title: Effects of selective endothelin (ET)-A receptor antagonist versus dual ET-A/B receptor antagonist on hearts of streptozotocin-treated diabetic rats.
abstract: OBJECTIVE
  The aim was to study the differences in the effectiveness of two types of endothelin (ET) receptor antagonists (selective ET-A or dual ET-A/B antagonists) on the hearts of streptozotocin (STZ)-induced diabetic rats (type I diabetes) at functional and biochemical/molecular levels.
  
  
  METHODS
  Citrate saline (vehicle) or STZ was injected into rats. The ET-A/B dual receptor antagonist (SB209670, 1mg/kg/day) and the ET-A receptor antagonist (TA-0201, 1mg/kg/day) were then administered to these rats. One week after injection, the animals were separated into those receiving SB209670, TA-0201 or vehicle by 4-week osmotic mini-pump.
  
  
  RESULTS
  The VEGF level and percent fractional shortening in the diabetic heart were significantly decreased compared to the non-diabetic heart, whereas SB209670 and TA-0201 treatments greatly and comparably prevented this decrease. SB209670 treatment was more effective in reversing decreased expressions of KDR and phosphorylated AKT, downstream of VEGF angiogenic signaling, than TA-0201 treatment. The eNOS levels in hearts were significantly higher in diabetic rats than in healthy rats, and this increase was significantly reduced by TA-0210 but not by SB209670 treatment.
  
  
  CONCLUSIONS
  Improvement of KDR mRNA and pAKT levels by SB209670 but not TA-0201 suggests that dual ET-A/-B blockade may be effective in improving intracellular systems of these components in the diabetic rat heart. However, the present study also showed that TA-0201 or SB209670 improved percent fractional shortening and VEGF levels of the diabetic hearts to a similar extent, suggesting that ET-A blockade and dual ET-A/-B blockade are similarly effective in improving cardiac dysfunction in the diabetic rats.
authors: Center for Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Japan; Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors: Yumi
authors: Y
authors: Miyauchi
authors: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors: Subrina
authors: S
authors: Jesmin
authors: Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors: Satoshi
authors: S
authors: Sakai
authors: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors: Junko
authors: J
authors: Kamiyama
authors: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors: Nobutake
authors: N
authors: Shimojo
authors: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors: Arifur
authors: A
authors: Rahman
authors: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors: Majedul
authors: M
authors: Islam
authors: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors: Sohel
authors: S
authors: Zaedi
authors: Center for Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Japan.
authors: Seiji
authors: S
authors: Maeda
authors: Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors: Hidekazu
authors: H
authors: Maruyama
authors: Department of Emergency and Critical Care Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors: Taro
authors: T
authors: Mizutani
authors: Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors: Satoshi
authors: S
authors: Homma
authors: Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
authors: Kazutaka
authors: K
authors: Aonuma
authors: Center for Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Japan; Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. Electronic address: t-miyauc@md.tsukuba.ac.jp.
authors: Takashi
authors: T
authors: Miyauchi
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004452:Echocardiography; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006352:Heart Ventricles / Q000737:chemistry; D007189:Indans / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000032:analysis; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D007189:Indans; D007328:Insulin; D011743:Pyrimidines; D013449:Sulfonamides; C113972:T 0201; D042461:Vascular Endothelial Growth Factor A; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-; D052250:Nitric Oxide Synthase Type III; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Diabetic heart; Endothelin receptor antagonist; KDR; VEGF signaling; pAKT