Regulatory mechanisms of cAMP levels as a multiple target for antiplatelet activity and less bleeding risk.
Platelet activation is a critical component of atherothrombosis. The multiple pathways of platelet activation limit the effect of specific receptor/pathway inhibitors, resulting in limited clinical efficacy. Recent research has confirmed that combination therapy results in enhanced antithrombotic efficacy without increasing bleeding risk. In this way, the best-known inhibitor and turn off signaling in platelet activation is cAMP. In this article we discuss the mechanisms of regulation of intraplatelet cAMP levels, a) platelet-dependent pathway: Gi/Gs protein-coupled receptors, phosphodiesterase inhibition and activation of PPARs and b) platelet-independent pathway: inhibition of adenosine uptake by erythrocytes. With respect to the association between intraplatelet cAMP levels and bleeding risk it is possible to establish that compounds/drugs with pleitropic effect for increased intraplatelet cAMP level could have an antithrombotic activity with less risk of bleeding.
Department of Clinical Biochemistry and Immunohaematology, Faculty of Health Sciences, Interdisciplinary Excellence Research Program on Healthy Aging (PIEI-ES), Universidad de Talca, Talca, Chile; Centro de Estudios en Alimentos Procesados (CEAP), CONICYT-Regional, Gore Maule, R09I2001, Chile. Electronic address: edfuentes@utalca.cl.
Eduardo
E
Fuentes
Department of Clinical Biochemistry and Immunohaematology, Faculty of Health Sciences, Interdisciplinary Excellence Research Program on Healthy Aging (PIEI-ES), Universidad de Talca, Talca, Chile; Centro de Estudios en Alimentos Procesados (CEAP), CONICYT-Regional, Gore Maule, R09I2001, Chile. Electronic address: ipalomo@utalca.cl.
Iván
I
Palomo
D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism*; D006470:Hemorrhage / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D006801:Humans; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
D047492:Peroxisome Proliferator-Activated Receptors; D010975:Platelet Aggregation Inhibitors; D000242:Cyclic AMP
Antiplatelet; Bleeding risk; PPARs; Platelet; Thrombosis; cAMP