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(Circulation. 2008;118:S46-S51.)
© 2008 American Heart Association, Inc.

Myocardial Protection, Perioperative Management, and Vascular Biology

Calcium-Activated Potassium Channels Contribute to Human Coronary Microvascular Dysfunction After Cardioplegic Arrest

Jun Feng, MD, PhD; Yuhong Liu, MD; Richard T. Clements, PhD; Neel R. Sodha, MD; Kamal R. Khabbaz, MD; Venkatachalam Senthilnathan, MD; Katherine K. Nishimura, BA; Seth L. Alper, MD, PhD; Frank W. Sellke, MD

Correspondence to Frank W. Sellke, MD, Division of Cardiothoracic Surgery, BIDMC, LMOB 2A, 110 Francis Street, Boston, MA 02215. E-mail fsellke{at}caregroup.harvard.edu

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.

Methods and 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 µm 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.

Conclusion— 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.

Key Words: calcium-activated potassium channels • cardioplegia • ischemia and reperfusion • microcirculation