Gastric cytoprotection by epidermal growth factor. Role of endogenous prostaglandins and DNA synthesis.
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Biomedical subjects
Publications and source records attributed to A Zmuda.
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Gastric mucosa of the rat generates both PGE2 and PGI2 activity in significantly higher concentrations in the antrum than in the fundus. Aspirin, given intravenously or intragastrically in doses producing gastric mucosal lesions, causes a dose-dependent decrease in the generation of mucosal PGE2 and PGI2, which is further enhanced by gastric perfusion of HCl. Exogenous PGE2 and PGI2 administered intravenously in doses not affecting gastric secretion almost completely prevented the formation of aspirin-induced ulcers. This study indicates that gastric mucosa is capable of generating PGE2 and PGI2 which may be responsible for its protection against chemical injury.
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Chopped samples of myometrium, decidua and extrinsic blood vessels from the pregnant rat uterus when incubated at room temperature generated a prostacyclin-like substance. Activity in the incubation mixtures was compared against authentic prostacyclin in two assay systems: relaxation of strips of bovine coronary artery and inhibition of ADP-induced aggregation of rabbit platelet-rich plasma. Results estimated from inhibition of platelet aggregation showed that activity generated by all samples was low on day 12 of pregnancy (less than 0.25 ng/mg). However at the time of delivery (day 22) myometrial synthesis had increased 18.5 fold to over 3 ng/mg of prostacyclin whereas decidual production had only increased 5 times. As there was no increase in synthesis by the extrinsic uterine blood vessels over this period it is proposed that the myometrial muscle cells are the probable source of the prostacyclin-like material.
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Experimental atherosclerosis in rabbits was associated with a suppression of prostacyclin generation from exogenous arachidonic acid by the coronary vascular bed. The spontaneous formation of prostacyclin by incubated rings of mesenteric artery was also diminished. These results suggest that in atherosclerosis an impaired activity of the endothelial prostacyclin synthexizing system contributes to the intra-arterial formation of thrombi.
Experimental atherosclerosis in rabbits was associated with increased aggregation of their platelets to arachidonic acid, and with increased generation of thromboxane A2 by their platelet-rich plasma. A heightened susceptibility of platelets to the anti-aggregatory action of prostacyclin against the ADP-induced aggregation was also observed. It is concluded that in advance atherosclerosis the platelet system is hypersensitive to biologically active metabolites of arachidonic acid.
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Eighteen patients with asthma and aspirin hypersensitivity have been challenged with increasing doses of aspirin, fenoprofen, ibuprofen, and dextropropoxyphene. Low doses of the first three drugs induced bronchoconstriction in all the patients as evidenced by fall in peak expiratory flow and appearance of clinical symptoms. There were no reactions to therapeutic doses of dextropropoxyphene. Aspirin, fenoprofen, and ibuprofen, but not dextropropoxyphene, inhibited prostaglandin synthetase activity in three different microsomal preparations, i.e., in bovine seminal vesicles, in rabbit brain, and in rabbit kidney medulla. Expected in vivo antienzymic potency of a drug, calculated from experiments using rabbit brain microsomes, corresponded roughly with its potency to induce bronchoconstriction in the challenge tests. An individual pattern of sensitivity to threshold doses of prostaglandin synthetase inhibitors was demonstrated for each patient. The results obtained suggest that precipitation of asthmatic attacks by nonsteroidal anti-inflammatory drugs is mediated through inhibition of prostaglandin biosynthesis. The degree of enzymic inhibition, which is sufficient to precipitate bronchoconstriction, is an individual hallmark. Knowing the threshold dose for any of prostaglandin synthetase inhibitors in a patient, one can predict the threshold doses for the rest of aspirin-like drugs in this particular patient.
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Rabbit aortic strips superfused with Krebs buffer pH 7.3 were relaxed in an endothelium-dependent manner by both acetylcholine (0.01-0.3 microM) and an increase in pH up to 7.6-8.5. These vasorelaxant effects were abrogated by methylene blue (50 microM), lidocaine (1.3-640 microM) and verapamil (2.5-5.0 microM). Nitrendipine (2.5-5.0 microM) abolished only acetylcholine-induced, but not pH-induced relaxations. It is concluded that activation of Na+/H+ exchange might be involved in triggering the release of an endothelium-derived relaxing factor.
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Blood plasma of patients with arteriosclerosis obliterans and diabetes showed a higher antioxidant potency as compared with plasma of healthy volunteers. Serum copper level in those patients was also elevated, but on the contrary to healthy subjects no correlation between serum copper level and plasma antioxidant potency was found. Similar changes were observed in rabbits fed four weeks with atherogenic diet. Administration of vitamin E increased plasma antioxidant potency, however, only in the patients suffering from arteriosclerosis obliterans with high regime of dosage of vitamin E (3 X 200 mg daily p.o.). N-ethylmaldimide-stimulated (malondialdehyde (MDA)) generation by washed platelets was suppressed by addition of homologous plasma to washed platelet preparation. Preincubation of rat aortic tissue with plasma from healthy volunteers resulted in an increase in PGI2-biosynthesis b 75%. We were not able to demonstrate the antioxidant activity of aortic endothelial cell homogenates. We conclude that antioxidant properties of plasma may play an important role in protection of serum lipids against autooxidation. Antioxidant ability of plasma is not exclusively correlated with plasma copper or ceruloplasmin level.
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