Grodzińska L

Corticosteroids inhibit prostaglandin release from perfused mesenteric blood vessels of rabbit and from perfused lungs of sensitized guinea pig

Infusion of norephinephrine (NE) (1 - 3 mug/ml/min) into the isolated mesenteric vascular preparation of rabbit resulted in a rise in perfusion pressure, which was associated with the release of prostaglandin E-like substance (PGE) at a concentration of 2.81 +/- 0.65 ng/ml in terms of PGE2. Indomethacin (3 mug/ml) abolished the NE-induced release of PGE. Arachidonic acid (0.2 mug/ml) in the presence of indomethacin did not restore the NE-induced release of PGE. Hydrocortisone (10 - 30 mug/ml) and dexamethasone (2 - 5 mug/ml) also inhibited the NE-induced release of PGE. The inhibitory action of both corticosteroids was abolished by arachidonic acid (0.2 mug/ml). Antigen-induced release of a prostaglandin-like substance (PGs) (43.1 +/- 3.8 ng/ml in terms of PGE2 and a rabbit aorta contracting substance (RCS) from perfused lungs of sensitized guinea pigs was completely abolished by indomethacin (5 mug/ml) or by hydrocortisone (100 mug/ml). Indomethacin, however, increased histamine release up to 280% of the control level, which was 470 +/- 54 ng/ml, while hydrocortisone diminished histamine release down to 30% of the control level. A superimposed infusion of arachidonic acid (1 mug/ml) into the pulmonary artery reversed the hydrocortisone-induced blockade of the release of RCS and PGs. It may be concluded that corticosteroids neither inhibit prostaglandin synthetase nor influence prostaglandin transport through the membranes but they do impair the availability of the substrate for the enzyme.

Stimulation of coronary vascular prostacyclin and inhibition of human platelet thromboxane A2 after low-dose nitroglycerin

Abstract Although glyceryl trinitrate (GTN) is an efficient agent in the treatment of angina pectoris, the underlying mechanism of action is poorly understood. We report here, that GTN at nanomolar concentrations stimulates the PGI2-formation of coronary vessels and by this mechanism inhibits thromboxane biosynthesis of human platelets. Bovine coronary arteries were incubated in Krebs-Henseleit buffer and exhibited a time-dependent PGI2-release, amounting to 25 ± 4 pmoles/100 mm2 surface within 20 min. In presence of GTN (1.3 and 13 nM) this basal release of PGI2 was significantly enhanced to 42 ± 7 and 51 ± 8 pmoles/100 mm2, respectively (n = 12, P

Platelet aggregability, thromboxane A2 and malonaldehyde formation following administration of aspirin to man.

Abstract Ingestion of aspirin at a single dose of 600 mg blocked arachidonic acid /AA/ induced platelet aggregation, thromboxane A 2 /TXA 2 / generation and malonaldehyde /MDA/ formation in platelet-rich plasma /PRP/ of 10 subjects. The ability of PRP to produce TXA 2 was abolished completely for 2–3 days. It reappeared thereafter, mounting sharply to the initial values within 8–13 days following removal from aspirin. The time of recovery of AA-induced platelet aggregability to the starting values corresponded well with that of TXA 2 , while blockade of MDA generation by aspirin appeared to be of somewhat shorter duration than that of TXA 2 . We conclude that: 1/ Measurements of platelet life-span by non-radioisotope method, using aspirin is likely to encircle the measurement of megakaryocyte function; 2/ In clinical trials of secondary prevention of myocardial infarction 600 mg aspirin given once every three to four days might well be a sufficient dose.

Platelet aggregation and thromboxane A2 formation in cat platelet rich plasma.

Summary Platelet aggregation in cat platelet rich plasma (PRP) was induced by the threshold concentrations of adenosine diphosphate (ADP 0.5–2.0 μM), collagen (1.0–5.0 μg/ml), arachidonic acid (/AA/50–150 μM) and thrombin (0.2–0.6 units/ml). Aggregation induced by the first three agents was associated with the release of thromboxane A 2 (TXA 2 ). TXA 2 was bioassayed on a strip of rabbit mesenteric artery against 11,9-epoxymethano analog of PGH 2 (EMA). The maximal TXA 2 synthetizing capacity of cat PRP was 2000–3000 ngEq EMA/ml as measured during the AA-induced (600–800 μM) platelet aggregation. Collagen-induced (10–50μg/ml) platelet aggregation was accompanied by the release of TXA 2 in an amount of 490±40 ngEq EMA/ml PRP. When PRP was aggregated by the threshold concentrations of AA or collagen then the amounts of the detected TXA 2 ranged from 100–250 ngEq EMA/ml. The second phase of ADP-induced (1–5 μM) platelet aggregation produced a short-lasting peak of the TXA 2 release in PRP (maximal rise up to 250 ngEq EMA/ml). AA-induced, collagen-induced and the second phase of ADP-induced platelet aggregation as well as the generation of TXA 2 by PRP, all of them were suppressed by the TXA 2 synthetase inhibitor — nictindole (10 nM-3 μM). It is concluded that in platelet aggregation induced by AA, collagen and ADP TXA 2 plays an important role.

Prostacyclin and blood glucose levels in humans and rabbits

In patients with peripheral vascular disease and in healthy rabbits, infusion of PGI2 but not of 6-keto PGF1 alpha induced a rise in blood glucose level and a pathological deviation in glucose tolerance test. In experiments in vitro, the increased concentrations of glucose produced dose-dependent inhibition of PGI2 release from isolated rat aortic rings. The link between PGI2 and carbohydrate metabolism is discussed.

Angiotensin-induced release of prostacyclin from perfused organs

Summary Angiotensin I, angiotensin II and bradykinin induce the release of a PGI 2 -like substance from perfused guinea pig lungs and rabbit mesenteric artery preparation. The PGI 2 -like releasing activity of angiotensin II is blocked by saralasin. Angiotensin I is ineffective in releasing of a PGI 2 -like substance when its conversion to angiotensinII is inhibited by captopril. It is concluded that angiotensin exerts its effect on the arachidonic acid cascade through specific membrane receptors.

Generation of Prostaglandin and Thromboxane-Like Substances by Large Airways and Lung Parenchyma

Anggard and Samuelsson (1965) were the first researchers to study the biosynthesis of prostaglandins in lungs. They found that the low speed supernatant (900 × g) of a homogenate of guinea pig lungs incubated with arachidonic acid converted 10% of the substrate to more polar products than arachidonic acid. These products were identified as PGF2α, PGE2 and their metabolites. Guinea pig lung homogenates were used by Vane (1971) in his work that lead to the discovery of the anti-prosta-glandin synthetase activity of aspirin like drugs. In rat lung homogenates dihomo-γ-linolenic acid is mainly converted to PGD1, similarily as prostaglandin endoper-oxides PGH1 and PGH2 are chiefly metabolized to PGD1 and PGD2, respectively (Nugteren and Hazelhof, 1973). Further studies on metabolism of radioactive arachidonic acid by whole homogenates of guinea pig lungs brought to unexpected results (Hamberg and Samuelsson, 1974). The formation of PGF2 and PGE2, both in 2–3% yield was confirmed.

Effect of prostacyclin (PGI2) on platelets and fibrinolytic activity in patients with arteriosclerosis obliterans

Summary Sixteen patients with arteriosclerosis obliterans were treated intravenously with PGI 2 at a dose of 5 ng/kg/min for a period of 72 hours. Three hours from the beginning of PGI 2 infusion a non-significant decrease in platelet susceptibility to ADP, collagen and a suppression of TXA 2 formation in collagen treated PRP were observed. However, continuation of the therapy was associated with an increased sensitivity of platelets to pro-aggregatory agents and an increased generation of TXA 2 by PRP. Three hours from the beginning of the infusion of PGI 2 thrombin time and recalcification plasma clotting time were significantly shortened while fibrinolytic activity as measured by euglobulin clot lysis time was doubled. Taking into account the above effects of PGI 2 it is suggested that for treatment of thromboembolic disorders a period of three hours of PGI 2 infusion or a shorter one would be more effective than 72 hours of PGI 2 therapy.

Hydrocortisone and the release of prostaglandins from spleen

An infusion of noradrenaline (1 mug/ml/min) released a PGE-like substance (PGEs) from superfused splenic strips of rabbits and from perfused cat spleen. The release of PGEs from rabbit splenic strips was not inhibited by the treatment of strips with hydrocortisone (40-150 mug/ml), but it was completely abolished in strips obtained from animals pretreated with hydrocortisone (1 mg/kg). The release of PGEs from the perfused cat spleen was reduced by hydrocortisone and abolished by indomethacin. It is concluded that the route of administration of hydrocortisone is essential for an appearance of its inhibitory effect on the PG release.

Effect of corticosteroids on the release of histamine and prostaglandins from fragments of mesentery of immunized guinea pigs

Summary When challenged with antigen fragments of mesentery of immunized guinea pigs released histamine and a prostaglandin-like substance (PGs). The release of both mediators was inhibited by hydrocortisone hemisuccinate (1.0–30.0 μg/ml) and dexamethasone (10.0 μg/ml). Indomethacin (10.0 μg/ml) and hydrocortisone hemisuccinate at low concentrations (0.05–0.6 μg/ml) suppressed the release of PGs, while the release of histamine was stimulated. It is suggested that glucocorticosteroids exert these effects due to their interaction with biomembranes.