Aspirin causes short-lived inhibition of bradykinin-stimulated prostacyclin production in man

Abstract

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.

Differential effect of aspirin on thromboxane and prostaglandin biosynthesis in man.

“…It has been variously suggested that lower doses of aspirin than those of proven efficacy could be either more or less effective than standard doses (see Ritter, 1988 for a review of these arguments). The present study emphasises the importance of dose interval rather than absolute dose (Moncada, 1982;Heavey et al, 1985), by demonstrating that it is possible to use a dose of aspirin (600 mg), that has proved effective in clinical trials, in such a way that thromboxane biosynthesis is profoundly and persistently inhibited but prostacyclin biosynthesis is unimpaired for much of the dose interval. In this context it is noteworthy that in a recent study of aspirin given on alternate days to apparently healthy American physicians, the rate of myocardial infarction was halved (The Steering Committee of the Physicians' Health Study Research Group, 1988), whereas a study in which aspirin was given more frequently (and in some instances in an enteric coated formulation) to British physicians, showed no effect on myocardial infarction rate (Peto et al, 1988 …”

“…Effects of bolus dose aspirin or salicylate on stimulated prostanoid biosynthesis The protocol for these studies was similar to that described previously (Heavey et al, 1985). Briefly, each subject was infused for 10 min with bradykinin ((Sigma Chemical Co., Poole, UK): O.8-1.2 ,ug kg-1 min-' intravenously as individually tolerated, with the same subject receiving the same dose on every occasion) before and 0.5, 1.5, 3 and 6 h after an intravenous bolus dose (600 mg) of sodium salicylate or aspirin (EgicJoulie).…”

“…synthesised by platelets (Hamberg et al, 1975) Inhibition of both anti-aggregatory and proCorrespondence: Professor J. M. Ritter, Department of Clinical Pharmacology, UMDS, Guy's Campus, London Bridge, London SE1 9RT aggregatory cyclo-oxygenase products gives rise to a situation which has been referred to as the 'aspirin dilemma' (Marcus, 1977). We have previously studied the effect of oral aspirin (600 mg) on bradykinin-stimulated PGI2 biosynthesis and concluded that in contrast to prolonged inhibition of platelet TXA2 biosynthesis, bradykinin-stimulated PGI2 biosynthesis recovers from inhibition within 6 h of aspirin administration (Heavey et al, 1985). The objectives of this present study were to investigate the mechanism underlying this rapid recovery and to determine the rate of recovery of basal (unstimulated) PGI2 and TXA2 synthesis after aspirin.…”

Vascular and neural mechanisms of ACh-mediated vasodilation in the forearm cutaneous microcirculation

“…Then, chewable ASA (Bayer, Morristown, NJ) in one of four doses (81, 648, 972, 1,944 mg) was given orally in random order. Thirty minutes after the administration of ASA, when the endothelium-derived prostacyclin is maximally inhibited (26), the response to dose-dependent application of ACh (1%) at the corresponding area of the opposite forearm was recorded. All tests were performed after an acclimatization period of at least 30 min.…”

The low‐chloride cough response is not inhibited by a single, high dose of aspirin.

“…We have chosen a high dose of aspirin, a potent inhibitor of cyclo-oxygenase, and have administered the drug in soluble form to improve bioavailability (Martindale, 1981). The 1 h gap between dosing and repeat cough challenge was sufficient to allow adequate absorption of the drug (Martindale, 1981) and ensured that repeat cough challenge was performed at the time of maximal cyclo-oxygenase inhibition (Heavey et al, 1985). Systemic administration of cyclo-oxygenase inhibitors to experimental animals also inhibits pulmonary prostanoid production of this time-point (Dworski et al, 1989;Snapper et al, 1983).…”