title: Calcium-activated potassium channels contribute to human coronary microvascular dysfunction after cardioplegic arrest.
abstract: BACKGROUND
  Cardioplegic arrest (CP) followed by reperfusion after cardiopulmonary bypass induces coronary microvascular dysfunction. We investigated the role of calcium-activated potassium (K(Ca)) channels in this dysfunction in the human coronary microvasculature.
  
  
  RESULTS
  Human atrial tissue was harvested before CP from a nonischemic segment and after CP from an atrial segment exposed to hyperkalemic cold blood CP (mean CP time, 58 minutes) followed by 10-minute reperfusion. In vitro relaxation responses of precontracted arterioles (80 to 180 mum in diameter) in a pressurized no-flow state were examined in the presence of K(Ca) channel activators/blockers and several other vasodilators. We also examined expression and localization of K(Ca) channel gene products in the coronary microvasculature using reverse transcriptase-polymerase chain reaction, immunoblot, and immunofluorescence photomicroscopy. Post-CP reperfusion relaxation responses to the activator of intermediate and small conductance K(Ca) channels (IK(Ca)/SK(Ca)), NS309 (10(-5) M), and to the endothelium-dependent vasodilators, substance P (10(-8) M) and adenosine 5diphosphate (10(-5) M), were significantly reduced compared with pre-CP responses (P<0.05, n=8/group). In contrast, relaxation responses to the activator of large conductance K(Ca) channels (BK(Ca)), NS1619 (10(-5) M), and to the endothelium-independent vasodilator, sodium nitroprusside (10(-4) M), were unchanged pre- and post-CP reperfusion (n=8/group). Endothelial denudation significantly diminished NS309-induced vasodilatation and abolished substance P- or adenosine 5 diphosphate-induced relaxation (P<0.05), but had no effect on relaxation induced by either NS1619 or sodium nitroprusside. The total polypeptide levels of BK(Ca), IK(Ca), and SK(Ca) and the expression of IK(Ca) mRNA were not altered post-CP reperfusion.
  
  
  CONCLUSIONS
  Cardioplegic arrest followed by reperfusion after cardiopulmonary bypass causes microvascular dysfunction associated with and likely in part due to impaired function of SK(Ca) and IK(Ca) channels in the coronary microcirculation. These results suggest novel mechanisms of endothelial and smooth muscle microvascular dysfunction after cardiac surgery.
authors.affiliation: Division of Cardiothoracic Surgery, BIDMC, LMOB 2A, 110 Francis Street, Boston, MA 02215, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Feng
authors.forename: Yuhong
authors.initials: Y
authors.lastname: Liu
authors.forename: Richard T
authors.initials: RT
authors.lastname: Clements
authors.forename: Neel R
authors.initials: NR
authors.lastname: Sodha
authors.forename: Kamal R
authors.initials: KR
authors.lastname: Khabbaz
authors.forename: Venkatachalam
authors.initials: V
authors.lastname: Senthilnathan
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Nishimura
authors.forename: Seth L
authors.initials: SL
authors.lastname: Alper
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
mesh_terms: D000368:Aged; D001160:Arterioles / Q000187:drug effects; D002315:Cardiopulmonary Bypass; D003331:Coronary Vessels / Q000378:metabolism / Q000503:physiopathology*; D003408:Cresols / Q000494:pharmacology; D005260:Female; D006324:Heart Arrest, Induced; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008833:Microcirculation / Q000503:physiopathology; D008875:Middle Aged; D015425:Myocardial Reperfusion; D010091:Oximes / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism; D010671:Phenylurea Compounds / Q000494:pharmacology; D011184:Postoperative Period; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D014664:Vasodilation; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C493327:6,7-dichloro-1H-indole-2,3-dione 3-oxime; D003408:Cresols; D007211:Indoles; D010091:Oximes; D010455:Peptides; D010671:Phenylurea Compounds; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D014665:Vasodilator Agents; C507624:1,3-bis(2-hydroxy-5-trifluoromethylphenyl)urea