Biomedical subjects
Publications and source records attributed to B M Peskar.
A specific radioimmunoassay for prostaglandin D2 was developed. Using the radioimmunoassay, prostaglandin D2 synthesis by human thrombocytes was measured. While the cyclooxygenase inhibitor indomethacin inhibits formation of prostaglandin D2, increased formation of prostaglandin D2 was observed in the presence of the thromboxane synthetase inhibitor imidazole.
The occurrence of three enzymes of prostaglandin metabolism, 15-hydroxy-prostaglandin-dehydrogenase, delta13 -reductase and prostaglandin E-9-keto-reductase was investigated in gastroscopically obtained biopsy specimens of human upper gastrointestinal mucosa. All three enzymes could be found in the mucosa of oesophagus, gastric fundus, corpus and antrum and duodenum. While the specific activity of 15-hydroxy-prostaglandin-dehydrogenase was highest and the specific activity of prostaglandin E-9-keto-reductase was lowest in all regions studied, differences of the specific activities of the enzymes between the regions are remarkably small. These results are discussed with respect to possible functions of endogenous prostaglandins in human gastrointestinal mucosa.
Prostaglandins (PGs) can be measured by bioassay or combined gas-chromatography/mass spectrometry or by radioimmunoassay. The main advantage of the latter method is its great sensitivity. On the other hand, difficulties, with this method can arise from the small molecular weight of PGs and the large number of structurally closely related PGs and PG metabolites which cross-react in the various radioimmunoassays thus influencing the specificity of the method. Exogenous PGs exert a variety of effects on the gastro-intestinal tract. The effects on the various organs differ between the PGs tested and are species-dependent. Endogenous PGs have been found both in human and animal tissues of the gastrointestinal tract. PGE2 and its 15-keto-13, 14-dihydro-metabolite are the main PGs found in human gastric juice, while much smaller concentrations of PGF2alpha and PGA2 and their metabolites were detected. In human gastric mucosa both PG synthetase and PG-metabolizing enzymes were found to occur. Both enzyme systems can be influenced specifically by drugs. Inhibition of PG synthetase seems to correlate with gastric mucosal irritation, while inhibition of enzymatic PG inactivation might be associated with protection of gastro-intestinal mucosa. Results from animal experiments as well as clinical observations on humans indicate, that endogenous PGs might be involved in such syndromes as diarrhea, colitis, gastritis, tumors, acute pancreatitis and gastric ulcers caused by nonsteroidal anti-inflammatory drugs. The exact role, however, played by PGs in physiology and pathophysiology of the gastro-intestinal tract, awaits further investigations.
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1. Specific radioimmunoassays for the prostaglandins E2, A2 and F2alpha were used to study the synthesis of prostaglandins by gastroscopically obtained small biopsy specimens of human gastric corpus mucosa. 2. Both prostaglandin E2 and prostaglandin F2alpha were found to be synthesized from arachidonic acid by themicrosomal fraction of human gastric mucosa. The synthesis of prostaglandin E2 exceeded that of prostagladin F2alpha by a factor of about 10. 3. Synthesis of prostaglandin A2 or prostaglandin B2 was not observed under the same incubation conditions. 4. Indometacin effectively inhibited synthesis of both prostaglandin E2 (ID50 4.2 microng/ml) and prostaglandin F2alpha (ID50 1.8 microng/ml) by human gastric mucosa, while paracetamol even in a concentration of 310 microng/ml did not influence prostaglandin synthesis. The anti-ulcer agent carbenoxolone, which has been shown to inhibit prostaglandin inactivation, at the same concentration only slightly inhibited (about 20%) prostaglandin synthesis. 5. The results support the hypothesis that the gastro-intestinal effects or side effects of several drugs are mediated by an influence on the enzymes of prostaglandin synthesis or inactivation.
1. Specific radioimmunoassays for the prostaglandins E2, F2alpha and A2 and the metabolites 13,14-dihydro-15-keto-prostaglandin E2, 15-keto-prostaglandin F2alpha and 13,14-dihydro-15-keto-prostaglandin F2alpha were used to study the metabolism of prostaglandins by gastroscopically obtained small biopsy specimens of human gastric fundus mucosa. 2. Three prostaglandin-metabolizing enzymes were found in the 100 000 X g supernatant of human gastric fundus mucosa, 15-hydroxy-prostaglandin-dehydrogenase, delta13-reductase and delta9-reductase. The specific activity was highest for 15-hydroxy-prostaglandin-dehydrogenase and lowest for delta9-reductase. 3. Formation of prostaglandin A2 (or B2) was not observed under the same conditions. 4. None of the three enzyme activities detected in the 100 000 X g supernatant was found in the 10 000 X g and 100 000 X g pellets of human gastric fundus mucosa. 5. The results indicate that high speed supernatant derived from human gastric mucosa can rapidly metabolize prostaglandin E2 and prostaglandin F2alpha to the 15-keto and 13,14-dihydro-15-keto-derivatives. Furthermore, prostaglandin E2 can be converted to prostaglandin F2alpha, the biological activity of which, on gastric functions, differs from that of prostaglandin E2.
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A complex system of interacting mediators exists in the gastric mucosa to strengthen its resistance against injury. In this system prostaglandins play an important role. Prostaglandin biosynthesis is catalysed by the enzyme cyclooxygenase (COX), which exists in two isoforms, COX-1 and COX-2. Initially the concept was developed that COX-1 functions as housekeeping enzyme, whereas COX-2 yields prostaglandins involved in pathophysiological reactions such as inflammation. In the gastrointestinal tract, the maintenance of mucosal integrity was attributed exclusively to COX-1 without a contribution of COX-2 and ulcerogenic effects of non-steroidal anti-inflammatory drugs (NSAIDs) were believed to be the consequence of inhibition of COX-1. Recent findings, however, indicate that both COX-1 and COX-2 either alone or in concert contribute to gastric mucosal defence. Thus, in normal rat gastric mucosa specific inhibition of COX-1 does not elicit mucosal lesions despite near-maximal suppression of gastric prostaglandin formation. When a selective COX-2 inhibitor which is not ulcerogenic when given alone is added to the COX-1 inhibitor, severe gastric damage develops. In contrast to normal gastric mucosa which requires simultaneous inhibition of COX-1 and COX-2 for breakdown of mucosal resistance, in the acid-challenged rat stomach inhibition of COX-1 alone results in dose-dependent injury which is further increased by additional inhibition of COX-2 enzyme activity or prevention of acid-induced up-regulation of COX-2 expression by dexamethasone. COX-2 inhibitors do not damage the normal or acid-challenged gastric mucosa when given alone. However, when nitric oxide formation is suppressed or afferent nerves are defunctionalized, specific inhibition of COX-2 induces severe gastric damage. Ischemia-reperfusion of the gastric artery is associated with up-regulation of COX-2 but not COX-1 mRNA. COX-2 inhibitors or dexamethasone augment ischemia-reperfusion-induced gastric damage up to four-fold, an effect abolished by concurrent administration of 16,16-dimethyl-PGE(2). Selective inhibition of COX-1 is less effective. Furthermore, COX-2 inhibitors antagonize the protective effect of a mild irritant or intragastric peptone perfusion in the rat stomach, whereas the protection induced by chronic administration of endotoxin is mediated by COX-1. Finally, an important function of COX-2 is the acceleration of ulcer healing. COX-2 is up-regulated in chronic gastric ulcers and inhibitors of COX-2 impair the healing of ulcers to the same extent as non-selective NSAIDs. Taken together, these observations show that both COX isoenzymes are essential factors in mucosal defence with specific contributions in various physiological and pathophysiological situations.