6-ketoprostaglandin-f1-alpha and Duodenal-Ulcer

Synthesis of prostaglandin E2 and 6-keto prostaglandin F1 alpha by cultured antral and fundic gastric mucosa obtained from 86 patients with active duodenal ulcer who were not receiving medication was 50% lower (p less than 0.01) than their respective synthesis by cultured gastric mucosa in normal subjects. Antral and fundic prostanoid synthesis in patients receiving chronic therapy with nonsteroidal antiinflammatory drugs was almost completely inhibited. The decreased synthesis of antral and fundic prostaglandin E2 and 6-keto prostaglandin F1 alpha in duodenal ulcer patients was not affected following ulcer healing achieved after 4 wk of therapy with placebo, arbacet, misoprostol, sucralfate, and pirenzepine. In contrast, following 4 wk of therapy with ranitidine, both antral and fundic prostaglandin E2 synthesis were significantly increased when compared with their respective synthesis before therapy. These results confirm that gastric prostanoid synthesis is decreased in patients with active duodenal ulcer and in subjects treated with nonsteroidal antiinflammatory drugs, suggesting that decreased endogenous prostanoid synthesis may contribute to the pathogenesis of mucosal damage. The induction of endogenous prostanoids by ranitidine may contribute to its therapeutic effect.

Topics: 6-Ketoprostaglandin F1 alpha; Adolescent; Adult; Alprostadil; Aluminum; Anti-Inflammatory Agents; Benzodiazepinones; Duodenal Ulcer; Female; Gastric Mucosa; Humans; Male; Middle Aged; Misoprostol; Pirenzepine; Prostaglandins E; Pyloric Antrum; Ranitidine; Sucralfate

In cysteamine-induced duodenal ulceration the endogenous prostacyclin level initially showed an elevation. This elevation later disappeared, and the endogenous prostacyclin level dropped to zero--that is, below the detection limit. During ulceration the mucosal DNA level decreased, a phenomenon that was directly proportional to ulceration. In the course of the ulcerative process in the duodenal mucosa a de novo protein synthesis took place. This process was most probably a mucus secretion and served as a protective reaction against damaging noxae. The mucosal cyclic adenosine 5'-monophosphate (cAMP) content increased in the so-called pre-ulcerative phase but later returned to the normal (physiologic) level. The changes in the cyclic guanosine 5'-monophosphate (cGMP) level were more pronounced than those of cAMP, and the final result was a decrease in the mucosal cAMP/cGMP ratio. In accordance with our previous results we conclude that a positive cAMP/cGMP 'shift' indicates antiulcerogenic, cytoprotective, reparative processes in the mucosa, whereas its decrease is connected to damaging noxae.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Cyclic AMP; Cyclic GMP; Cysteamine; DNA; Duodenal Ulcer; Female; Intestinal Mucosa; Mucus; Rats; Rats, Wistar; RNA

The effect of prostacyclin and its analogues, -6-keto-prostaglandin-F1 alpha and 6-beta-prostaglandin-I1, on cysteamine induced duodenal ulceration of rats has been investigated. It seems that neither prostacyclin nor its analogues have antiulcerogenic effect in this model.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Anti-Ulcer Agents; Cysteamine; Duodenal Ulcer; Epoprostenol; Female; Prostaglandins, Synthetic; Rats; Rats, Inbred Strains

Intracisternal injection of calcitonin (0.01-5 micrograms) dose dependently prevented the development of duodenal ulcers induced by cysteamine in female rats. By contrast, intravenous infusion of the peptide at a dose 50 times higher than an effective intracisternal dose, had no effect. Intracisternal injection of calcitonin increased by three fold the generation of 6-keto-PGF1 alpha, the stable hydrolysis product of PGI2, in the duodenal mucosa. These studies demonstrated that calcitonin acts within the brain to potently suppress duodenal ulcers induced by cysteamine. The mechanisms of the antiulcer effect may involve changes in prostaglandin generation along with alterations of gastrointestinal secretion and motility associated the central injection of calcitonin. Growing evidence suggests that salmon calcitonin may act as a neuromodulator or neurotransmitter in the central nervous system. Specific binding sites have been demonstrated for calcitonin in the hypothalamus, brain stem and dorsal horn of the spinal cord using homogenate and membrane preparations or in vitro autoradiography methods. The peptide injected into the cerebrospinal fluid (CSF) produces a wide spectrum of biological effects including analgesia, hyperthermia, changes in pituitary hormone release, decrease in food and water intake, locomotor activity, and blood pressure. Numerous studies also demonstrated that calcitonin acts within the brain to markedly influence gastrointestinal secretory and motor function in rats and dogs and gastric ulceration in rats. In particular, intracisternal injection of salmon calcitonin was found very potent to selectively inhibit gastric ulcers elicited by stress, aspirin and central thyrotropin-releasing factor but not by necrotizing agents. In the present study, we further investigated the antiulcer effect of salmon calcitonin using the well established cysteamine experimental model to induce duodenal ulcers in rats. Part of this work has been reported in abstract form.

Topics: 6-Ketoprostaglandin F1 alpha; Animals; Calcitonin; Cysteamine; Duodenal Ulcer; Duodenum; Female; Intestinal Mucosa; Male; Rats; Rats, Inbred Strains

Mepirizole (60 and 200 mg/kg) administered s.c. induced damage in the surface epithelial cells of the rat proximal duodenum as early as 2 hr after the treatment. 16,16-Dimethyl prostaglandin E2 (dmPGE2, 30 micrograms/kg) administered s.c. significantly protected the duodenal mucosa against mepirizole-induced damage for up to 6 hr. Gastric acid secretion in acute fistula preparations was significantly reduced 1 hr after administration of mepirizole (60 and 200 mg/kg). The secretion reverted to the control level 2 hr later. In the 60 mg/kg-treated group, however, there was a significant increase in the acid output for up to 6 hr. Duodenal HCO3- secretion, stimulated with 10 mM HCl was significantly inhibited with mepirizole (60 and 200 mg/kg). Mepirizole (60 and 200 mg/kg) significantly increased the amount of acid in the duodenum for 2 to 6 hr after the treatment. dmPGE2 (30 micrograms/kg) significantly inhibited gastric acid secretion, stimulated duodenal HCO3- secretion, and reduced the increased amount of acid in the duodenum in response to mepirizole. Endogenous prostaglandin E2 and 6-keto prostaglandin F1 alpha in the duodenal mucosa were significantly reduced by mepirizole (200 mg/kg) 1 to 2 hr later. Mepirizole-induced duodenal damage appears to be caused by the increased amount of acid in the duodenum.

Topics: 16,16-Dimethylprostaglandin E2; 6-Ketoprostaglandin F1 alpha; Animals; Bicarbonates; Duodenal Ulcer; Epirizole; Gastric Juice; Intestinal Mucosa; Male; Prostaglandins; Pyrazoles; Rats; Rats, Inbred Strains

In 13 patients with endoscopically proven duodenal ulcer, biopsies were obtained from the stomach body and antrum and from the duodenal bulb before and, in 10, after 4 weeks of cimetidine treatment (1 g/day). The specimens were organ-cultured for 90 min, and prostanoid accumulation in the medium was determined by radio-immunoassay. After 4 weeks of cimetidine treatment, prostaglandin E2 and 6-keto-prostaglandin F1 alpha synthesis by cultured specimens obtained from the body of the stomach (1304 +/- 197 and 497 +/- 124, no. +/- 10) was significantly higher than their respective synthesis before therapy (734 +/- 90 and 222 +/- 26; no. = 13) (X +/- SE, pg/mg wet wt/90 min). Prostanoid synthesis by cultured specimens from the antrum and duodenum was not significantly different before and after cimetidine treatment. It is therefore suggested that cimetidine, in addition to its antisecretory effects, accelerates ulcer healing also by induction of endogenous gastric prostanoid synthesis.

Topics: 6-Ketoprostaglandin F1 alpha; Cimetidine; Dinoprostone; Duodenal Ulcer; Duodenum; Fatty Acids; Female; Gastric Mucosa; Humans; Intestinal Mucosa; Male; Prostaglandins E; Prostanoic Acids; Thromboxane B2

Cultured duodenal mucosa obtained from normal subjects synthesized and secreted significantly less prostaglandin E2 (PGE2), 6-keto-PGF1 alpha, and thromboxane B2 (TXB2) than cultured gastric mucosa obtained from the same subjects. Accumulation of PGE2, 6-keto-PGF1 alpha, and TXB2--the stable metabolites of prostacyclin I2 and thromboxane A2, respectively--by cultured gastric mucosa obtained from 21 untreated patients with active duodenal ulcer was significantly lower than their respective accumulation by cultured gastric mucosa obtained from 14 normal subjects. Accumulation of all three prostanoids by cultured duodenal mucosa obtained from patients with active duodenal ulcer and from normal subjects was not significantly different. PGE2, 6-keto-PGF1 alpha, and TXB2 accumulation was five to six times higher than their respective content in fresh tissue before culture and was inhibited by flufenamic acid. These results suggest that a decrease in endogenous gastric prostanoid synthesis may have a role in the pathogenesis of peptic ulcer disease.

Topics: 6-Ketoprostaglandin F1 alpha; Culture Techniques; Dinoprostone; Duodenal Ulcer; Duodenum; Female; Gastric Mucosa; Humans; Intestinal Mucosa; Male; Prostaglandins E; Thromboxane B2; Thromboxanes