Extracellular NAADP affords cardioprotection against ischemia and reperfusion injury and involves the P2Y11-like receptor

•Extracellular NAADP promotes cardiac preconditioning via the P2Y11-like receptors.•P2Y11-like receptors are able to induce prosurvival kinase activation in rat cardiomyocyte.•NAADP is released during ischemia suggesting a paracrine survival role. Extracellular nucleotides may play important regulatory roles within the cardiovascular system and notably in cardioprotection. We aimed to look for a possible pharmacological preconditioning effect of extracellular NAADP ([NAADP]e) against ischemia/reperfusion injury. [NAADP]e has been recently reported to be a full agonist of the P2Y11 receptor. Therefore, we characterized the involvement of the P2Y11-like receptor in mediating ischemic/reperfusion tolerance induced by [NAADP]e. The cardioprotective effects of [NAADP]e were evaluated in a model of ischemia/reperfusion carried out on Langendorff perfused rat hearts. This model was also instrumented with a microdialysis probe. Furthermore, using isolated cardiomyocytes, we assessed cAMP, inositol phosphate accumulation and prosurvival protein kinases activation induced by [NAADP]e pretreatement. Pretreatment with 1μM [NAADP]e induced cardioprotective effects with regards to functional recovery, necrosis and arrhythmogenesis (p