AbstractThe lysophospholipids sphingosine 1‐phosphate (S1P) and lysophosphosphatidic acid (LPA) reduce mortality in hypoxic cardiac myocytes. S1P is also cardioprotective in both mouse and rat models of cardiac ischemia/reperfusion (I/R) injury. Although these results are consistent with prior work in other cell types, it is not known what signaling events are critical to cardioprotection, particularly with respect to ceramide and the preservation of mitochondrial function, which is essential for cardiac cell survival. Neither receptor regulation nor signaling has been studied during I/R in the heart with or without the application of S1P or LPA. The role of sphingosine kinase in I/R and in ischemic preconditioning (IPC) has not been defined, nor has the fate or function of S1P generated by this enzyme, particularly during preconditioning or I/R, been elucidated. Whether S1P infused systemically in animal models of myocardial infarction in which survival is an end‐point will be hemodynamically tolerated has not been determined. If not, the substitution of agents such as the monosialoganglioside GM‐1, which activates sphingosine kinase, or the development of alternative ligands for S1P receptors will be necessary. © 2004 Wiley‐Liss, Inc.