S1P1 Receptor Modulation Preserves Vascular Function in Mesenteric and Coronary Arteries after CPB in the Rat Independent of Depletion of Lymphocytes

Abstract

BackgroundCardiopulmonary bypass (CPB) may induce systemic inflammation and vascular dysfunction. Sphingosine 1-phosphate (S1P) modulates various vascular and immune responses. Here we explored whether agonists of the S1P receptors, FTY720 and SEW2871 improve vascular reactivity after CPB in the rat.MethodsExperiments were done in male Wistar rats (total n = 127). Anesthesia was induced by isoflurane (2.5–3%) and maintained by fentanyl and midazolam during CPB. After catheterization of the left femoral artery, carotid artery and the right atrium, normothermic extracorporeal circulation was instituted for 60 minutes. In the first part of the study animals were euthanized after either 1 hour, 1 day, 2 or 5 days of the recovery period. In second part of the study animals were euthanized after 1 day of postoperative period. We evaluated the contractile response to phenylephrine (mesenteric arteries) or to serotonin (coronary artery) and vasodilatory response to acethylcholine (both arteries).ResultsContractile responses to phenylephrine were reduced at 1 day recovery after CPB and Sham as compared to healthy control animals (Emax, mN: 7.9±1.9, 6.5±1.5, and 11.3±1.3, respectively). Mainly FTY720, but not SEW2871, caused lymphopenia in both Sham and CPB groups. In coronary and mesenteric arteries, both FTY720 and SEW2871 normalized serotonin and phenylephrine-mediated vascular reactivity after CPB (p<0.05) and FTY720 increased relaxation to acetylcholine as compared with untreated rats that underwent CPB.ConclusionPretreatment with FTY720 or SEW2871 preserves vascular function in mesenteric and coronary artery after CPB. Therefore, pharmacological activation of S1P1 receptors may provide a promising therapeutic intervention to prevent CPB-related vascular dysfunction in patients.

Sinusoidal protection by sphingosine-1-phosphate receptor 1 agonist in liver ischemia-reperfusion injury

“…9,10 Several studies have reported that the role of S1P/S1PR1 maintained vascular tone by eNOS activation. Samarska et al 13 have reported that the activation of S1PR1 promotes vasorelaxation responses in vessels, such as coronary artery and mesenteric artery, because of vascular NO synthesis derived from eNOS activation. Zheng et al 28 have reported that S1P, which is one of the bioactive lipids of S1PR1, protected SECs from ethanol-induced injury in primary cultures and isolated perfused rat livers, and that the protective effect of S1P was mediated by the activation of eNOS.…”

“…7 From a pharmacological point of view, S1PR1-selective agonists could serve as novel therapeutics. The development of the highly selective S1PR1 agonist, SEW2871, which was originally identified in 2004, 8 has enabled examination of S1PR1-mediated cell responses, using animal models such as renal IRI, 9,10 myocardial IRI, 11 heart transplant, 12 cardiopulmonary bypass, 13 and acute pancreatitis. 14 Using a renal IRI mouse model, Lien et al 9 revealed that SEW2871 administration significantly attenuated renal damage by reducing neutrophil/macrophage infiltration and cytokine production in the kidney.…”

Sphingosine-1-Phosphate Receptor-1 Selective Agonist Enhances Collateral Growth and Protects against Subsequent Stroke

“…Therefore, the Akt/eNOS vasodilation pathway may be more important than cell proliferation pathway in S1PR1 selective agonist–induced collateral growth of the leptomeningeal arteries. In a previous study in a cardiopulmonary bypass rat model, in which shear stress is activated by the change in arterial pressure [ 24 ], SEW2871 enhanced coronary artery dilation by activating S1PR1 on endothelial cells, which release NO through activation of eNOS [ 25 ]. However, SEW2871 has no significant vasodilation effect on isolated rat arteries in the absence of shear stress [ 23 ].…”

The Correlation Between the Parameters of Peripheral Blood and Oxygen Absorption After Revascularization for Coronary Artery Disease

“…В то же время для больных, оперированных в условиях ИК или параллельного ИК в раннем послеоперационном периоде, характерно ишемическое/реперфузионное повреждение и значительная выраженность системного воспалительного ответа с нарушением баланса между про-и противовоспалительными медиаторами при сравнении с больными, оперированными на работающем сердце [19]. Системный воспалительный ответ приводит к прогрессированию эндотелиальной дисфункции со вторичным отёком и/или гипоперфузией тканей [18]. Нейтрофилы, являющиеся основной популяцией лейкоцитов, в наибольшей степени несут ответственность за развитие послеоперационных осложнений.…”