title: Decreased contractile response to endothelin-1 of peripheral microvasculature from diabetic patients.
abstract: BACKGROUND
  We compared the contractile responses to endothelin-1 (ET-1) with and without the inhibition of ET-A receptors and protein kinase C-alpha (PKC-α) in the human peripheral microvasculature of diabetic and case-matched, nondiabetic patients.
  
  
  METHODS
  Chest wall skeletal muscle was harvested from patients with and without diabetics undergoing cardiac surgery. Peripheral arterioles (90-180 μm in diameter) were dissected from the harvested tissue. Microvascular constriction was assessed by videomicroscopy in response to ET-1 with and without an endothelin-A (ET-A) receptor antagonist, an endothelin B (ET-B) antagonist, or a PKC-α inhibitor.
  
  
  RESULTS
  ET-1 induced a dose-dependent contractile response of skeletal muscle arterioles from diabetic and nondiabetic patients. The contractile response of diabetic arterioles from both prebypass and postbypass to ET-1 (10(-9) mol/L) was decreased compared with those of nondiabetic patients (P < .05). The contractile responses of microvessels of both diabetics and nondiabetics to ET-1 were inhibited in the presence of either ET-A receptor antagonist BQ123 (10(-7) mol/L) or the PKC-α inhibitor safingol (2 × 10(-5) mol/L, P < .05, respectively). In contrast, the ET-1-induced vasoconstriction was not affected by the administration of the ET-B receptor antagonist BQ788 (10(-7) mol/L). There were no differences in skeletal muscle levels of the ET-A and ET-B receptors between diabetic and nondiabetic groups.
  
  
  CONCLUSIONS
  Diabetic patients demonstrated a decreased contractile response to ET-1 in human peripheral microvasculature. The contractile response of diabetic vessels to ET-1 occurs via activation of ET-A receptors and PKC-α. These results provide novel mechanisms of ET-1-induced contraction in vasomotor dysfunction in patients with diabetes.
authors: Division of Cardiothoracic Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors: Jun
authors: J
authors: Feng
authors: Yuhong
authors: Y
authors: Liu
authors: Kamal R
authors: KR
authors: Khabbaz
authors: Robert
authors: R
authors: Hagberg
authors: Michael P
authors: MP
authors: Robich
authors: Richard T
authors: RT
authors: Clements
authors: Cesario
authors: C
authors: Bianchi
authors: Frank W
authors: FW
authors: Sellke
mesh_terms: D000368:Aged; D001160:Arterioles / Q000187:drug effects / Q000503:physiopathology*; D003920:Diabetes Mellitus / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology*; D005260:Female; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D051571:Protein Kinase C-alpha / Q000502:physiology; D044022:Receptor, Endothelin A / Q000502:physiology; D044023:Receptor, Endothelin B / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D019332:Endothelin-1; D017127:Glycation End Products, Advanced; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D051571:Protein Kinase C-alpha