Influence of an alpha-1-adrenoceptor antagonist, nicergoline, on placental prostanoid production in streptozotocin-induced diabetic pregnant rats.

The aim of this study was to determine if placental prostanoids could mediate the vasodilating action of an alpha-1-adrenoceptor antagonist, nicergoline (400 micrograms/kg i.p.), during late pregnancy in streptozotocin-induced diabetic rats (40 mg/kg i.v.). Placental prostanoid concentrations were evaluated by radioimmunoassay. Prostaglandin E2 levels showed a highly significant increase in diabetic and nondiabetic rats treated with nicergoline (p less than 0.001). 6-Keto-PGF1 alpha concentrations were slightly increased in diabetic rats compared to controls, and this increase was reversed by both nicergoline and insulin treatments. In all groups studied thromboxane B2 levels were comparable. It is concluded that prostaglandin E2 could mediate the vasodilating action of nicergoline on the placental irrigation and, therefore, improved the hemodynamic state of this organ in diabetic rats.

Postischemic cerebral microvascular responses to norepinephrine and hypotension in newborn pigs.

We examined the effects of 20 minutes' cerebral ischemia on cerebral microcirculatory responses to topical norepinephrine and systemic hypotension in three groups (sham-operated control, 2-3 hours postischemia, and 24 hours postischemia) of anesthetized newborn pigs equipped with closed cranial windows. Cerebral ischemia may eliminate the prostanoid vasodilator system from the cerebral circulation. Norepinephrine (10(-4) M) decreased pial arteriolar diameters similarly in all three groups (27%, 28%, and 21%, respectively), but only the sham-operated group exhibited pial arteriolar dilation in response to hypotension (28% at 33 mm Hg). Two-three and 24 hours after cerebral ischemia, hypotension decreased pial arteriolar diameters (21% and 17%, respectively). In sham-operated piglets, norepinephrine and hypotension increased cortical periarachnoid cerebrospinal fluid prostanoid concentrations. However, neither norepinephrine nor hypotension altered cerebral prostanoid production 2-3 or 24 hours after cerebral ischemia. Therefore, we conclude that after cerebral ischemia, autoregulatory pial arteriolar dilation in response to hypotension is absent, while vasoconstriction in response to norepinephrine is intact.

Influence of iloprost on eicosanoid generation and lipid levels in experimental myocardial ischemia in dogs.

Anaesthetized mongrel dogs were subjected to occlusion of a coronary artery. The resulting myocardial infarction was observed for three hours. One hour after occlusion, infusion of the stable prostacyclin analogue iloprost or saline was started. In the control group myocardial infarction was associated with an increase of the ratio TXB2/6-keto-PGF1a which was abolished by iloprost treatment. After occlusion in the control group, the atherosclerosis index (TC-HDLC): HDLC was increased, but in the iloprost-treated group it was significantly decreased. The results of this study suggest that the administration of iloprost is able to prevent changes in eicosanoid metabolism and lipoprotein pattern after coronary artery occlusion in dogs.

Effects of cimetidine on prostanoid production in the gastric corpus specimens from rats.

In order to examine the effect of cimetidine on the production of prostanoids in the stomach mucosa, the amounts of prostaglandin (PG) E2, F1 alpha and thromboxane (TX) B2 were determined after the specimens from the rat stomach corpus were incubated in the presence of cimetidine. Cimetidine significantly stimulated the production of PGE2 in the specimens at a concentration of 10 microM, but did not significantly affect the production of PGF1 alpha and TXB2 at concentrations of 1 to 100 microM.

Alterations in rabbit renal microvascular prostanoid synthesis in acute renal failure.

Vasodepressor prostanoids have been suggested to regulate renal hemodynamics after nephrotoxic injury and thus protect the kidney against the effects of prolonged ischemia. This study assessed whether changes in two microvascular vasodilator prostanoids would correlate with changes seen in renal hemodynamics in rabbits with nephrotoxic renal injury produced by either uranyl nitrate or mercuric chloride. Rabbits were killed at 3, 24, and 72 h after the nephrotoxin injections and 6-ketoprostaglandin (PG) F1 alpha and PGE2 synthesis was measured in vitro in isolated renal microvessels. At the end of 24 h, synthesis of both prostanoids was significantly increased in all nephrotoxin-treated animals, an observation not noted at the end of 3 h. At 72 h, 6-keto-PGF1 alpha production remained elevated. Pretreatment with mepacrine blocked the increased prostanoid production seen in uranyl nitrate-treated animals. Thus, renal microvascular vasodilator prostanoid biosynthesis is increased 24-72 h after nephrotoxin administration. These data suggest that the biosynthesis of prostacyclin and PGE2 may contribute to the maintenance of renal blood flow in the first few days after acute renal injury and further suggest that a mechanism for this increase may be stimulation of phospholipase A2.

Phospholipid profile and production of prostanoids by murine colonic epithelium: effect of dietary fat.

Dietary fat and abnormal production of various prostanoids have been linked to various disease states of the large bowel, including cancer of the colon. Studies were conducted to determine the effect of dietary fat (beef tallow or corn oil) on the lipid composition and prostanoid production of the murine colon. Female C57BL/6J mice were fed high-fat (HF) diets (47% of calories as fat) or low-fat (LF) diets (10% of calories as fat). After four wk of dietary treatment, the mucosa was scraped, and lipids were extracted from the mucosal and muscle layers. The fat content of the diets did not significantly alter the amount of phospholipid (PL) or neutral lipid in the colonic tissue. However, the HF affected the PL profile of the colonic mucosa. For example, the ratio of phosphatidylcholine (PC) to phosphatidylethanolamine (PE) was significantly higher for both the HF groups compared with that of the two LF groups (0.76 +/- 0.15 and 0.80 +/- 0.13 vs 0.31 +/- 0.20 and 0.34 +/- 0.18). Production of 13,14-dihydro-15-keto-PGE2 (measured as bicyclic PGE2) and TXB2 (a stable metabolite of TXA2) and PGF1 alpha (a stable metabolite of PGI2) was unaffected by the dietary treatments. The muscle had a different PL profile (PC:PE is 2.6 +/- 0.1) than the mucosa and contributed a larger proportion of the prostanoids formed. This study demonstrates that the phospholipid polar head group composition of normal colonic mucosa is altered by dietary fat, but the ability of the mucosa to synthesize metabolites of PGE2, TXA2 and PGI2 is not affected.

Reduction by prostacyclin of acetaminophen-induced liver toxicity in the mouse.

The effect of prostacyclin on acetaminophen-induced liver injury has been investigated in the mouse. Two structurally unrelated thromboxane synthetase inhibitors, OKY 1581 and benzyl imidazole, were also examined in order to investigate the role of the prostacyclin-thromboxane balance in the development of hepatic lesions. Whereas prostacyclin or OKY 1581 given shortly after acetaminophen prevented mortality and reduced liver necrosis, as assessed by serum ALT activity and histology, benzyl imidazole was only effective if given prior to acetaminophen. Acetaminophen overdose resulted in an enhanced prostaglandin and thromboxane generation by liver homogenates. While OKY 1581 inhibited thromboxane production by the liver homogenates, prostacyclin synthesis was increased. Pretreatment with the cyclooxygenase inhibitor indomethacin blocked both the increase in prostacyclin generation and the protective effect of OKY 1581. Benzyl imidazole inhibited the synthesis of thromboxane but did not enhance prostacyclin production. In addition, the protective effect of benzyl imidazole was unaltered by indomethacin pretreatment. Furthermore, whereas benzyl imidazole interfered with hepatic drug metabolism, as assessed by prolongation of the pentobarbitone sleeping time, prostacyclin and OKY 1581 were without activity. Prostacyclin treatment can prevent acetaminophen-induced liver necrosis in mice. Enhanced prostacyclin synthesis by the selective thromboxane synthetase inhibitor OKY 1581 also exerts a protective role in this model.

Arachidonate metabolism in myocardial ischemia and reperfusion.

Circulatory blood corpuscles have enzymes catalyzing arachidonic acid. Platelets have cyclo-oxygenase system which produce highly vasoconstrictive and thrombogenic thromboxane A2 (TXA2). Neutrophils have another type of arachidonate metabolism system, lipoxygenase enzymes, which produce hydroxyeicosatetraenoic acids (HETE) and leukotrienes (LT), mediating inflammatory reactions. These arachidonate metabolites were found to play important roles in the evolution of myocardial ischemia. Thromboxane B2 (TXB2) a stable metabolite of TXA2, was elevated in peripheral blood of patients with angina pectoris. This elevation of TXB2 was supposed to be derived from platelet activation in coronary circulation due to altered production of TXA2 and prostacyclin (PGI2). Augmentation of TXA2 was also observed in patients with acute myocardial infarction. TXA2 synthetase inhibitors decreased plasma levels of TXB2 in these patients accompanied by attenuation of infarct size. Neutrophils were found to accumulate in ischemic myocardium and were augmented at reperfusion phase especially at interface between infarcted and risk zone. These infiltrated neutrophils may also provide deleterious effects on myocardial cells by producing lipoxygenase metabolites. In fact, a chemotactic and vasoconstrictive lipoxygenase product, 12-HETE, was produced selectively in ischemic myocardial tissue of an occlusion-reperfusion model. During evolution of myocardial cell damage, platelets and neutrophils, accumulated in ischemic tissue, may contribute to the exacerbation of microcirculatory disorders by producing vasoactive prostanoids, leading to expansion of myocardial necrosis. We should gain insights into these cellular interactions through arachidonate metabolism under normal and catastrophic conditions of coronary circulation.

Thrombosis associated with antiphospholipid antibodies cannot be explained by effects on endothelial and platelet prostanoid synthesis.

The effect of 23 antiphospholipid antibody positive SLE sera, 4 antiphospholipid antibody negative SLE sera and 17 control sera on endothelial prostacyclin and platelet thromboxane A2 production was studied. Endothelial cells and platelets were stimulated with different agonists. Depending on the stimulus used, 4-19% of the SLE sera inhibited the prostacyclin release, whereas 4-28% enhanced prostacyclin production. Our data suggest that the pathophysiological mechanisms underlying decreased prostacyclin production are heterogeneous. Follow-up of two patients showed that prostacyclin inhibitory activity was variable in time. Platelet thromboxane production was normal or increased, but never decreased in the presence of the SLE sera. An imbalance in thromboxane A2/prostacyclin ratio was present in some patients, but did not correlate with a history of thrombosis. We conclude that, in general, interference of antiphospholipid antibodies with endothelial or platelet prostanoid synthesis does not explain the occurrence of thromboembolic manifestations in antiphospholipid antibody positive SLE patients.

What about the effects of dietary lipids on endogenous prostanoid synthesis? A state-of-the-art review.

The endogenous prostanoid synthesis can principally be influenced by a variation of the polyunsaturated fatty acid supply in food. Withholding an essential fatty acid supply in food for a length of time results in a low rate of formation of prostanoids. However, there is no simple correlation between the amount of prostaglandin precursor fatty acid supplied with food and the biosynthesis of prostanoids in the different organs. A progressive increase of the intake of polyunsaturated fatty acids results in irregular changes in the prostanoid synthesis of the organism. The impact of various parameters should be taken into account, e.g., the period of feeding, the preexperimental state of the organism, the kind of polyunsaturated fatty acid related to a particular family of fatty acids, interactions with other components of food, differences of the species, organ specificities, aspects of chronoperiodicity, interactions of the prostanoids (and polyunsaturated fatty acids, respectively) with other metabolic circuits on a different level of integration, and details in the methods applied in the determination of prostanoids. Above all, care must be taken to prevent too general conclusions being drawn about the influence on the endogenous synthesis of prostanoids by dietary polyunsaturated fatty acids.

Enteropooling in piglets induced by soya-peptone mediated via an increased biosynthesis of prostanoids.

The enteropooling activity of soya-peptone was studied in germfree piglets. The enteropooling activity was restricted to the proximal part of the jejunum and was found to be blocked by aspirin. The hypothesis that soya-peptone acts via an increased biosynthesis/release of prostanoids was further studied using guinea-pig lung parenchyma. In this tissue soya-peptone induces the release of TXB2, which was inhibited by indomethacin (3 microM). The involvement of cholinergic, histaminergic and serotonergic pathways in the soya-peptone-mediated response was excluded, using antagonists. The conclusion was reached that soya-peptone can stimulate/modulate the biosynthesis of cyclic eicosanoids and that it exerts its enteropooling activity via the same mechanism in the jejunum of piglets.

Effect of cimetidine on human gastric and duodenal prostanoid synthesis.

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.

[The effect of indomethacin and carprofen on gastric prostaglandin biosynthesis]. / Wirkung von Indometacin und Carprofen auf die gastrale Prostaglandin-Biosynthese.

The effect of indometacin (3 X 50 mg daily), carprofen (Imadyl) (2 X 150 mg daily) and placebo (3 X daily) on gastric juice secretion, acidity, prostanoid concentration (PGE2, PGF2 alpha and TXB2) and excretion of the major urinary metabolite of PGF (PGF-MUM) were investigated in a single-blind cross-over study in nine healthy volunteers after 3-day treatment periods separated by one-week washout periods between treatments. Indometacin proved to be a classical cyclooxygenase inhibitor (strong inhibition of PGE2 and TXB2 before and after pentagastrin stimulation and of PGF-MUM) while carprofen was an atypical inhibitor (weak inhibition of PGE2 before pentagastrin stimulation and no inhibition after, strong inhibition of TXB2 but without influence on PGF-MUM). The weak inhibition of PGE2-biosynthesis by carprofen might be related to its low incidence of gastric side effects.