Inhibitors of platelet signal transduction as anti-aggregatory drugs

Abstract

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 vivo these precursors may be metabolised to prostacyclin in the endothelium and consequently provide additional platelet anti-aggregatory activity. A rather new target for 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.

Platelet adhesion signalling and the regulation of thrombus formation

“…The roles of nitric oxide (NO) and prostacyclin (PGI2) are well established in the inhibition of platelet function (Geiger, 2001;Radomski et al, 1987). However, platelet activation can also be inhibited by signalling through the adhesion molecule PECAM-1 (also known as CD31) (Cicmil et al, 2002;Jones et al, 2001;Patil et al, 2001).…”

Time-resolved in silico modeling of fine-tuned cAMP signaling in platelets: feedback loops, titrated phosphorylations and pharmacological modulation

“…The complex regulation of this pathway includes endothelium released factors activating platelet nucleotide cyclases and in consequence cyclic nucleotide-dependent protein kinases that in turn phosphorylate major components of the platelet activation pathways thus preventing platelet aggregation [1]. Platelet phosphodiesterases (PDEs) counterbalance the action of nucleotide cyclases [2-5]. Regulators of cAMP levels are of strong pharmacological interest and have clinical and therapeutic implications [4].…”

Novel epinephrine and cyclic AMP-mediated activation of BCAM/Lu-dependent sickle (SS) RBC adhesion

“…The downstream effects of cAMP are primarily attributed to cAMP-dependent protein kinase A (PKA), the most well-studied downstream effector of cAMP. 10 This pathway is important in down-regulating the adhesion of other hematopoietic cells, such as the rapid cAMP-and PKA-dependent reduction in platelet adhesiveness, [11][12][13][14][15][16] and a similar, albeit more gradual, reduction in leukocyte adhesiveness mediated by this pathway. 17,18 In contrast, more limited reports describe a gradual increase in the adhesion of leukocytes to various substrates, 19 as well as the adhesion of T lymphocytes to laminin, 20 in response to cAMP-and PKA-mediated signaling pathways.…”