Anales RANF

S2-05 DRUG-INDUCED CARDIOVASCULAR TOXICITY MEDIATED BY P2X7 RECEPTORS: THE EXAMPLE OF ABACAVIR A. Álvarez 1,2 , M.A. Blanch-Ruiz1, A. Sánchez-López 1 , R. Ortega-Luna1, M.A. Martínez-Cuesta 1,2 , J.V. Esplugues 1,2,3 1 . University of Valencia, Valencia, Spain; 2. Center for Biomedical Research Network: Digestive and Liver Diseases (CIBERehd); 3 . FISABIO, Valencia, Spain. Abacavir (ABC), a guanosine analogue belonging to the nucleoside reverse transcriptase inhibitor family, is one of the most widely employed antiretroviral drugs in HIV therapy. However, a long-lasting controversy surrounding its association with an increased cardiovascular risk has been fueled by discrepancies in published clinical data and, in particular, by the lack of a credible mechanism of action that could explain such detrimental actions. Recent experimental evidence with human samples and in animal models relates ABC with vascular inflammation, a leading contributor to the atherosclerotic plaque and thrombosis. It has been demonstrated that the drug induces an increase in leukocyte-endothelial cell interactions and interactions of platelets with different vascular and blood cells involved in the early phases of thrombi formation, such as endothelium and leukocytes. Moreover, ABC has been shown to promote the formation of arterial thrombi and the complete obstruction of blood flow in resistance vessels. Finally, research has shown that the in vitro and in vivo actions of the drug are blocked by pharmacological antagonists of P2X7 ATP receptors, and that such actions are absent in P2X7-deficient mice. Likewise, the thrombus formation induced by ABC in vivo is prevented by selective pharmacological blockade of these receptors and is absent in P2X7-deficient mice. It has been hypothesized that the structural analogy between ABC and endogenous purinergic mediators such as ADP and ATP endows the drug with the ability to interfere with the purinergic system and to induce a vascular inflammatory response, an effect involving the activation of P2X7 ATP receptors. It remains to be determined if such an effect is unique to ABC or common to other drugs.