title: S1P1 receptor modulation preserves vascular function in mesenteric and coronary arteries after CPB in the rat independent of depletion of lymphocytes.
abstract: BACKGROUND
  Cardiopulmonary 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.
  
  
  METHODS
  Experiments 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).
  
  
  RESULTS
  Contractile 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.
  
  
  CONCLUSIONS
  Pretreatment 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.
authors.affiliation: Department of Anesthesiology, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Iryna V
authors.initials: IV
authors.lastname: Samarska
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Hjalmar R
authors.initials: HR
authors.lastname: Bouma
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Buikema
authors.affiliation: Department of Anesthesiology, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Hubert E
authors.initials: HE
authors.lastname: Mungroop
authors.affiliation: Department of Anesthesiology, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Houwertjes
authors.affiliation: Department of Anesthesiology, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Absalom
authors.affiliation: Department of Anesthesiology, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Anne H
authors.initials: AH
authors.lastname: Epema
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Henning
mesh_terms: D000818:Animals; D001784:Blood Gas Analysis; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D002452:Cell Count; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology*; D000068876:Fingolimod Hydrochloride; D005500:Follow-Up Studies; D015850:Interleukin-6 / Q000097:blood; D008214:Lymphocytes / Q000166:cytology* / Q000187:drug effects; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects / Q000502:physiology*; D010069:Oxadiazoles / Q000494:pharmacology; D011409:Propylene Glycols / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D049349:Receptors, Lysosphingolipid / Q000819:agonists / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D015850:Interleukin-6; D010069:Oxadiazoles; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; C503964:SEW2871; D013876:Thiophenes; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine