New benzoyl urea derivatives as novel NR2B selective NMDA receptor antagonists.

A novel series of benzoyl urea derivatives was prepared and identified as NR2B selective NMDA receptor antagonists. The influence of the substitution of the piperidine ring on the biological activity of the compounds was studied. Compound 9 was active in the formalin test in mice.

Effect of [D-Met2,Pro5]enkephalinamide on gastric ulceration and transmucosal potential difference.

The effects of [D-Met2,Pro5]enkephalinamide, morphine and naloxone have been examined in two different models of experimentally elicited gastric mucosal lesions. One of them was the classic cold-restraint stress-induced ulceration. The other was a less frequently applied procedure, involving the measurement of decreases in the transmucosal potential difference, which is also a sensitive indicator of mucosal damage. The opioid agonists studied, [D-Met2,Pro5]enkephalinamide and morphine, aggravated, whereas naloxone, the pure opiate antagonist, mitigated the lesions in both models. The protective action of naloxone points to an eventual role of endogenous opioids in the generation of these types of mucosal lesions. Morphine is selective ligand of mu-opiate receptors. The enkephalin analogue, however, binds to both mu- and delta-receptors. Therefore, the potent pro-ulcerogenic action of the enkephalin analogue indicates that both the mu- and delta-receptors were involved in these models of experimental gastric lesions. The clarification of the eventual role of kappa-receptors requires further experimental work with a selective ligand of this subtype of opiate receptors.

Naloxone-insensitive modulation of gastric acid output by [D-Met2,Pro5]enkephalinamide in rats.

Studies from our laboratory have previously shown that two opioid agonists (morphine and [D-Met2,Pro5]enkephalinamide) aggravate, whereas naloxone inhibits cold-restraint stress-induced ulceration in rats. In the present study the effects of these substances were examined using the Shay-model. Contrary to expectations, both naloxone and the opioid agonists decreased gastric acid output. Naloxone in combination with either opioid agonist failed to reverse their inhibitory action. Thus the secretory activity of the stomach may be modulated by opioids in both naloxone-reversible and irreversible ways.

Biological determination of gastrointestinal peptide hormones.

Procedures for the determination of secretin, gastrin, cholecystokinin-pancreozymin, glucagon and villikinin in various species are reported. The sensitivities of the individual methods are dealt with.

The role of adrenergic receptors in the regulation of gastric motility in the rat.

Gastric motility was investigated under the effect of adrenergic receptor agonist and antagonist substances in albino rats of both sexes and weighing 150 to 180 g. Gastric evacuation was studied, after introducing 2 ml/100 g of Novobarium suspension in the stomach, by radioscopy and radiography. Epinephrine (Tonogen) was found to inhibit gastric motility, this inhibition being effective even after pylorotomy. The dominantly alpha adrenergic agonist phenylephrine (Sympathomim) had not any effect; the alpha blocker phenoxybenzamine (Dibenzyline) slightly depressed gastric evaluation. A marked inhibitory influence was noted with stimulating the beta receptors by isoproterenol (Prophylon), while propranolol (Inderal) slightly accelerated gastric evacuation by blocking beta receptors. A pretreatment by phenoxybenzamine of the animals did not affect epinephrine influence whereas a pretreatment by propranolol completely abolished the inhibitory effect of epinephrine on gastric motility. These results suggest the presence of a slight beta receptor tone in gastric motility at rest, and indicate further that epinephrine exerts its inhibitory effect on gastric motility via adrenergic beta receptors.

Mucosal lesions due to gastric distension in the rat.

The pathogenesis of acute gastric mucosal lesions produced by distension of the rat stomach was studied. One hour of distension with 0.1 N HCl, but not saline, produced lesions in the glandular stomach in all rats. Histologic studies revealed marked thinning of the mucosa plus thrombus formation in the ulcerated area. Gastric distension with 8 ml HCl (per 100 g body weight) produced severe lesions, 4 ml minimal lesions and 2 ml no lesions. Intragastric pressure in the 8-ml group remained above 110 mm H2O for the first 10 min. Distension with 8 ml acid/100 g body weight for just 10 min resulted in significant lesion formation. Acid distension did not cause generalized disruption of the gastric mucosal barrier to H+ back-diffusion. It appears that an intragastric pressure of over 110 mm H2O for 10 min damages the mucosa by pressure (with thinning) and ischemia (with thrombosis), resulting in decreased resistance to acid peptic digestion and consequent acute lesion formation.

The effect of truncal vagotomy on the bicarbonate-ion secretion of the stomach in rat.

The effect of truncal vagotomy on the gastric bicarbonate-ion, H-ion and chloride-ion secretions of the rat was studied experimentally. In the first half hour after truncal vagotomy, besides the known decrease of the H-ion, also the bicarbonate-ion and chloride-ion secretions were found reduced. The decrease in bicarbonate ion secretion was smaller as compared to the H-ion secretion. After two hours, there was no difference in bicarbonate-ion and chloride-ion secretions as compared to the controls and to the vagotomized groups. According to their results, following truncal vagotomy applied in the surgical management of ulcer, the bicarbonate-ion secretion of the stomach decreases immediately after operation. This decrease is, however, only transitory the bicarbonate-ion secretion becoming normal within a short time.

The changed activity of the serum kallikrein-kinin system after ligation of the superior mesenteric artery in rats.

The aim of the experiments was to study the effect of ligation of the superior mesenteric artery on the activity of the kinin-kallikrein system in the plasma and on arterial blood pressure. Ligation of 60 minutes did not change the free kallikrein activity of the plasma, while prekallikrein activity significantly decreased. Blood pressure showed a tendency to increase but not to a significant degree. Five minutes after the release of the ligation (during the period when the functional parameters of the intestinal mucosa returned to normal) free kallikrein activity increased and the arterial blood pressure decreased significantly. A rinse of the intestine with 5 p.c. glucose solution prior to the release of ligation prevents the increase in free kallikrein activity and the fall of blood pressure. The substances absorbed from the bowel lumen and activating the kinin system are probably responsible for the circulation failure following the ligation of the superior mesenteric artery.

Effect of vibration on the activity of the plasma kallikrein-kinin system in the rat.

Rats were exposed to whole body vibration horizontally for four hours at 5 Hz frequency and 2 cm amplitude. Of the components of the plasma kallikrein-kinin system the free (spontaneous) and kaolin-activated kallikrein (prekallikrein) activities, the concentration of bradykinin, the bradykinin splitting total kininase activity, total kallikrein-inhibitor activity and the concentration of alpha 2-macroglobulin, a major plasma kallikrein inhibitor, were estimated. Results showed that in response to acute vibration plasma free kallikrein activity was increased significantly in association with a significant reduction of prekallikrein concentration. The concentrations of bradykinin and total kininase activity were significantly elevated, too. Neither total kallikrein-inhibitor activity nor the concentration of alpha 2-macroglobulin were changed indicating that the plasma kallikrein inhibitors did not play a role in the alterations of plasma free kallikrein and prekallikrein activities. During acute vibration the plasma kallikrein-kinin system was activated probably by the enhanced catecholamine secretion. We suggest that the biological importance of this phenomenon is in the defense against the impaired microcirculation caused by catecholamines.

The role of endogenous prostaglandins in maintaining the integrity of the gastric mucosa in Shay's ulcer model after truncal vagotomy in rat.

The changes in the difference in the transmucosal potential of the stomach, in the ion flux of the mucosa and the prostaglandin content of the mucosa were studied after pyloric ligation combined with truncal vagotomy in rats. Results indicate that 10 hours following insertion of the pyloric ligation, and still prior to appearance of macroscopic ulceration, the mucosal barrier is damaged indicated by the decrease in PD value and by a changed ion flux. The development of these changes is prevented by truncal vagotomy performed simultaneously with pyloric ligation. Following pyloric ligation, simultaneously with the damage of the mucosal barrier, the PGF2 alpha concentration of the antrum and the rumen decreased. The 6-keto-PGF1 alpha content remained unchanged, while TXB2 content of the rumen increased. After truncal vagotomy the 6-keto-PGF1 alpha level of the antrum and the rumen and the TXB2 level of the rumen are increased. After truncal vagotomy performed simultaneously with pyloric ligation, the TXB2 content of the gastric mucosa increases with an increase also in the 6-keto-PGF1 alpha level of the rumen and the antrum and one in the PGF1 alpha content of the antrum, too. It is assumed that the beneficial effect of truncal vagotomy on the mucosal barrier is due to factors which are the known (i) decrease in H-ion secretion (ii) the unchanged bicarbonate secretion and (iii) the influencing of the prostaglandin level of the mucosa.

[Experimental animal studies on the significance of endogenous prostaglandins in maintaining the integrity of the stomach mucosa after truncal vagotomy]. / Tierexperimentelle Untersuchungen zur Bedeutung der endogenen Prostaglandine für die Aufrechterhaltung der Magenmukosaintegrität nach trunkulärer Vagotomie.

The changes of the transmucosal potential difference, the ionic flow, and the prostaglandin content were investigated after pylorus ligation, truncus vagotomy, and pylorus ligation with truncus vagotomy in Shay rats. A damage of the mucosa appeared already 10 hours after the pylorus ligation. This was presented in a clear decrease of the transmucosal potential difference and a change of the ionic flow. These damages could be prevented by simultaneous truncus vagotomy. A decrease of the PGF2 alpha content in the gastric antrum and rumen as well as an increase of the TXB2 in the gastric rumen were observed after additional pylorus ligation. The 6-keto-PGF1 alpha and the TXB2 content in the gastric antrum and rumen increased after truncus vagotomy. TXB2 in the rumen, 6-keto-PGF1 alpha in the rumen and antrum, as well as PGF2 alpha in the antrum ascended after pylorus ligation with simultaneous truncus vagotomy. The truncus vagotomy shows additionally a protective effect for the mucosa and influenced synergistically the content in prostaglandin after these results besides the notorious importance for the secretion of H+ion and bicarbonate.

[Experimental animal studies of the effect of selective proximal vagotomy on the prostaglandin content of the gastric mucosa in the Shay ulcer model]. / Tierexperimentelle Untersuchungen zum Effekt der selektiven proximalen Vagotomie auf den Prostaglandingehalt der Magenmukosa beim Shay-Geschwürmodell.

Mucosa damage, these appear in the Shay ulcer model before the macroscopic ulceration, can be prevented by the selective proximal vagotomy. Changes of the potential difference and the prostaglandin content were discovered after pylorus ligation, and Thromboxane was increased, PGF2 alpha and TXB2 were nearly constant, whereas 6-keto-PGF1 alpha increased clearly in the rumen. The 6-keto-PGF1 alpha and the PGF2 alpha content and Thromboxane remained unchanged and the potential difference was normalized in case of selective proximal vagotomy and pylorus ligation. The SPV is significant as you know for the secretion of H+ion and bicarbonate, but also for the normalization of increased TXB2 on the basis of our investigation results.

Effect of proximal selective vagotomy on gastric prostaglandin content in the Shay-rat ulcer model.

During Shay-ulcer formation damages to the barrier of the gastric mucosa develop even before the appearance of macroscopic ulceration. Proximal selective vagotomy prevents these damages. Following pyloric ligation the prostaglandin content of the mucosa changes in parallel with the injuries of the mucosal barrier: TXB2 content of the forestomach increases, while PGF2 alpha content of both the forestomach and the antrum decreases. Following PSV operation the 6-keto-PGF1 alpha content of the mucosa decreases, whereas PGF2 alpha and TXB2 contents exhibit no alteration. As a combined effect of proximal selective vagotomy pretreatment and pyloric ligation the 6-keto-PGF1 alpha and PGF2 alpha contents of the mucosa remain low and the TXB2 increase, otherwise detectable after pyloric ligation, does not take place.