title: Late dual endothelin receptor blockade with bosentan restores impaired cerebrovascular function in diabetes.
abstract: OBJECTIVE
  Up-regulation of the endothelin (ET) system in type-2 diabetes increases contraction and decreases relaxation in basilar artery. We showed that 1) ET-receptor antagonism prevents diabetes-mediated cerebrovascular dysfunction; and 2) glycemic control prevents activation of the ET-system in diabetes. Here, our goal is to determine whether and to what extent glycemic control or ET-receptor antagonism reverses established cerebrovascular dysfunction in diabetes.
  
  
  METHODS
  Non-obese type-2 diabetic Goto-Kakizaki rats were administered either vehicle, metformin (300 mg/kg/day) or dual ET-receptor antagonist bosentan (100mg/kg) for 4-weeks starting at 18-weeks after established cerebrovascular dysfunction (n=5-6/group). Control group included vehicle-treated aged-matched Wistar rats. Blood glucose and pressure were monitored weekly. At termination, basilar arteries were collected and cumulative dose-response curves to ET-1 (0.1-500 nM), 5-HT (1-1000 nM) and acetylcholine (Ach, 0.1 nM-5 μM) were studied by wire myograph. Middle cerebral artery (MCA) myogenic reactivity and tone were measured using pressurized arteriograph.
  
  
  RESULTS
  There was no difference in ET-1 and 5-HT-mediated constrictions. Endothelium-dependent relaxation was impaired in diabetes. Bosentan improved sensitivity to Ach as well as the maximum relaxation. Myogenic-tone is decreased over the course of the disease. Both treatments improved the ability of MCAs to develop tone at 80 mm Hg and only bosentan improved the tone at higher pressures.
  
  
  CONCLUSIONS
  These results suggest that contractile response is not affected by glycemic control or ET-receptor antagonism. Meanwhile, dual ET-receptor blockade is effective in partially improving endothelium-dependent relaxation and myogenic response in a blood pressure-independent manner even after established cerebrovascular dysfunction and offers therapeutic potential.
authors.affiliation: Charlie Norwood Veterans Administration Medical Center, University of Georgia College of Pharmacy, USA; Department of Physiology, Georgia Regents University, Augusta, GA, USA.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Abdelsaid
authors.affiliation: Charlie Norwood Veterans Administration Medical Center, University of Georgia College of Pharmacy, USA; Department of Physiology, Georgia Regents University, Augusta, GA, USA.
authors.forename: Handong
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Physiology, Georgia Regents University, Augusta, GA, USA.
authors.forename: Maha
authors.initials: M
authors.lastname: Coucha
authors.affiliation: Charlie Norwood Veterans Administration Medical Center, University of Georgia College of Pharmacy, USA; Center for Pharmacy and Experimental Therapeutics, University of Georgia College of Pharmacy, USA; Department of Physiology, Georgia Regents University, Augusta, GA, USA. Electronic address: aergul@gru.edu.
authors.forename: Adviye
authors.initials: A
authors.lastname: Ergul
mesh_terms: D000818:Animals; D000077300:Bosentan; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology*; D065131:Endothelin B Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D066298:In Vitro Techniques; D055442:Metabolome / Q000187:drug effects; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use; D020768:Middle Cerebral Artery / Q000187:drug effects / Q000503:physiopathology; D024510:Muscle Development / Q000187:drug effects; D017208:Rats, Wistar; D044022:Receptor, Endothelin A / Q000378:metabolism*; D044023:Receptor, Endothelin B / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D065131:Endothelin B Receptor Antagonists; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D013449:Sulfonamides; D008687:Metformin; D000077300:Bosentan
keywords: Basilar artery; Endothelial function; Endothelin; Middle cerebral artery; Myogenic tone