Inhibitors of platelet signal transduction as anti-aggregatory drugs

In the treatment and prevention of cardiovascular diseases, inhibition of platelet aggregation is of fundamental importance. Inhibition of platelet aggregation can be achieved by either inhibition of membrane receptors or by interception of signalling pathways. While receptor antagonism provides high specificity. the inhibition of platelet signal transduction is more effective. The effectiveness results from the inhibition of platelets. regardless of the cause of activation These common pathway inhibitors are either intercepting platelet activating mechanisms or amplifying the action of endogenous platelet inhibitors. The physiological anti-aggregants are the endothelial factors NO and prostacyclin, which elevate intracellular cGMP or cAMP content, respectively. By administration of NO-releasing agents. prostacyclin analogues or other cyclic nucleotide elevating drugs the: platelet anti-aggregatory action of endothelial factors can be effectively mimicked. Besides antiplatelet activity these drugs also act on vascular smooth muscle causing relaxation and therefore vasodilation, an additional beneficial effect. Inhibition of phosphodiesterases causes elevation of platelet cyclic nucleotide content and thus inhibits platelet aggregation and causes vasodilation. Another relevant target for anti-aggregatory treatment is the arachidonic acid metabolic pathway. This pathway can be intercepted by blockade of either cyclooxygenase-1 (COX-1) or thromboxane synthase. Inhibition of these enzymes may be further amplified by additional antagonism of the thromboxane receptor thus not only preventing formation of thromboxane but also activation of thromboxane receptor by thromboxane precursors. which were particularly effective in clinical trials. In vitro these precursors may be metabolised ro prostacyclin in the endothelium and consequently provide additional platelet anti-aggregatory activity. A rather nem; target fur platelet anti-aggregatory treatment is the ecto-nucleotidase CD-39 which limits the plasma level of nucleotides. While several of the novel anti-aggregatory drugs were disappointing in clinical studies combinations of drugs with different effector enzymes showed potent antithrombotic efficacy.