Indeed, hypo reactivity of VSM to adrenomimetics may depend on changes in the endothelium, as found in septic shock. Possibly, S1P1 agonist thus improve postoperative vascular contractile reactivity via modulation of this endothelium-dependent mechanisms. CPB was priory reported to cause a GSK J1 pronounced vascular dysfunction. In several rat models, CPB induced endothelial dysfunction, mainly after recovery. However, in our study the endothelium-dependent relaxation to ACh did not differ between Sham and CPB rats and was comparable to that in untreated Controls, demonstrating that endothelial function was intact at 1 day post-CPB. The lack of the endothelial vascular dysfunction in our study may be explained by differences between VU 0364439 models and experimental protocols. The model we employed is a modification of the previously widely published model. Our model differs on three points: miniaturization of the extracorporeal circuit to 15 ml avoids both blood transfusion and excessive hemodilution. Moreover, our model employs arterial inflow via the left common carotid artery to the aortic arch instead of inflow via the tail artery. All these factors may influence CPB-mediated endothelial dysfunction. In addition, differences with previously employed models regarding duration of the extracorporeal circulation and the postoperative recovery period may influence vascular reactivity. However, similar to the clinical setting, CPB, but not Sham, featured the activation of a systemic inflammatory response, demonstrating the fitness of our model to preclinically evaluate the potential of experimental therapeutic interventions. Despite the lack of the endothelial dysfunction, FTY720 and SEW2871 both enhanced total relaxation to ACh in all groups, although augmentation of the endothelium-dependent relaxation was most pronounced in CPB. Most likely, in coronary artery, the enhanced relaxation to FTY720 and SEW2871 is caused by activation of S1P1 and/or S1P3 receptors on endothelial cells, which evoke the release of NO through the activation of eNOS.