Calcium-activated potassium channels contribute to human coronary microvascular dysfunction after cardioplegic arrest

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 mu m 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 (IKCa/SKCa)(,) NS309 (10(-5) M), and to the endothelium-dependent vasodilators, substance P (10(-8) M) and adenosine 5' diphosphate (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 (BKCa), 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 BKCa, IKCa, and SKCa and the expression of IKCa 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 SKCa and IKCa channels in the coronary microcirculation. These results suggest novel mechanisms of endothelial and smooth muscle microvascular dysfunction after cardiac surgery.