Jane Bevan

Differential inhibition by low-dose aspirin of human venous prostacyclin synthesis and platelet thromboxane synthesis.

The capacity of venous tissue for prostacyclin synthesis was determined in 68 patients undergoing surgery for removal of varicose veins. A single dose of aspirin (81 mg or 300 mg) taken 14 h preoperatively strongly inhibited its synthesis, and the effect of 300 mg was still evident 48 h after ingestion. A single dose of 40 mg aspirin taken 14 h preoperatively had no effect on prostacyclin synthesis. The capacity of blood platelets to synthesise thromboxane (measured as malondialdehyde) was determined in volunteers before and at various times after ingestion of 300 mg or 40 mg aspirin. Both doses had an inhibitory effect that lasted for at least 96 h. The length of time for which the amount of thromboxane synthesised was insufficient to support platelet aggregation and the platelet release reaction depended on both the donor and the dose of aspirin. If prostacyclin and thromboxane are important in the pathogenesis of thrombosis, then doses of aspirin much lower than those used previously should be tested. The long-lasting effect of 300 mg aspirin on both venous tissue and platelets indicates that this dose is unlikely to produce a favourable prostacyclin/thromboxane balance.

Effects of a selective inhibitor of thromboxane synthetase on human blood platelet behaviour.

Abstract The selective thromboxane synthetase inhibitor UK-34787 always inhibited thromboxane and malondialdehyde generation in intact platelets but had diverse effects on platelet behaviour. At concentrations similar to those required to inhibit thromboxane synthesis, UK-34787 inhibited arachidonate-induced aggregation and release reaction in platelet rich plasma from some, but not all, individuals. On this basis, individuals were designated “responders” or “non-responders”. Low concentrations of UK-34787 inhibited platelet responses to collagen but only a high concentration had any effect on platelet responses to adrenaline or adenosine diphosphate.

A regimen for low-dose aspirin?

The effects of different regimens of 40 mg aspirin on platelet thromboxane A2 synthesis and vascular prostacyclin synthesis were determined in patients who were undergoing elective surgery for removal of varicose veins. Aspirin 40 mg taken at intervals of 48 hours consistently reduced platelet thromboxane A2 synthesis to a level at which it failed to support platelet aggregation and the associated release reaction. This effect lasted for at least 36 hours. In contrast, aspirin 40 mg every 72 hours did not have the same consistent effect. Both dose regimens led to a reduction in vascular prostacyclin synthesis 12 hours after the last dose, but 36 or 72 hours after the last dose prostacyclin synthesis was not reduced; thus the inhibition of prostacyclin synthesis was short lived. If the balance between platelet thromboxane A2 and vascular prostacyclin synthesis is important in thrombosis 40 mg aspirin every 48 hours may have the maximum antithrombotic effect.

Verapamil is a potent inhibitor of 5-HT-induced platelet aggregation.

We have studied the effects of verapamil, diltiazem and amlodipine on 5-HT-induced platelet aggregation and compared the results with those obtained for other platelet aggregating agents. Experiments were carried out using both human whole blood and platelet-rich plasma (PRP). Verapamil (but not diltiazem or amlodipine) inhibited 5-HT-induced platelet aggregation at much lower concentrations (IC50 = about 1 microM) than were required for inhibition of aggregation induced by other aggregating agents. Like some other selective inhibitors of 5-HT-induced platelet aggregation, it was not possible to completely overcome the inhibition by increasing the concentration of 5-HT. The antiaggregatory effects of verapamil were similar, but not identical, in whole blood and PRP. These results show that the Ca2+ channel blocker verapamil has some selectivity as an inhibitor of 5-HT-induced platelet aggregation and that this behaviour as a 5-HT antagonist should be taken into account when interpreting any therapeutic benefit ascribed to this drug.

Effects of combination of 5-hydroxytryptamine receptor antagonists on 5-HT-induced human platelet aggregation

Summary1.We have examined the effects of fourteen 5-HT-receptor antagonists on 5-HT-induced platelet aggregation in whole blood. Two different types of inhibitory profile were obtained. The inhibitory effects of seven of the antagonists (designated type 1) could be surmounted by increasing the concentration of 5-HT; the inhibitory effects of the other antagonists (type 2) were insurmountable by 5-HT.2.The effects of combinations of pairs of different antagonists were investigated. The inhibitory effects of pairs of type 1 antagonists and of pairs of type 2 antagonists were additive. However, a type 1 antagonist interfered with the inhibitory effects of a type 2 antagonist.3.The two types of antagonist differed in the rate at which they inhibited 5-HT-induced aggrogation, a type 2 antagonist exerting its effect more slowly than a type 1 antagonist.4.Two possible explanations of these results are considered. It is possible that there are two different types of receptors on the surface of platelets, one causing stimulation and the other causing allosteric inhibition of platelet aggregation. Alternatively, the results may stem from different rates of association and dissociation of the agents at a single 5-HT receptor.