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Are histamine-h3-receptors involved in gastric mucosal protection in the rat?
Pha~nrc~cologit~al Rrsaarch.
393
Vol. 29, No. 4, 1004
TIME-COURSE OF THE ANTI-ULCER AND ANTI-SECRETORY EFFECTS OF CGRP IN RATS A. CARUSO,
G. CLEMENTI,
V. M. C. CUTULI, A. PRATO, and M. AMIGO-ROXAS
Institute of Pharmacology,
University ofcatania,
E. de BERNARDIS
Italy
We have previously shown that the calcitonin-gene-related peptide (CGRP), given i.v. (0.002 to 20 ng kg-‘), prevents in a dose-dependent manner 4-h reserpineinduced gastric mucosal damage. The peptide revealed also significant anti-ulcer, anti-secretory and anti-peptic activity in 3-h pylorus-ligated rats. The aim of the present study was to determine the time-course of CGRP effects in these experimental models. Studies were performed on 36-h fasted male rats, kept in individual cages, with water ad fibitum until 1 h before testing. CGRP (20 ng kg-‘, i.v.) was administered immediately before reserpine (25 mg kg-‘, s.c.) or pylorus ligation. Saline controls and CGRP-treated rats were killed 4, 8 and 18 h after reserpine injection and 2, 3,4 and 8 h after ligating the pylorus. Reserpine-induced lesions were reduced by 80 and 40% after 4 and 8 h, respectively, from the i.v. injection of CGRP, while no protection was found at 18 h. In the pylorus-ligated rats, CGRP significantly reduced either ulcer index, gastric acid output or peptic activity only 2, 3 and 4 h after administration, with maximal inhibition (about 40-50%) at 3 h. These effects completely disappeared after 8 h. The results confirm the anti-ulcer and anti-secretory/anti-peptic activity of CGRP, and demonstrate that this peptide exerts its action only’ for a short length of time, probably due to its kinetic properties.
ARE HISTAMINE-H3-RECEPTORS INVOLVED IN GASTRIC MUCOSAL PROTECTION IN THE RAT? G. MORINI
and G. CORUZZI
Institute of Pharmacology,
University of Par-ma, Italy
Histamine has been demonstrated to be present in high concentration in the gastric mucosa and it has been hypothesized to be a mediator both in the development of acute gastric mucosal injury and in cytoprotection. The involvement of histamineH3-receptors has been examined by testing the activity of the H3-agonist (R)-amethylhistamine and of the H3-antagonist thioperamide on ethanol- and aspirininduced gastric lesions in the rat. (R)-a-methylhistamine, administered in the dose range l-100 mg kg-’ i.g., dose-dependently reduced the severity of hemorrhagic mucosal lesions produced by absolute ethanol, EDSO being 10.72 mg kg-’
(5.24-21.87). The protective activity of the H3-agonist was not influenced by the pretreatment with thioperamide at doses up td 3 mg kg-’ i.g. Lesion formation, induced by aspirin 200 mg kg-’ i.g., was inhibited by treatment with (R)-amethylhistamine (l-100 mg kg-’ i.g.). In the same dose range the H3-agonist did not modify or slightly enhanced gastric acid output in pylorus-ligated rat. The present findings provide evidence that (R)-acmethylhistamine is effective in protecting the gastric mucosa. The question whether this effect could be ascribed to the activation of H3-receptors is still open. This issue will be clarified in further studies by using other agonists and antagonists.
INVOLVEMENT OF ,u AND SRECEPTORS IN GASTRIC PROTECTION INDUCED BY OPIOIDS IN THE RAT G. M. SCOT0 Institute
of Pharmacology
and
and C. PARENT1
Phurmacognosy,
University
of Catania,
Italy
Opioids, administered either centrally or peripherally, have a significant protective effect on stress-induced gastric lesions in the rat [l-3]. This effect is antagonized by naloxone, suggesting the involvement of opioid receptors. In the present study we have extended our investigations to examine the effect of DAGO and DPDPE, parenterally active analogues of encephalins with very high affinity, respectively for p and 6 receptors, on the development of gastric lesions induced by coldrestraint stress (CRS) in the rat. The intraperitoneal (1 mg kg-‘) and intracerebroventricular (1 ,ug per rat) administration of DAGO and DPDPE significantly reduced the incidence and severity of CRS-induced damage. Pretreatment with p antagonist naltrexone (2 mg kg-’ s.c.) and with 6 antagonist naltrindole (2 mg kg-’ s.c.) prevented these protective effects. It might be argued that stimulation of p and 6 receptors could contribute to gastric protection induced by opioids on gastric ulcers in stress conditions. Indomethacin (5 mg kg-’ i.p.) decreased the protective action of DAGO and DPDPE suggesting a possible involvement of mucosal prostaglandins in the effect of p and 6 agonists on stress-induced gastric erosions.
REFERENCES I. Ferri S, e/ ul. Pharm RPS Comm 1983; l&409-18.
2. Glavin 3. Scoto
393
Vol. 29, No. 4, 1004
TIME-COURSE OF THE ANTI-ULCER AND ANTI-SECRETORY EFFECTS OF CGRP IN RATS A. CARUSO,
G. CLEMENTI,
V. M. C. CUTULI, A. PRATO, and M. AMIGO-ROXAS
Institute of Pharmacology,
University ofcatania,
E. de BERNARDIS
Italy
We have previously shown that the calcitonin-gene-related peptide (CGRP), given i.v. (0.002 to 20 ng kg-‘), prevents in a dose-dependent manner 4-h reserpineinduced gastric mucosal damage. The peptide revealed also significant anti-ulcer, anti-secretory and anti-peptic activity in 3-h pylorus-ligated rats. The aim of the present study was to determine the time-course of CGRP effects in these experimental models. Studies were performed on 36-h fasted male rats, kept in individual cages, with water ad fibitum until 1 h before testing. CGRP (20 ng kg-‘, i.v.) was administered immediately before reserpine (25 mg kg-‘, s.c.) or pylorus ligation. Saline controls and CGRP-treated rats were killed 4, 8 and 18 h after reserpine injection and 2, 3,4 and 8 h after ligating the pylorus. Reserpine-induced lesions were reduced by 80 and 40% after 4 and 8 h, respectively, from the i.v. injection of CGRP, while no protection was found at 18 h. In the pylorus-ligated rats, CGRP significantly reduced either ulcer index, gastric acid output or peptic activity only 2, 3 and 4 h after administration, with maximal inhibition (about 40-50%) at 3 h. These effects completely disappeared after 8 h. The results confirm the anti-ulcer and anti-secretory/anti-peptic activity of CGRP, and demonstrate that this peptide exerts its action only’ for a short length of time, probably due to its kinetic properties.
ARE HISTAMINE-H3-RECEPTORS INVOLVED IN GASTRIC MUCOSAL PROTECTION IN THE RAT? G. MORINI
and G. CORUZZI
Institute of Pharmacology,
University of Par-ma, Italy
Histamine has been demonstrated to be present in high concentration in the gastric mucosa and it has been hypothesized to be a mediator both in the development of acute gastric mucosal injury and in cytoprotection. The involvement of histamineH3-receptors has been examined by testing the activity of the H3-agonist (R)-amethylhistamine and of the H3-antagonist thioperamide on ethanol- and aspirininduced gastric lesions in the rat. (R)-a-methylhistamine, administered in the dose range l-100 mg kg-’ i.g., dose-dependently reduced the severity of hemorrhagic mucosal lesions produced by absolute ethanol, EDSO being 10.72 mg kg-’
(5.24-21.87). The protective activity of the H3-agonist was not influenced by the pretreatment with thioperamide at doses up td 3 mg kg-’ i.g. Lesion formation, induced by aspirin 200 mg kg-’ i.g., was inhibited by treatment with (R)-amethylhistamine (l-100 mg kg-’ i.g.). In the same dose range the H3-agonist did not modify or slightly enhanced gastric acid output in pylorus-ligated rat. The present findings provide evidence that (R)-acmethylhistamine is effective in protecting the gastric mucosa. The question whether this effect could be ascribed to the activation of H3-receptors is still open. This issue will be clarified in further studies by using other agonists and antagonists.
INVOLVEMENT OF ,u AND SRECEPTORS IN GASTRIC PROTECTION INDUCED BY OPIOIDS IN THE RAT G. M. SCOT0 Institute
of Pharmacology
and
and C. PARENT1
Phurmacognosy,
University
of Catania,
Italy
Opioids, administered either centrally or peripherally, have a significant protective effect on stress-induced gastric lesions in the rat [l-3]. This effect is antagonized by naloxone, suggesting the involvement of opioid receptors. In the present study we have extended our investigations to examine the effect of DAGO and DPDPE, parenterally active analogues of encephalins with very high affinity, respectively for p and 6 receptors, on the development of gastric lesions induced by coldrestraint stress (CRS) in the rat. The intraperitoneal (1 mg kg-‘) and intracerebroventricular (1 ,ug per rat) administration of DAGO and DPDPE significantly reduced the incidence and severity of CRS-induced damage. Pretreatment with p antagonist naltrexone (2 mg kg-’ s.c.) and with 6 antagonist naltrindole (2 mg kg-’ s.c.) prevented these protective effects. It might be argued that stimulation of p and 6 receptors could contribute to gastric protection induced by opioids on gastric ulcers in stress conditions. Indomethacin (5 mg kg-’ i.p.) decreased the protective action of DAGO and DPDPE suggesting a possible involvement of mucosal prostaglandins in the effect of p and 6 agonists on stress-induced gastric erosions.
REFERENCES I. Ferri S, e/ ul. Pharm RPS Comm 1983; l&409-18.
2. Glavin 3. Scoto