and chronic treatment, was completely prevented or reversed by intragastric perfusion with physiological amounts of acid (0.15 N HCl, 2.5 ml/h). The hypergastrinaemia was, however, largely resistant to high doses of atropine (4.3 mumol/kg) and of the M1 selective muscarinic antagonist telenzepine (10 mumol/kg). In contrast, the modest increase in plasma gastrin induced by gastric perfusion with NaHCO3 was completely suppressed by the high atropine dose and was attenuated by small doses of atropine or telenzepine (0.01 mumol/kg and 1 mumol/kg). These results demonstrate that, in the rat, blockade of the H+,K(+)-ATPase can potently induce gastrin release in the absence of a meal. Moreover, they suggest that interruption of the negative feedback between acid and gastrin release is the main mechanism through which this class of drugs releases gastrin in the rat. Since a similar degree of gastrin release cannot be achieved by alkalinization of gastric contents, additional hormonal or neural regulatory factors may contribute to the drug-induced hypergastrinaemia.

Adenosine Triphosphatases↗

PubMed1991

Telenzepine inhibits electrically-stimulated, acetylcholine plus histamine-mediated acid secretion in the mouse isolated stomach by blockade of M1 muscarine receptors.

1. The muscarine receptor mediating electrically-stimulated acid secretion in the mouse isolated stomach was characterized using a variety of muscarine receptor antagonists confirming the M1 nature of the antagonist effect of telenzepine. 2. Field stimulation (7 V, 10 Hz, 0.5 ms) resulted in a plateau acid secretion over at least 90 min which was completely blocked by either 1 mumol/l TTX or H2 receptor antagonists (100 mumol/l cimetidine or 10 mumol/l lupitidine). Ranitidine, which is known to potently inhibit mucosal acetylcholine esterase, was ineffective. Compound 48/80 at 100 mumol/l, which depletes mucosal histamine stores, initially mimicked electrical stimulation but subsequently prevented it from inducing acid secretion. 3. 10 muscarine receptor antagonists with differing relative affinities for M1, M2 and M3 receptors were introduced at 1 mumol/l to inhibit electrically-stimulated acid secretion. The percentages inhibition were plotted against binding affinities of the antagonists at either M1, M2 or M3 binding sites. A statistically significant correlation between functional and binding data was detected only when based on M1 affinities. 4. It is concluded that field stimulation, which probably mimicks vagal drive, results in muscarinic M1 receptor activation on paracrine cells to release histamine. Histamine then stimulates parietal cells to secrete acid. Hence, according to the present and our previous data, telenzepine inhibits acid secretion under these conditions by blocking M1 receptors at least partially located on histamine-releasing paracrine cells.

Acetylcholine↗

PubMed1991

Voltage-clamp experiments reveal receptor type-dependent modulation of chloride secretion in the guinea pig colonic mucosa by intestinal opioids.

The influence of four opioid antagonists on short circuit current (Isc), transepithelial potential difference (Pdo) and tissue conductance (Gt) in the guinea pig colonic mucosa was investigated in vitro under both basal and PGE1 plus theophylline-stimulated conditions. The experiments aimed at identifying the opioid receptor type(s) endogenously activated to control chloride secretion. Under blockade of sodium-dependent Isc by amiloride (100 mumol/l), net anion secretion was regarded to equal the lumen-negative shift in Isc upon addition of 1 mumol/l PGE1 plus 100 mumol/l theophylline. It was significantly elevated by 100 nmol/l of the kappa-selective antagonist nor-binaltorphimine (nor-BNI). This augmenting effect was totally abolished in amiloride-free buffer or by omission of chloride. 1 mumol/l TTX completely prevented the effect of both PGE1 plus theophylline and nor-BNI. Both the kappa agonist U 69593 (10 nmol/l) and the calcium channel agonist Bay K 8644 (1 mumol/l) significantly depressed net anion secretion stimulated by PGE1 plus theophylline. Nor-BNI at 10 nmol/l prevented the suppressive effect of both Bay K 8644 and U 69593. This suggests release of endogenous opioids by the calcium channel agonist Bay K 8644 and competition between the kappa agonist U 69593 and the kappa antagonist nor-BNI. In contrast to the kappa antagonist nor-BNI, the mu antagonist CTOP-NH2 at 100 nmol/l significantly impaired, while the mu-selective agonist DAGO at 0.2 nmol/l augmented, net anion secretion stimulated by PGE1 plus theophylline. The effect of CTOP-NH2 was abolished in chloride-free buffer.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1991

Two types of chloride channels in hen colon epithelial cells identified by patch-clamp experiments.

Freshly isolated epithelial cells from hen colon were investigated using the patch-clamp technique. The aim of this investigation was to characterise the cellular conducting site for Cl- secretion. In cell-attached mode two types of Cl(-)-channels were found. Both showed distinct outward rectification. The channel types differed in single channel conductances and the marked voltage dependence of the open probabilities. A low conductance Cl(-)-channel was observed with a mean conductance at negative holding potentials of g- = 9 pS, and of g+ = 34 pS at positive potentials. This channel was predominantly open at negative potentials, corresponding to cell hyperpolarization. The second channel type observed had conductances of g- = 35 pS and g+ = 77 pS, and showed increasing open probabilities with increasing holding potentials (cell depolarisation). Both channel types were blockable by the Cl(-)-channel blocker NPPB. These data in combination with previously published transepithelial transport data on hen colon indicate that these channels are the Cl- secretory sites in colon epithelium.

Animals↗

PubMed1991

The novel proton pump inhibitor pantoprazole elevates intragastric pH for a prolonged period when administered under conditions of stimulated gastric acid secretion in the gastric fistula dog.

The duration of intragastric pH-elevation upon administration of the novel H+K(+)-ATPase inhibitor pantoprazole and its pharmacodynamic interaction with H2 receptor blockade was assessed in the gastric fistula dog using the intragastric 24 hour pH-metry. Gastric acid secretion was stimulated by s.c. pentagastrin infusion. Group A received i.v. saline (controls), group B once an i.v. bolus of pantoprazole and group C twice the H2-receptor antagonist famotidine. Group D received the doses of famotidine and pantoprazole used in groups B and C. The intragastric pH-elevating effect of pantoprazole was not prolonged but, in fact, significantly shortened by the pretreatment with famotidine. Moreover, this effect depended on the pretreatment-dose of famotidine. The results underline that substituted benzimidazoles like pantoprazole need to be chemically activated in the acidic compartment of the parietal cell to produce a sustained intragastric pH-elevation. With regard to the potential therapeutic implication of these observations it is speculated that pantoprazole may be most effective in patients with high gastric acid secretion but may display reduced duration of intragastric pH-elevation under conditions of low acid secretion when acid blockade is not required.

2-Pyridinylmethylsulfinylbenzimidazoles↗

PubMed1991

Receptor classification using antagonists without determining pA2 values.

Albeit time-consuming, the most rigorous method of classification of receptor subtypes is the determination of pA2 values. However, this methodology requires the knowledge of absolute concentrations of both agonists and antagonists--something that may not necessarily be calculable under certain experimental conditions. Wolfgang Kromer offers a different method for classification using antagonists which is not dependent on absolute affinities, and which has the additional advantage of speed.

Alkaloids↗

PubMed1991

Is field (vagal) stimulation of gastric acid secretion mediated by M1 or non-M1 muscarinic receptors? A methodical problem exemplified in the mouse stomach in vitro.

1. Highly controversial claims have been put forward in the literature as to the involvement of either M1 or non-M1 muscarinic receptors in the field (vagal) stimulation of gastric acid secretion. This mini-review considers three available sets of data obtained in the mouse isolated, lumen-perfused stomach. 2. While pA2 values seemed to favour non-M1 receptors, a comparison between M1 selective versus non-selective antagonists on the one hand and field stimulation versus bethanechol stimulation on the other clearly pointed to M1 receptors being involved. 3. In the present review we discuss a novel experimental approach supporting the latter concept of M1 receptors. This novel approach provides a simple though provocative way to deal with the particular difficulties in determining pA2 values in the acid-secreting gastric mucosa. It is based on the rank order in the effects of different antagonists relative to their receptor type-dependent affinities, when employed at a fixed concentration, rather than on their pA2 values.

Animals↗

PubMed1990

Characterization of the muscarine receptor type on paracrine cells activated by McN-A-343 in the mouse isolated stomach.

An attempt was made to characterize the muscarine receptor type(s) involved in acid secretion in the mouse isolated stomach when stimulated by the muscarinic agonist McN-A-343. A series of 8 muscarinic antagonists was used with preference for M1 receptors (telenzepine and pirenzepine), M1 and M2 receptors (secoverine), M2 receptors (AF-DX 116 and himbacine) and M1 and M3 receptors (p-F-HHSiD and HHSiD). BTM-1086 was used as a high affinity antagonist at the M1 receptor however with little selectivity. Receptor type preferences were determined in binding experiments with [3H]telenzepine in cortical membranes (M1) and [3H]N-methylscopolamine in atrial (M2) or salivary gland (M3) membranes, derived from guinea pigs. No antagonist with M3 preference could be identified in the binding studies. A fixed antagonist concentration of 1 mumol/l was used to antagonize acid secretion stimulated by 10 mumol/l McN-A-343. By plotting the percentage inhibition obtained in the functional test against the Ki values determined in binding experiments for each antagonist at M1, M2 and M3 binding sites, an affinity-inhibition curve could only be constructed when based on the antagonist affinities to the M1 receptor. No statistically significant fit was found using antagonist affinities to the M2 or M3 receptor. Thus, in accordance with the presumed M1 selectivity of the agonist McN-A-343, the rank order of potencies of different antagonists point to the M1 nature of the muscarine receptor which stimulates acid secretion in the mouse isolated stomach upon activation by McN-A-343.(ABSTRACT TRUNCATED AT 250 WORDS)

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

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↗