The present study, which utilizes the isolated guinea-pig heart model [10], aimed to investigate the role of cross-talk between the vascular O2− sources in acute ET-1 and AT-II signaling to mediate O2− production and endothelial dysfunction, and MAPKs phosphorylation (i.e., intraluminal and cytosolic manifestations of the oxidative stress, respectively). The gene discussed is EDN1; the disease is endothelial dysfunction.