Acetylsalicylic acid (aspirin) inhibits prostanoid synthesis by irreversible acetylation of fatty acid cyclooxygenase (EC 1.14.99.1). It thereby inhibits synthesis of pro-aggregatory thromboxane A2 (TXA2) by platelets and is widely used in the treatment and prophylaxis of vascular disease. Its efficacy, however, may be reduced since it also inhibits formation of prostacyclin (PGI2) which is a vasodilator and anti-aggregatory agent. There is uncertainty over the optimum dose regimen for aspirin since although it inhibits platelet thromboxane production for many days, the magnitude and duration of its effect on PGI2 production by vascular endothelium in vivo is unknown. Resting plasma concentrations of PGI2 (measured as the stable hydrolysis product 6-oxo-PGF1 alpha) are at or below the limit of sensitivity of the most sensitive assays and cannot therefore be used to demonstrate a reduction in production. Bradykinin stimulates PGI2 synthesis by cultured human vascular endothelial cells and we have shown that it stimulates PGI2 production by man in vivo. We report here that an oral dose of aspirin (600 mg) causes rapid and substantial inhibition of bradykinin-stimulated PGI2 production, but recovery occurs within 6 hours; this implies that endothelial PGI2 synthesis would be spared most of the time during dosing once daily with even this relatively large dose of aspirin.
1 Bradykinin, angiotensin II, arginine vasopressin (AVP) or des-amino-D-arginine vasopressin (DDAVP) were administered by intravenous infusion to 10 healthy men.2 The concentration of 6-oxo-prostaglandin Fic, (6-oxo-PGF,,), the stable hydrolysis product of prostacyclin (PGI2), was measured in plasma using gas chromatography/negative ion chemical ionisation mass spectrometry.3 Dose-related increases in plasma concentrations of 6-oxo-PGF,a occurred during administration of bradykinin (100-3200 ng kg -' min '). The concentrations of 6-oxo-PGF,. rose from baseline values in the range < 1.0-4.9 pg ml-' to 24.9-47.6 pg ml-' at maximum tolerated infusion rates.4 There were no changes in the concentrations of 6-oxo-PGFIr during administration of angiotensin II, AVP or DDAVP at infusion rates which caused haemodynamic changes.
1 Bradykinin was infused intravenously into conscious rabbits to determine its effect on the concentration of prostaglandins in plasma. 6-Oxo-prostaglandin (PG) F, the stable hydrolysis product of prostacyclin, and 13,14-dihydro-15-oxo-PGF.,, a metabolite derived from PGE2 and PGF2,,, were measured by gas chromatography-electron capture mass spectrometry. 2 Incremental infusions of bradykinin (0.4-3.2 Zg kg-' min-') increased plasma concentrations of both 6-oxo-PGF,, and 13,14-dihydro-15-oxo-PGF2,,.3 Aspirin (10mg kg-', i.v.) inhibited bradykinin-stimulated 6-oxo-PGF,a and 13, 14-dihydro-1 5-oxo-PGF2,, synthesis at 30 min and 6 h. At 24 h, the mean bradykinin-stimulated 13,14-dihydro-15-oxo-PGF2, concentration was 66% of its original value, whilst 6-oxo-PGF,, remained substantially inhibited. 4 The different rates ofrecovery of bradykinin-stimulated production ofthe two prostaglandins after inhibition by aspirin suggests that intravenous bradykinin stimulates prostacyclin and PGE2/PGF2., production in distinct cell populations which synthesize cyclo-oxygenase at different rates.
1 Bradykinin, prostaglandin E2 (PGE2), PGD2 and vehicle (saline) were each administered intravenously on separate occasions to 6 healthy men for a period of 60 min.2 13,14-Dihydro-I5-oxo-PGF2. was identified in plasma samples obtained during intravenous infusions of bradykinin and PGE2 but not during infusions of PGD2 or saline. 3 The structure of this metabolite was verified by comparison of three different derivatives with authentic standards, using gas chromatography/electron capture mass spectrometry.4 Bradykinin increased plasma concentrations of l3,14-dihydro-15-oxo-PGF2. from baseline values in the range < 5-10 pg ml-' to 28 -403 pg ml '. PGE2 increased plasma concentrations of 13,14-dihydro-1 5-oxo-PGF2, from baseline values in the range < 5-17 pg ml ' to 160-603 pg ml '. Neither PGD2 nor the vehicle affected 13,14-dihydro-I5-oxo-PGF2. concentrations. 5 We conclude that bradykinin-stimulated 13,14-dihydro-15-oxo-PGF2, may be derived from PGE2 or PGF2,. The possibility that these prostaglandins are synthesized by stimulation of microvascular endothelium during bradykinin infusion is discussed.
The object of this study was to investigate clinical conditions in which increased production of prostacyclin (PGI2) has been reported. 6-Oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha) is the stable hydrolysis product of PGI2 and was measured in plasma from patients undergoing hepatic or cardiac surgery and in unoperated patients with vascular and hepatic disease, using gas chromatography/mass spectrometry. Blood obtained simultaneously from portal and peripheral veins, during emergency surgery for bleeding oesophageal varices in six patients with cirrhosis of the liver, contained very high concentrations of 6-oxo-PGF1 alpha (range 99-11,485 pg/ml of plasma). 6-Oxo-PGF1 alpha was higher in portal than in peripheral blood in five out of six patients. Six unoperated patients with cirrhosis and oesophageal varices which were not bleeding all had normal peripheral plasma concentrations of 6-oxo-PGF1 alpha less than 2 pg/ml (normal up to 5 pg/ml). Seventeen patients with severe vascular disease had normal basal plasma 6-oxo-PGF1 alpha concentrations (less than 2 pg/ml). Eighteen subjects with atheromatous coronary artery disease underwent aorta-coronary artery grafting, and plasma concentrations of 6-oxo-PGF1 alpha were markedly elevated during surgery (range 55-1207 pg/ml). We conclude that surgery stimulates PGI2 production substantially, and argue that the function of PGI2 may be to limit intravascular extension of thrombus from sites of haemostasis. Inappropriate PGI2 synthesis may contribute to the massive haemorrhage characteristic of oesophageal variceal bleeding.
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