Prevention of stress-induced gastric ulcers by dopamine agonists in the rat

Dopamine (DA) and DA agonists have been shown to exert a protective role against the formation of duodenal ulcers. The effect of stimulation of DA receptors on the development of stress-induced gastric ulcers is currently unknown. Accordingly, we evaluated the effect of several DA agonists on the development of gastric ulcers induced by 3 h of cold + restraint stress (CRS) in rats. Apomorphine, d-amphetamine, methylphenidate, and threo-dl-p-hydroxymethylphenidate (an hydroxylated analog of methylphenidate), significantly reduced both the incidence and severity of CRS-induced gastric ulcers. The gastric cytoprotection afforded by these agents was dose-related, and completely antagonized by pretreatment with the peripheally acting DA antagonist domperidone. Because domperidone blocks peripheral, but not central, DA receptors, and since the entry of threo-dl-p-hydroxymethylphenidate across the blood-brain barrier into the brain is restricted to a great extent, we conclude that stimulation of peripheral DA receptors is primarily involved in the gastric cytoprotection induced by dopamimetics.The pathogenesis of stress-induced gastric ulcers remains largely unknown, and significant efforts have been made over the last decade to functionally characterize some of the factors involved in the etiology of this disease. Considerable attention has been focused on gastric acid secretion, but its primary role in stress-induced gastric ulcer disease remains uncertain. In fact, agents which effectively inhibit or neutralize gastric acid secretion such as cimetidine or antacids do not necessarily exert protection against stress-induced gastric ulcers (1,2). Moreover, in our original studies with neurotensin, a brain and gastrointestinal peptide, we have found that central administration of this neuropeptide, which completely prevents the development of cold + restraint stress (CRS)-induced gastric ulcers, does not appreciably alter gastric acid secretion (2). These findings support the contention that gastric acid secretion may not be an important factor in the development of this type of gastric ulcer.There is, however, considerable evidence that the automatic nervous system plays an intermediary role in the development of these ulcers (3,4). In this regard, surgical or pharmacological blockade of the vagal (cholinergic) division of the autonomic nervous system prevents the appearance of stress-associated gastric ulcers (5,6). Direct stimulation of catecholamine receptors, or indirect activation via increased sympathetic outflow to the periphery (7,4,8–11) appears to produce a salutary effect of stress-induced gastric ulcers.Szabo and his associates (12, 13, 14) have extensively studied the anti ulcer effects of dopamine (DA) in duodenal ulcer formation. Whether DA also modifies the development of stress-induced gastric ulcers is currently unknown.We have therefore evaluated the effect of selected DA receptor agonists and antagonists on CRS-induced gastric ulcer formation in rats.     

Peripheral benzodiazepine binding sites in kidney: modifications by diabetes insipidus

Using [3H] diazepam as ligand, it is possible to distinguish neuronal binding sites from those present on glial elements and in peripheral tissues (non-neuronal). The function of the "non-neuronal" binding sites is still obscure. Preliminary data showed a distribution of [3H] diazepam binding sites in kidney that could suggest a localization along the renal tubules. This is the site at which a renal peptide, arginine-vasopressin (AVP) is supposed to act. In an attempt to examine the function of these "non-neuronal" sites, we studied the [3H] diazepam binding in kidney of Brattleboro rats which lack AVP and present the symptoms of diabetes insipidus. The homozygous Brattleboro rats showed an increase in the apparent number of benzodiazepine binding sites (Bmax) compared to Long-Evans control rats. Replacement of AVP in these animals results in a reversal of the electrolyte alterations of diabetes insipidus and in an increase of the affinity of the [3H] diazepam binding. These findings may indicate a possible relationship between benzodiazepine binding sites and vasopressin action in kidney and may support receptor function of these "non-neuronal" binding sites.     

Germacranolides from Schkuhria anthemoidea

The isolation of eucannabinolide and three new sesquiterpene lactones from Schkuhria anthemoidea is reported. The structures and stereochemistries of the new compounds were established by chemical and spectroscopic means. The structure of santhemoidin B was confirmed by X-ray crystallography.     

Immobilization of white-tailed deer with xylazine hydrochloride and ketamine hydrochloride and antagonism by tolazoline hydrochloride

Fourteen penned and 17 free-ranging white-tailed deer (Odocoileus virginianus Rafinesque) were singularly or repeatedly immobilized with 100 mg xylazine hydrochloride (HCl) and 300 mg ketamine HCl. The mean times from intravenous injection to ambulation for 1.0, 2.0, and 4.0 mg/kg body weight doses of tolazoline HCl were 13.5, 10.5, and 9.2 min. Deer not receiving tolazoline HCl recovered in an average of 168 min. Heart rates significantly (P less than 0.001) increased from 47 to 83 beats/min after tolazoline HCl administration, representing a return to normal rate. Tolazoline HCl had no effect on respiratory rate. A total of 85 reversals with tolazoline HCl resulted in no apparent adverse reactions.     

Isolation of yeast with killer activity and its breeding with an industrial baking strain by protoplast fusion

Summary Wild strains of Saccharomyces cerevisiae were isolated from dairy products, bakery goods, fresh fruit and vegetables, and tested for killer activity. Four isolates out of 238 strains possessed killer activity. The best of these was converted to the petite form and hybridized with an industrial strain of Saccharomyces cerevisiae by protoplast fusion. Thirty-eight out of 104 isolates had killer activity, and some of these had good dough-raising activity as well.     

Ultrastructural organization of freeze-fractured interphase nuclei

The morphology of intact or membrane-deprived interphase nuclei has been analysed by freeze-fracture electron microscopy. This method appears particularly useful for providing information on the distribution and organisation of chromatin and ribonucleoproteins in the absence of dehydration and embedding artifacts of conventional electron microscope techniques which, among other effects, appear to affect heterochromatin distribution, inducing its aggregation along the nuclear envelope. The main levels of chromatin superstructure, from nucleosome to solenoid fibres, are detectable in the replicas of freeze-fractured nuclei on the basis of the size of their shadow, a parameter particularly suitable for automated image analyses.     

Glutathione redox cycle enzyme activities in erythrocytes of multiple sclerosis patients

The erythrocytes of multiple sclerosis patients with elevated superoxide dismutase levels were tested for the activities of glutathione redox cycle enzymes. No differences were observed between multiple sclerosis and normal control erythrocytes when the activities were referred to either hemoglobin concentration or lactate dehydrogenase content. Our results indicate that no adaptative changes occur in the activities of glutathione redox cycle enzymes in erythrocytes of multiple sclerosis subjects as a consequence of an elevated superoxide dismutase level.     

Study of the hydrolysis and ionization constants of Schiff base from pyridoxal 5''-phosphate and n-hexylamine in partially aqueous solvents. An application to phosphorylase b.

Formation and hydrolysis rate constants as well as equilibrium constants of the Schiff base derived from pyridoxal 5'-phosphate and n-hexylamine were determined between pH 3.5 and 7.5 in ethanol/water mixtures (3:17, v/v, and 49:1, v/v). The results indicate that solvent polarity scarcely alters the values of these constants but that they are dependent on the pH. Spectrophotometric titration of this Schiff base was also carried out. We found that a pKa value of 6.1, attributed in high-polarity media to protonation of the pyridine nitrogen atom, is independent of solvent polarity, whereas the pKa of the monoprotonated form of the imine falls from 12.5 in ethanol/water (3:17) to 11.3 in ethanol/water (49:1). Fitting of the experimental results for the hydrolysis to a theoretical model indicates the existence of a group with a pKa value of 6.1 that is crucial in the variation of kinetic constant of hydrolysis with pH. Studies of the reactivity of the coenzyme (pyridoxal 5'-phosphate) of glycogen phosphorylase b with hydroxylamine show that this reaction only occurs when the pH value of solution is below 6.5 and the hydrolysis of imine bond has started. We propose that the decrease in activity of phosphorylase b when the pH value is less than 6.2 must be caused by the cleavage of enzyme-coenzyme binding and that this may be related with protonation of the pyridine nitrogen atom of pyridoxal 5'-phosphate.     

Involvement of chondroitin sulphate in preventing adhesive cellular interactions

Glycosaminoglycans isolated from native non-adhesive surfaces of both endothelial and mesothelial origin and from endothelial cells cultured in vitro were analyzed by electrophoresis and characterized by chemical and enzymatic breakdown. All the surfaces examined expose in vivo chondroitin 6-sulphate as the main glycosaminoglycan. Under in vitro culture, the exposure of chondroitin sulphate is reduced. Paper chromatography of hydrolysis products upon degradation by chondroitinase AC shows equal amounts of both 6- and 4-sulphated disaccharides. At the same time, the surfaces lose their non-adhesiveness to leukocytes. The addition of fibroblast growth factor to endothelial monolayers restores both non-adhesiveness to leukocytes and exposure of chondroitin sulphate. These results seem to indicate that the exposure of chondroitin sulphate is important in preventing cellular adhesion.     

Calcium-dependent activation and deactivation of rod outer segment phosphodiesterase is calmodulin-independent

ATP-dependent activation and deactivation of retinal rod outer segment phosphodiesterase is affected by calcium [Kawamura, S. and Bownds, M. D., J. Gen. Physiol. 77:571-591(1981)]. Our data demonstrate that although calmodulin has been found in rod outer segments [Liu, Y. P. and Schwartz, H., Biochim. Biophys. Acta 526:186-193(1978); Kohnken, R. E. et al, J. Biol. Chem. 256:12517-12522(1981)], this protein is not involved in calcium-dependent phosphodiesterase activation at light levels at which calcium clearly affects this enzyme's activity. Furthermore, calmodulin does not mediate the calcium-dependent deactivation of phosphodiesterase.