The effect of different prostaglandins on cysteamine-induced duodenal ulcer in the rat

Most of the experiments have verified the cytoprotective effect of prostaglandins on the gastric mucosa and only few observations are known to deal with "cytoprotection" exerted on the duodenal or intestinal mucosa. Duodenal ulcers were produced by cysteamine (CEA). The treatment with different prostaglandins (PGI2, PGF2 alpha, PGE2) was carried out every six hours during the 48-hour experimental period. The obtained results indicate that neither prostacyclin nor prostaglandin-F2 alpha has any significant effect on CEA-induced duodenal ulceration, while prostaglandin-E2 exerts a slight anti-ulcerogenic effect. It is possible that cytoprotection is not the result of the same process in the duodenal and gastric mucosa: alternatively, three prostaglandins are not involved in the pathomechanism of CEA-induced duodenal ulceration.     

The role of prostaglandins in the regulation of gastric mucosal blood flow

It has been postulated that endogenous gastric prostaglandin activity contributes to the maintenance of non-stimulated gastric mucosal blood flow. Prostacyclin and PGE₂ increase mucosal blood flow in the non-stimulated canine stomach. Inhibition of prostaglandin synthesis by aspirin or indomethacin causes a reduction of 30% to 50% in non-stimulated gastric mucosal blood flow in dog and rat. These observations are consistent with the hypothesis that endogenous prostaglandin activity within the gastric mucosa contributes to the maintenance of its blood flow.Also it has been postulated that endogenous prostaglandins may, in part, mediate the vasodilation associated with stimulated gastric acid secretion. Exogenous prostacyclin and PGE₂ inhibit stimulated acid secretion while increasing mucosal blood flow. Indomethacin and aspirin-inhibited endogenous prostaglandin synthesis has been reported to increase stimulated acid secretion and reduce mucosal blood flow in anesthetized rat and dog. In gastric secretory fluid, prostaglandins have been detected during gastrin stimulation by some investigators and a dose response relationship between rate of secretion and fluid prostaglandin output has been observed. These observations are consistent with the hypothesis that endogenous prostaglandins may, in part, contribute to the regulation of mucosal blood flow during stimulated acid secretion. Further studies, directly measuring specific endogenous prostaglandins and their metabolic products within the gastric mucosa during stimulated and inhibited acid secretion will be necessary to prove or disprove this hypothesis.     

Anti-implantation effect of prostaglandins in the rat.

PGF2alpha and PGE2 have been instilled in small amounts (5mug) into the uterine horns of pregnant rats at different intervals following mating. Unilateral as well as bilateral injections have been used. Three parameters have been taken into consideration at laparotomy performed on the 13th day of pregnancy: a) the number of implantation sites; b) the number of viable fetuses; and c) the number of corpora lutea present on the ovarian surface. Both PGs proved able to inhibit implantation, to affect the development of embryos and to exert some luteolytic activity when given between D-1 and D-6 of pregnancy.     

The effect of etodolac on bile salt and histamine-mediated gastric mucosal injury in the rat

The effect of the selective cyclo-oxygenase-type-2 (COX-2) inhibitor etodolac on gastric mucosal integrity and gastric acid secretion was investigated in the rat. Etodolac was given in doses comparable with those being used in man for therapy of rheumatic conditions. The effect of etodolac was studied in the presence of a mild barrier breaker and in the presence of increased rates of endogenous acid secretion. In conscious pylorus-ligated rats, etodolac given intragastrically in 16 or 32 mg /kg for 3 h did not by itself give rise to visible gastric mucosal injury. Etodolac, however, exacerbated gastric mucosal injury evoked by intragastric application of acidified sodium taurocholate (5 mM in 150 mM HCl) in a dose-dependent manner. This effect of edotolac was independent of changes in gastric acid secretory responses. In rats whose gastric acid secretion was stimulated by intraperitoneal histamine (5 mg/kg), and etodolac (given i.g. in doses of 16 or 32 mg/kg) also increased gastric mucosal injury caused by histamine dose-dependently in the 3-h pylorus-ligated rats. Etodolac decreased gastric mucus in the saline- and in the sodium taurocholate-treated rats. In urethane-anaesthetized acute gastric fistula rats, intragastric etodolac (32 mg/kg) did not modify basal gastric acid secretion. Our data suggest that etodolac, a selective COX-2 inhibitor, impairs gastric mucosal resistance and can exacerbate gastric mucosal injury caused by other mucosal barrier breaking agents. Cyclooxygenase type-2 thus contributes to the gastric mucosal defences.     

Further analysis of prostacyclin's effect on rat gastric mucosal nucleic acid content.

Graded single and multiple oral doses of prostacyclin enhance, in a direct dose-dependent manner, the DNA and RNA content of rat gastric (antral and fundic) mucosa, resulting in a decreased RNA/DNA ratio. This latter phenomenon is a convincing sign of new cell formation. The arithmetical (theory of functions) analysis of the data resulted in equations, defined mathematically, of prostacyclin's dose-dependent effect.     

Effect of clonidine on second messenger systems in rat adrenal gland.

Clonidine, an alpha 2-adrenergic agonist, also binds to non-adrenergic imidazole receptors in brain and peripheral tissues. In adrenal medulla, however, clonidine appears to bind only to imidazole receptors. To assess whether the signal transduction mechanism of imidazole receptors differs from alpha 2-adrenergic receptors, we studied the actions of clonidine on the turnover of phosphoinositide and the production of cAMP and cGMP in slices of rat adrenal gland. Clonidine did not modify basal or carbachol mediated increases in phosphoinositide turnover or production of cAMP, however it increased the production of cGMP. The increase in cGMP was slow and unaffected by the addition of the phosphodiesterase inhibitor, IBMX. We conclude that the second messenger response triggered by clonidine in adrenal differs from that usually coupled to alpha 2-adrenergic receptors. Whether the effect is mediated by cell surface imidazole receptors remains to be established.     

Effects of ethanol on gastric acid secretion and gastric mucosal cyclic AMP in the rat.

The effect of ethanol on the secretion of gastric acid and the content of cyclic AMP of the gastric mucosa was studied in rats. Intravenously, ethanol (10 to 800 mg/kg) had no effect on the output of acid. Upon local application into the stomach, ethanol (1 to 10%) caused a concentration-dependent inhibition of the output of gastric acid. The effect was evident within 5 min. At the concentration of 1 %,ethanol decreased the rate of acid secretion maximally by about 30%. At the concentration of 3 %, the maximal inhibition was about 70 %. At the concentration of 10 %, ethanol caused a total cessation of the output of acid within 20 to 60 min.Five and 25 min after the administration of 10 % ethanol into the stomach, the gastric mucosal content of cyclic AMP was decreased by approximately 50 %. Also in vitro, the mucosal content of cyclic AMP was decreased by ethanol within 5 min. The decrease was about 30 % with 2.5 % ethanol, approximately 60 % with 10 % ethanol, and approximately 45 % with 20 % ethanol. Alcohol inhibited the activity of the cyclic AMP phosphodiesterase of the gastric mucosa in a competitive manner. The K_i-value was 0.16 M which would correspond to an alcohol concentration of 9.1 % (v/v). Ethanol caused a concentration-dependent inhibition of the activity of the gastric mucosal adenyl cyclase. By 0.166 M (9.4 %) alcohol the inhibition was nearly 100 %.It is concluded that the ethanol-induced decrease of cyclic AMP in the gastric mucosa is due to a decreased formation of the nucleotide. The accompanying inhibition of the output of acid by ethanol is consistent with the view that cyclic AMP is an intracellular regulator of the gastric acid secretion. In view of the role of cyclic AMP in the control of the integrity of the cells, it is suggested that the ethanol-induced damage of gastric mucosa might also be, at least partly, due to the decreased mucosal content of cyclic AMP.     

Pharmacology of stomoxytachykinin receptor depends on second messenger system

STKR is a neurokinin receptor derived from the stable fly, Stomoxys calcitrans. Insect tachykinin-related peptides, also referred to as "insectatachykinins", produce dose-dependent calcium and cyclic AMP responses in cultured Drosophila melanogaster Schneider 2 (S2) cells that were stably transfected with the cloned STKR cDNA. Pronounced differences in pharmacology were observed between agonist-induced calcium and cyclic AMP responses. The results indicate that the pharmacological properties of STKR depend on its coupling to a unique second messenger system. Therefore, a model postulating the existence of multiple active receptor conformations is proposed. This article presents the first evidence that an insect peptide receptor with dual coupling properties to second messenger systems can display agonist-dependent functional differences.     

The second messenger cascade in olfactory receptor neurons.

The molecular cloning of components involved in the cAMP second messenger cascade has allowed their biochemical characterization and revealed properties that are important for their role in sensory transduction. Recent evidence suggests inositol 1,4,5-trisphosphate functions as an additional second messenger in olfactory signalling. The interaction of these two pathways may contribute to the sensitivity of the olfactory system.     

The effect of catecholamines and prostaglandins upon human and rat erythrocytes.

Both human and rat erythrocytes respond to low doses (10(-11)--10(-9) M) of L-isoproterenol and L-epinephrine with an increased degree of hypotonic hemolysis and a decreased rate of filtration through standardized paper filters. The receptors in both cell types have many of the characteristics of beta-receptors for catecholamines. However, hormone-receptor interaction in the human cell does not lead to an increase in intracellular cyclic AMP concentration, but in the rat cell, hormone-receptor interaction does lead to a significant increase in cyclic AMP content. Thus, catecholamine-beta-receptor interaction, at least in the human red cell, leads to a change in red cell properties which are not mediated by adenylate cyclase activation. Likewise, prostaglandin E2, at 10(-12)--10(-10) M, causes are increased degree of hypotonic hemolysis and a decreased rate of filtration through standardized paper filters, but it also does not increase the cycliC AMP content of the human erythrocyte but does increase that of the rat erythrocyte. Nevertheless, exogenous cyclic AMP, when added at a concentration of 10(-8) M to washed human erythrocytes, increases the degree of hypotonic hemolysis. Conversely, prostaglandin E1, at 10(-12)--10(-10) M, causes a decreased degree of hypotonic hemolysis and an increased rate of filtration through a standard filter. Both prostaglandin E2 and the catecholamines decrease the size of a rapidly exchangeable calcium pool, and prostaglandin E1 increases it.     

Effects of putative diuretic factors on intracellular second messenger levels in the Malpighian tubules of Aedes aegypti

Intracellular levels of the second messengers, 3',5'-cyclic adenosine monophosphate (cAMP) and inositol 1,4,5-trisphosphate (IP(3)) were measured in the Malpighian tubules of Aedes aegypti following the in vitro application of 5-hydroxytryptamine (5-HT) and the putative mosquito diuretic peptides, Culex salinarius diuresin and mosquito leucokinins (culekinin depolarizing peptides (CDPs) I, II, III, A. aegypti leucokinin peptides (ALPs) I, II, III). The C. salinarius diuresin significantly (p<0.05) increased tubule intracellular cAMP concentrations. Treatment of tubules with either 5-HT or CDP-II resulted in significant increases in both intracellular cAMP and IP(3) concentrations. All of the mosquito leucokinins, with the exception of CDP-I, significantly stimulated intracellular IP(3) in isolated tubules. These data suggest that the mosquito leucokinins may function on the Malpighian tubules of A. aegypti by increasing the intracellular Ca(2+) levels through the release of IP(3) sensitive Ca(2+) stores. The physiological relevance of these data to the regulation of mosquito Malpighian tubule function is discussed.     

The effect of vitamin E on the intracellular distribution of the different oxidation states of selenium in rat liver

1. The liver intracellular distribution of (75)Se, (75)Se(2-) and (75)SeO(3) (2-) formed from orally administered Na(2) (75)SeO(3) was studied in rats given four different dietary treatments. 2. Subcellular fractionation was done by using sucrose density gradients in a B XIV zonal centrifuge rotor, and conditions were established so that separation of lysosomal, mitochondrial, smooth- and rough-surfaced endoplasmic reticulum, and soluble fractions was achieved. 3. Marker enzymes acid phosphatase, succinate-2 - p - iodophenyl - 3 - p -nitrophenyl - 5 - phenyltetrazolium reductase and glucose 6-phosphatase were used, together with electron microscopy, to establish the identity of the fractions. 4. The dietary treatments investigated were: (a) vitamin E-deficient diet for 3 months, re-fed with vitamin E during the terminal 5 days; (b) vitamin E-deficient diet; (c) adequate diet; (d) vitamin E- and selenium-deficient diet, re-fed with vitamin E during the terminal 5 days. 5. In adequately fed rats, selenide was particularly associated with the mitochondrial fractions; in vitamin E-deficient rats, little selenide was found and the buoyant density of the mitochondria was increased, whereas re-feeding with vitamin E showed a restoration of the normal pattern. In vitamin E- and selenium-deficient rats, re-fed with vitamin E, there was no tendency for selenide to be localized in the mitochondria. 6. In the microsomal regions of the gradients, adequately fed rats showed a concentration of selenide, particularly in the smooth endoplasmic reticulum fractions, and to a lesser extent in the rough endoplasmic reticulum fractions. This was not observed in vitamin E-deficient rats, and the normal pattern was restored on re-feeding with vitamin E, both in rats given the vitamin E-deficient diet and the vitamin E- and selenium-deficient diet. 7. Some selenide was also found in the soluble fractions, when vitamin E was present, and a substantial proportion of this selenide was found to pass through a dialysis membrane. 8. These results are taken to support our hypothesis that the active form of selenium may be selenide located in non-haem iron-containing proteins, and that the function of vitamin E may be to protect the selenide from oxidation.     

The effect of glucose on the synthesis of prostaglandins by the renal papilla of the rat in vitro.

Renal pappillae from rats were incubated in vitro. The release of prostaglandin by this tissue was found to be inversely related to the glucose concentration of the buffer. Estimates of prostaglandin release were determined by a rat stomach strip bioassay, and in some instances, gas-chromatography and mass spectrometry. When incubated in the presence of C14-arachidonic acid, the specific activity of prostaglandins E2 and F2 alpha released by the tissue was lower at the lower glucose concentration. Provision of 625 micrograms/ml of exogenous arachidonic acid in the buffer obliterated the effect of glucose on prostalglandin release. These data indicate that increasing amounts of glucose suppresses prostaglandin synthesis in the renal papilla of the rat, and that the mechanism of this phenomenon is related to the release of arachidonic acid from its storage pools in tissue lipids.     

The effect of sialoadenectomy on gastric mucosal integrity in the rat: roles of epidermal growth factor and prostaglandin E2

Removal of the salivary glands (SALX) in rats has been shown to increase the susceptibility of gastric mucosa to ulcerogens. In the present study, we have investigated the role of specific salivary glands in this response. In addition, we have examined whether a functional link exists between the salivary glands, epidermal growth factor (EGF), and prostaglandin E2 (PGE2) by determining whether SALX decreases the responsiveness of the mucosa to the protective actions of either of both of these agents. Removal of the parotid salivary glands did not significantly increase ulceration in response to intragastric administration of 100% w/v ethanol. Animals were examined 60 min after ethanol administration. Removal of the submandibular-sublingual gland complexes was associated with a significant increase in the area of mucosal damage and a decrease in gastric pit depth in ethanol-treated animals when compared with sham-operated control rats. Furthermore, in both SALX and control animals, exogenous PGE2 and EGF resulted in a dose-dependent reduction in both groups of animals, although the protective effects of PGE2 and EGF were attenuated in SALX rats. PGE2 and EGF administered in combination resulted in the same degree of protection in both SALX and control rats. Sialoadenectomy resulted in a reduction in mucosal PGE2 synthesis. EGF administration did not consistently increase mucosal PGE2 synthesis. Conversely, sialoadenectomy did not reduce mucosal levels of EGF nor did exogenous PGE2 consistently increase salivary or mucosal content of EGF.(ABSTRACT TRUNCATED AT 250 WORDS)