A. Dembińska-Kieć

The generation of prostacyclin by arteries and by the coronary vascular bed is reduced in experimental atherosclerosis in rabbits

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.

Prostacyclin and thromboxane A2 biosynthesis capacities of heart, arteries and platelets at various stages of experimental atherosclerosis in rabbits

Abstract Atherosclerosis was induced by feeding rabbits with 1 g of cholesterol and 3 g of olive oil daily for 1, 3 and 5 months. Arachidonic acid (AA)-induced generation of prostacyclin (PGI 2 ) by perfused hearts and spontaneous generation of PGI 2 by slices of mesenteric arteries and aortas were strongly suppressed after 1 and 3 months of the diet, while after 5 months a tendency for PGI 2 synthesizing capacity to recover was observed. Aggregatability of blood platelets in platelet-rich plasma (PRP) by exogenous AA and endogenous thromboxane A 2 (TXA 2 ) was increased but not earlier than 3 months on the diet. On the other hand, platelet sensitivity to the pro-aggregatory action of adenosine diphosphate (ADP) and to the anti-aggregatory action of PGI 2 was heightened as early as 1 month from the beginning of the experiment. These findings suggest that the first stage of experimental atherosclerosis may be causally related to the strong suppression of PGI 2 generation by arteries, whereas the metabolism of AA in platelets remains unchanged. At this early stage of atherosclerosis increased susceptibility of platelets in PRP to both ADP and PG1 2 may be due to the lowering of cyclic AMP levels in platelets as a consequence of PGI 2 deficiency. A genuine enhancement of AA metabolism in blood platelets occurs only at the second stage of experimental atherosclerosis. This stage is particularly dangerous since an increased generation of TXA 2 by platelets in PRP is combined with a decreased generation of PGI 2 by arteries. At the last stage of atherosclerosis observed, a slow recovery of the enzymic activity occurs in arteries.

Role of locally generated prostaglandins in adaptive gastric cytoprotection

This study was designed to determine the role of mucosal generation of prostaglandins (PGs) in the ability of mild irritants (20% ethanol or 5% NaCl) to protect against the formation of mucosal lesions caused by necrotizing agents (100% ethanol or 25% NaCl) or acidified aspirin (ASA). Mild irritants protected against damage from necrotizing agents but not from ASA. This protection was accompanied by increased mucosal generation of PGE2 and PGI2-like substances. Exogenous PGE2 and PGI2 applied topically to the gastric mucosa in a nonantisecretory dose greatly inhibited the formation of lesions induced by either necrotizing agents or ASA. Pretreatment with indomethacin, which suppressed the generation of mucosal PGs augmented formation of lesions by necrotizing agents and partly counteracted the protective effect of mild irritants. We conclude that mild irritants, and exogenous PGs inhibit the formation of gastric lesions by necrotizing agents, at least in part, by mucosal generation of PGs.

Experimental atherosclerosis in rabbits: Platelet aggregation, thromboxane A2 generation and anti-aggregatory potency of prostacyclin

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.

Role of mucosal prostaglandins and DNA synthesis in gastric cytoprotection by luminal epidermal growth factor.

This study compares the effect of epidermal growth factor and prostaglandins (PGE2 or PGI2), applied topically to gastric mucosa, on gastric secretion and formation of ASA-induced gastric ulcerations in rats. Epidermal growth factor given topically in non-antisecretory doses prevented dose-dependently the formation of ASA-induced ulcers without affecting prostaglandin generation but with a significant rise in DNA synthesis in the oxyntic mucosa. The anti-ulcer effect of topical prostaglandins was also accompanied by an increase in DNA synthesis. This study indicates that topical epidermal growth factor, like PGE2 or PGI2, is cytoprotective and that this cytoprotection is not mediated by the inhibition of gastric secretion or prostaglandin formation but related to the increase in DNA synthesis in oxyntic mucosa.

Prostacyclin formation by myometrial & decidual fractions of the pregnant rat uterus

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.

Aspirin-sensitive asthma: The effect of aspirin on the release of prostaglandins from nasal polyps

Summary Nasal polyp pieces and homogenates from 14 aspirinsensitive patients and 22 subjects without this sensitivity were incubated in the presence of arachidonic acid (33 μM) and aspirin (167 μM). The prostaglandin-like material generated was bioassayed in PGE2 — equivalents. In polyp pieces of aspirin sensitive patients aspirin completely inhibited the arachidonate-stimulated release of prostaglandins (p 0.1). Aspirin also more effectively inhibited prostaglandin biosynthesis in polyp homogenates from aspirin-sensitive patients than in the control group. Thus, the enzymic system generating prostaglandins in polyp pieces of aspirin-sensitive patients has an increased susceptibility to the inhibitory action of aspirin.

Role of prostaglandin and thromboxane biosynthesis in gastric necrosis produced by taurocholate and ethanol

The effects of a new selective inhibitor of thromboxane biosynthesis, OKY-1581, and a potent inhibitor of cyclooxygenase, indomethacin, on gastric mucosal lesions induced by turocholate or ethanol and mucosal generation of prostaglandins have been studied in rats. OKY-1581 prevented, dose dependently, the formation of taurocholate- but not ethanol-induced gastric necrosis, and this effect was accompanied by an increase in gastric mucosal generation of prostaglandin E2 and I2-like activity and a reduction in the thromboxane generation during platelet aggregation. OKY-1581 enhanced the cytoprotective action of “mild” irritants such as 5 mM taurocholate against gastric damage by 100 mM taurocholate, whereas indomethacin produced opposite effects. This study indicates: (1) the inhibition of thromboxane biosynthesis results in increased generation of prostaglandins which seems to contribute to the gastric mucosal integrity and, (2) thromboxanes may be involved in the pathogenesis of taurocholate-induced gastric mucosal lesions.

A potent inhibitor of thromboxane A2 biosynthesis in aggregating human blood platelets

Summary 1′(Isopropyl-2-indolyl)-3-pyridyl-3-ketone (L 8027) inhibited biosynthesis of thromboxane A 2 from arachidonic acid in human platelet rich plasma and inhibited platelet aggregation. The anti-enzymic and anti-aggregating potencies of L 8027 were closely linked to each other and both of them were inversely proportional to concentrations of arachidonic acid which platelets were exposed to. Very low concentrations of L 8027 (0.1 fM – 40 nM) were needed to inhibit generation of thromboxane A 2 and aggregation of platelets by the threshold pro-aggregatory concentrations of arachidonic acid. A concentration of 4 uM of L 8027 was sufficient to inhibit platelet aggregation induced by any concentration of arachidonic acid. L 8027 inhibits the activity of the arachidonate cyclo-oxygenase in many biological systems including platelets. However, unlike indomethacin L 8027 is a more potent thromboxane A 2 synthetase inhibitor than a prostaglandin synthetase inhibitor.

The influence of saturated fatty acids on prostaglandin synthetase activity

Abstract Saturated fatty acids (C10, C12, C14, C16 and C18) as well as lauryl sulphate inhibit the microsomal prostaglandin synthetase of bovine seminal vesicles (BSVM). The most potent inhibitors are lauryl sulphate, lauric and myristic acids ( ic 50 = 250 μ M ). The last two acids are strong ligands to hydrophobic sites of albumin. Indomethacin is also strongly bound to the hydrophobic sites of albumin; however, indomethacin inhibits the generation of prostaglandins at a concentration approximately 2500 times lower than the most active fatty acid inhibitor. The inhibitory action of fatty acids and indomethacin on prostaglandin synthetase activity has been measured by estimation of either PGE2 or malondialdehyde, which are generated from arachidonic acid by BSVM. The former procedure is more reliable and reproducible than the latter.