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Biomedical subjects

M Pawlik

Publications and source records attributed to M Pawlik.

At least 37 records · Page 2Linked to original sources
PubMed2001

Effect of central and peripheral actions of histamine and its metabolite N-alpha methyl histamine on gastric secretion and acute gastric lesions.

N alpha-methylhistamine (N alpha-MH) is one of unusual metabolite of histamine that was found in Helicobacter pylori-infected stomach and is believed to interact with specific histamine H1, H2 and H3-receptors to stimulate gastric acid secretion and gastrin release from isolated G-cells but the effects of N alpha-MH on gastric mucosal integrity have been little studied. This study was designed; 1) to compare the effect of intraperitoneal (i.p.), intracerebroventricular (i.c.v.) and gastric topical (intragastric i.g.) application of exogenous N alpha-MH with that of standard histamine on gastric secretion in rats equipped with gastric fistula (series A) and 2) to compare the effect of i.c.v. administration of histamine and N alpha-MH with that of peripheral (i.p. and i.g.) application of these amines on gastric lesions induced by 100% ethanol (series B) in rats with or without capsaicin-induced deactivation of sensory nerves. The area of gastric lesions was determined planimetrically, gastric blood flow (GBF) was assessed by H2-gas clearance method and venous blood was collected for determination of plasma gastrin levels by RIA. N alpha-MH and histamine (0.1-10 mg/kg i.p. or i.g.) dose-dependently increased gastric acid output (series A); whereas i.c.v. administration of histamine or N alpha-MH inhibited dose-dependently this secretion; the dose attenuating gastric acid output by 50% (ED50) being 4 and 6 microg/kg i.c.v. Both, N alpha-MH and histamine (2 mg/kg i.p. and i.g.) attenuated significantly the area of gastric lesions induced by 100% ethanol (series B) while producing significant rise in the GBF and plasma immunoreactive gastrin increments. Central application of N alpha-MH and histamine (0.01-5 microg/kg i.c.v.) inhibited ethanol-induced gastric damage whereas higher doses ranging from 10-100 microg/kg of histamine and N alpha-MH were significantly less effective. Capsaicin-induced deactivation of sensory nerves by itself augmented significantly ethanol damage and attenuated significantly the protective and hyperemic effects of histamine and its methylated analog applied i.p. but failed to affect significantly those caused by i.c.v. administration of these amines. We concluded that: 1) central histamine and N alpha-MH inhibits gastric acid secretion and exhibits gastroprotective activity against ethanol in similar manner to that afforded by parenteral and topical histamine and N-alphaMH, 2) central N-alphaMH- and histamine-induced protection involve the enhancement in gastric microcirculation unrelated to neuropeptides released from capsaicin-sensitive afferent nerves, and 3) the major difference between central and peripheral histamine and its methylated analog is the influence on gastric acid secretion which does not appear to play any major role in gastroprotective activity of these agents.

Animals↗
PubMed2000

Gastroprotective and ulcer healing effects of nitric oxide-releasing non-steroidal anti-inflammatory drugs.

BACKGROUND & AIM: New class of nitric oxide-releasing non-steroidal anti-inflammatory drugs was shown to inhibit cyclooxygenase and prostaglandin generation without causing mucosal damage but whether these agents are capable of affecting gastric mucosal damage induced by strong irritants and healing of chronic gastric ulcers remains to be studied. In this investigation, effects of nitric oxide-releasing aspirin and nitric oxide-releasing naproxen were compared with those of native agents on gastric lesions provoked by 100% ethanol and on healing of chronic acetic acid ulcers. RESULTS: Both, nitric oxide-releasing aspirin and naproxen dose-dependently attenuated ethanol-induced damage and produced a significant rise in gastric blood flow but did not delay healing of gastric ulcers while native aspirin and naproxen had no influence on ethanol-induced gastric damage but significantly prolonged ulcer healing, reduced gastric blood flow and suppressed mucosal generation of prostaglandin E2. The gastroprotective and hyperaemic effects of both nitric oxide-non-steroidal anti-inflammatory drugs were completely abolished by ODQ, an inhibitor of guanylyl cyclase-cGMP system but not influenced by suppression of nitric oxide-synthase with L-NNA. The damaging effects of native acetyl salicylate acid or naproxen were aggravated by acidification of these non-steroidal anti-inflammatory drugs but the exogenous acid added to nitric oxide-acetyl salicylate acid or nitric oxide-naproxen failed to influence their effect. Despite inhibiting of PGE2 generation, both nitric oxide-releasing derivatives and native aspirin and naproxen failed to affect expression of cyclooxygenase-1 mRNA but upregulated the cyclooxygenase-2 mRNA. Concurrent inhibition of cyclooxygenase-2 by selective inhibitor NS-398 which by itself delayed ulcer healing and attenuated the gastric blood flow at ulcer margin, significantly worsened the effects of these nitric oxide-non-steroidal anti-inflammatory drugs and their parent drugs on ulcer healing and the gastric blood flow at the ulcer margin. CONCLUSIONS: 1) Coupling of nitric oxide to aspirin or naproxen attenuates ethanol-induced damage, possibly due to an increase in gastric microcirculation mediated by excessive release and action of nitric oxide that probably compensates for PG deficiency induced by non-steroidal anti-inflammatory drugs; and 2) nitric oxide-non-steroidal anti-inflammatory drug, unlike classic non-steroidal anti-inflammatory drugs, does not affect intact gastric mucosa and fails to delay the healing of pre-existing ulcers.

Animals↗
PubMed2000

Involvement of cyclooxygenase (COX)-2 products in acceleration of ulcer healing by gastrin and hepatocyte growth factor.

Ulcer healing involves expression of various growth factors including hepatocyte growth factor (HGF) at the ulcer margin and the rise in plasma gastrin but the effects of locally applied HGF and gastrin, which are known to act as trophic factors for the gastric mucosa, with or without neutralizing antibodies against HGF and gastrin or COX-1 and COX-2 inhibitors on ulcer healing and the expression of cyclooxygenase (COX)-1 and COX-2 during this healing have been little studied. Rats with gastric ulcers induced by serosal application of acetic acid (ulcer area 28 mm2) received a submucosal injection of either: 1)vehicle (saline), 2) HGF and 3) gastrin with or without neutralizing antibodies against HGF and gastrin or treatment with indomethacin (2 mg/kg-d i.p.), a non-specific inhibitor of COX, or NS-398 (5 mg/kg-d i.g.) and Vioxx (10 mg/kg-d i.g.), both highly specific COX-2 inhibitors. Each growth factor and specific antibodies against HGF and gastrin (100 ng/100 microl each) were injected just around the ulcer immediately after ulcer induction and this local application was repeated at day 2 following anesthesia and laparotomy. At day 13 and 21, the area of ulcers was determined by planimetry, the gastric blood flow (GBF) at ulcer margin was examined by H2-gas clearance technique and mucosal generation of PGE2 and the expression of COX-1 and COX-2 mRNA in the non-ulcerated and ulcerated gastric mucosa was analyzed using RT-PCR. The gastric ulcers healed progressively within 21 days and this effect was accompanied by significant increase in the GBF at the ulcer margin and expression of COX-2 mRNA and COX-2 protein at the ulcer area. Treatment with HGF and gastrin significantly accelerated the rate of ulcer healing and raised GBF at ulcer margin causing further significant upregulation of COX-2 mRNA and COX-2 protein (but not of COX-1 mRNA ) in the ulcerated mucosa. The upregulation of COX-2 mRNA induced by HGF was significantly attenuated by the concurrent local treatment with antibody against this growth peptide. Indomethacin and both COX-2 inhibitors significantly prolonged the ulcer healing, while suppressing the generation of PGE2 in non-ulcerated and ulcerated gastric mucosa and the GBF at ulcer margin. The acceleration of ulcer healing by HGF and gastrin and accompanying rise in the GBF at ulcer margin were significantly attenuated by the concurrent treatment with indomethacin or NS-398 and Vioxx. HGF injections produced a significant rise in the plasma gastrin levels and this was significantly attenuated by the cotreatment with NS-398. We conclude that 1) neutralization of HGF and gastrin by their specificantibodies delays ulcer healing due fall in the microcirculation around the ulcer and a decrease in the COX-2 expression, 2) COX-2 derived prostaglandins may play an important role in acceleration of the ulcer healing by various growth factors including HGF and gastrin, 3) enhancement of the local pool for growth factors such as HGF and gastrin at the ulcer site could offer a new modality for treatment of gastric ulcer.

Animals↗
PubMed1996

The role of ascorbic acid and xylitol in etomidate-induced adrenocortical suppression in humans.

Etomidate-induced suppression of cortisol biosynthesis is a result of a blockade of 11-beta-hydroxylation in the adrenal gland, mediated by the imidazol radical of etomidate. Since the generation of steroids requires reductive and energy rich equivalents, the present study examined whether supplementation with ascorbic acid or xylitol, a major source of NADPH, could attenuate adrenal suppression by etomidate in human subjects by promoting the turnover rate of 11-beta-hydroxylase. During continuous etomidate/alfentanil anaesthesia for pelviscopic surgery 30 female patients received either Ringer's lactate, xylitol (0.25 g kg-1 h-1) or ascorbic acid (0.5 g h-1) intravenously (i.v.). The plasma concentrations of cortisol, aldosterone and dehydroepiandrosterone (DHEA) were recorded for 5 h after end of surgery and a stimulation with synthetic ACTH was performed. The results showed no evidence of a clinically relevant attenuating effect of ascorbic acid or xylitol on etomidate-induced adrenocortical suppression. However, the observed suppression of cortisol levels was not enough to allow an attenuating affect to be measured.

Adolescent↗
PubMed1991

[3H]harman binding experiments. I: A reversible and selective radioligand for monoamine oxidase subtype A in the CNS of the rat.

Harman (1-methyl-beta-carboline) is an endogenous compound with neurotropic properties in rats and humans. In a novel in vitro binding assay, the binding site of [3H]harman has been characterized in the rat crude mitochondrial (P2) fraction. The binding was saturable and reversible. Only a single high-affinity binding site was detected by kinetic, saturation, and displacement analyses in the cerebral cortex of the rat. The linear Scatchard plots revealed equilibrium dissociation constant (KD) values of approximately 2.5 nM at 0 degrees C, approximately 9 nM at 23 degrees C, and approximately 30 nM at 37 degrees C. Among six CNS regions (hypothalamus, hippocampus, cerebral cortex, striatum, cerebellum, and spinal cord), the highest density of binding sites (Bmax) was determined in the hypothalamus (approximately 5.5 pmol/mg of protein) and the lowest in the spinal cord (approximately 2.0 pmol/mg of protein). Several drugs known to affect serotonergic, adrenergic, dopaminergic, cholinergic, or GABAergic neurotransmission inhibited specific binding at best in the micromolar range. In contrast, potent and selective inhibitors of monoamine oxidase subtype A were active in the lower and middle nanomolar range. The displacing potency (apparent Ki) of substrates and inhibitors of monoamine oxidase correlated positively and highly significantly with the corresponding values of the inhibition of monoamine oxidase activity of subtype A (r = 0.92, p less than 0.001, n = 17) but not of subtype B (r = -0.47, p greater than 0.05, n = 15). In conclusion, [3H]harman was identified as a specific ligand of the active site of the A subtype of monoamine oxidase in rat brain.

Animals↗
PubMed1991

[3H]harman binding experiments. II: Regional and subcellular distribution of specific [3H]harman binding and monoamine oxidase subtypes A and B activity in marmoset and rat.

[3H]Harman (1-[3H]methyl-beta-carboline) was used in a novel radioligand binding assay to label selectively and with high affinity monoamine oxidase (MAO) type A. The concentration of the enzyme was determined in six CNS regions of the primate species marmoset (Callithrix jacchus) and of the rat: hypothalamus, hippocampus, cerebellum, cerebral cortex, striatum, and spinal cord. The specific [3H]harman binding in the CNS of the marmoset reveals the same pharmacological profile and other characteristics (affinity, saturability, and reversibility) as in the CNS of the rat. The regional distribution of the [3H]harman binding density (Bmax) in the CNS exhibits a distinct pattern in the marmoset and the rat and a 35 (hypothalamus) to 75% (hippocampus) lower Bmax in the marmoset than in the rat. The Bmax values of [3H]harman binding in the CNS of the marmoset and the rat combined as well as those from visceral organs of the rat (liver, heart, lung, thymus, spleen, and kidney) correlated positively and highly significantly with the respective Vmax values of specific MAO activity of the A type but not of the B type, determined with kynuramine as the substrate. In subcellular fractionation experiments with rat cerebral cortex, the highest [3H]harman binding density (Bmax) and MAO-A activity (Vmax) were detected in mitochondrial fractions and severalfold lower values in the synaptosomal membrane fraction. In conclusion, we suggest that [3H]harman binding is a biochemical tool as a selective marker to quantify MAO-A in the CNS of different mammalian species as well as in extraneuronal tissues.

Aging↗
PubMed1988

Demonstration of a distinct class of high-affinity binding sites for [3H]norharman [( 3H]beta-carboline) in the rat brain.

Specific binding sites were demonstrated for some beta-carbolines in the rat brain with [3H]norharman as a ligand. The ligand displayed a high affinity for synaptosomal membranes which had been fractionated by a sucrose gradient. The calculated apparent KD value was 1.55 nmol/l and the maximum number of binding sites 148 fmol/mg protein. Displacement studies showed an exclusive specificity for a small group of beta-carbolines but not for the previously described inverse agonists at the benzodiazepine receptor nor for tryptamine and other indoles, as well as pargyline, a monoamine oxidase inhibitor. Further analysis revealed other binding sites for [3H]norharman, with an apparent KD value of 36 nmol/l that are presumably located on mitochondrial membranes. Binding to these sites was also not displaced by pargyline. Pargyline displaced [3H]norharman from a third population of binding sites on mitochondrial membranes with the apparent KD value of 46 nmol/l. These findings could explain the pharmacological effects of norharman and other beta-carbolines in vivo.

Alkaloids↗