title: Use of intermediate/small conductance calcium-activated potassium-channel activator for endothelial protection.
abstract: OBJECTIVE
  Endothelial dysfunction occurs in hypoxia-related states such as ischemic heart disease or heart surgery. Intermediate- and small-conductance calcium-activated potassium channels (IKCa and SKCa) are closely related to endothelium-dependent hyperpolarizing factor-mediated endothelial function. However, the status of these KCa under hypoxia is unknown. We investigated whether endothelial dysfunction under hypoxic state is related to the alterations of IKCa and SKCa and whether use of IKCa/SKCa activator may protect endothelium from hypoxia-reoxygenation injury.
  
  
  METHODS
  Isometric tension measurement, patch-clamp technique, intracellular membrane potential recording, and molecular methods were used to study porcine coronary arteries and endothelial cells.
  
  
  RESULTS
  Hypoxia-reoxygenation (60-30 minutes) decreased endothelium-dependent hyperpolarizing factor-mediated relaxation at normothermia in Krebs solution (43.3%±6.3% vs 82.3%±2.9%) and in St Thomas' Hospital cardioplegic solution (28.9%±1.8% vs 78.1%±3.0%) (P<.001) as well as at hypothermia in St Thomas' Hospital solution (43.1%±2.6%, P<.001). Hypoxia-reoxygenation markedly reduced endothelial IKCa (2.8±0.6 vs 6.9±0.6 pA/pF) and SKCa currents (1.5±0.3 vs 4.3±0.4 pA/pF) (P<.05) and downregulated endothelial IKCa expression. IKCa/SKCa activator 1-ethyl-2-benzimidazolinone enhanced K+ current in endothelial cells that was blunted by hypoxia. Further, 1-ethyl-2-benzimidazolinone restored (P<.001) endothelium-dependent hyperpolarizing factor-mediated relaxation with hyperpolarization recovered from 6.0±0.3 to 7.8±0.4 mV (P<.05).
  
  
  CONCLUSIONS
  In porcine coronary arteries, hypoxia markedly reduced endothelial K+ currents related to IKCa and SKCa with downregulation of protein expression and endothelium-derived hyperpolarizing factor function. IKCa/SKCa activator may preserve endothelium-dependent hyperpolarizing factor-mediated relaxation with enhancement of K+ current in endothelial cells and cellular membrane potential hyperpolarization in smooth muscle cells and may become a new strategy to protect coronary endothelium in cardiac surgery or transplantation.
authors.affiliation: Department of Surgery, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong. qyang@surgery.cuhk.edu.hk
authors.forename: Qin
authors.initials: Q
authors.lastname: Yang
authors.forename: Jun-Hao
authors.initials: JH
authors.lastname: Huang
authors.forename: Yu-Bun
authors.initials: YB
authors.lastname: Man
authors.forename: Xiao-Qiang
authors.initials: XQ
authors.lastname: Yao
authors.forename: Guo-Wei
authors.initials: GW
authors.lastname: He
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001685:Biological Factors / Q000378:metabolism; D015687:Cell Hypoxia; D002478:Cells, Cultured; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000819:agonists* / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000819:agonists* / Q000378:metabolism; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001562:Benzimidazoles; D001685:Biological Factors; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D026902:Potassium Channel Blockers; D051640:Small-Conductance Calcium-Activated Potassium Channels; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; C102635:1-ethyl-2-benzimidazolinone; D011188:Potassium