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.

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PubMedDate not supplied

Mg(2+)-induced vasodilation in human forearm vasculature is inhibited by N(G)-monomethyl-L-arginine but not by indometacin.

We have investigated the mechanism of the vasodilator action of Mg(2+) in human forearm resistance vasculature. Venous occlusion plethysmography was used to measure vasodilator responses to Mg(2+) infused via the brachial artery in healthy men, and to determine effects on Mg(2+) responses of indometacin (an inhibitor of cyclo-oxygenase) and of N(G)-monomethyl-L-arginine (L-NMMA, an inhibitor of the L-arginine/nitric oxide, L-arg/NO, pathway). Magnesium sulphate infusion (0.05, 0.1, 0.2 mmol x min(-1)) increased plasma Mg(2+) concentration to 1.57+/-0.16 mmol x l(-1) in venous blood from the infused arm at the highest dose. There was a dose-related increase in forearm blood flow in the infused arm to a maximum of 6.37+/-1.37 ml x min(-1) x dl forearm(-1) at the highest dose corresponding to an increase of 159+/-25% in blood flow relative to the non-infused arm. There was no tachyphylaxis during a second infusion following a 21-min recovery period. Indometacin had no effect on vasodilator responses to Mg(2+), whereas L-NMMA inhibited Mg(2+) responses (area under the dose-response curve) by 43+/-6% (p = 0.0003 by repeated-measures ANOVA). Therefore the L-arg/NO pathway is responsible, in part, for the vasodilator action of Mg(2+) in human forearm resistance vasculature.

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