title: Inactivation of Endothelial Small/Intermediate Conductance of Calcium-Activated Potassium Channels Contributes to Coronary Arteriolar Dysfunction in Diabetic Patients.
abstract: BACKGROUND
  Diabetes is associated with coronary arteriolar endothelial dysfunction. We investigated the role of the small/intermediate (SK(Ca)/IK(Ca)) conductance of calcium-activated potassium channels in diabetes-related endothelial dysfunction.
  
  
  RESULTS
  Coronary arterioles (80 to 150 μm in diameter) were dissected from discarded right atrial tissues of diabetic (glycosylated hemoglobin = 9.6±0.25) and nondiabetic patients (glycosylated hemoglobin 5.4±0.12) during coronary artery bypass graft surgery (n=8/group). In-vitro relaxation response of precontracted arterioles was examined in the presence of the selective SK(Ca)/IK(Ca) activator NS309 and other vasodilatory agents. The channel density and membrane potential of diabetic and nondiabetic endothelial cells was measured by using the whole cell patch-clamp technique. The protein expression and distribution of the SK(Ca)/IK(Ca) in the human myocardium and coronary arterioles was examined by Western blotting and immunohistochemistry. Our results indicate that diabetes significantly reduced the coronary arteriolar response to the SK(Ca)/IK(Ca) activator NS309 compared to the respective responses of nondiabetic vessels (P<0.05 versus nondiabetes). The relaxation response of diabetic arterioles to NS309 was prevented by denudation of endothelium (P=0.001 versus endothelium-intact). Diabetes significantly decreased endothelial SK(Ca)/IK(Ca) currents and hyperpolarization induced by the SK(Ca)/IK(Ca) activator NS309 as compared with that of nondiabetics. There were no significant differences in the expression and distribution of SK(Ca)/IK(Ca) proteins in the coronary microvessels.
  
  
  CONCLUSIONS
  Diabetes is associated with inactivation of endothelial SK(Ca)/IK(Ca) channels, which may contribute to endothelial dysfunction in diabetic patients.
authors: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Providence, RI (Y.L., A.K.S., A.E., F.W.S., J.F.).
authors: Yuhong
authors: Y
authors: Liu
authors: Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, Providence, RI (A.X., S.D.).
authors: An
authors: A
authors: Xie
authors: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Providence, RI (Y.L., A.K.S., A.E., F.W.S., J.F.).
authors: Arun K
authors: AK
authors: Singh
authors: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Providence, RI (Y.L., A.K.S., A.E., F.W.S., J.F.).
authors: Afshin
authors: A
authors: Ehsan
authors: Department of Medicine, Providence VA Medical Center, Alpert Medical School of Brown University, Providence, RI (G.C.).
authors: Gaurav
authors: G
authors: Choudhary
authors: Division of Cardiology, Cardiovascular Research Center, Rhode Island Hospital, Providence, RI (A.X., S.D.).
authors: Samuel
authors: S
authors: Dudley
authors: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Providence, RI (Y.L., A.K.S., A.E., F.W.S., J.F.).
authors: Frank W
authors: FW
authors: Sellke
authors: Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Providence, RI (Y.L., A.K.S., A.E., F.W.S., J.F.).
authors: Jun
authors: J
authors: Feng
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001160:Arterioles / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000175:diagnosis / Q000378:metabolism* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000819:agonists / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials; D008875:Middle Aged; D015398:Signal Transduction; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000819:agonists / Q000378:metabolism*; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D006442:Glycated Hemoglobin; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D051640:Small-Conductance Calcium-Activated Potassium Channels; D014665:Vasodilator Agents; C517652:hemoglobin A1c protein, human
keywords: coronary microcirculation; coronary microvascular function; diabetes mellitus; potassium channels; vascular endothelial function