Abstract
Background: Inactivation of small-conductance calcium-activated potassium (SK) channels contributes to coronary microvascular dysfunction in patients after cardioplegic arrest, cardiopulmonary bypass (CP/CPB) and cardiac surgery. SK-channel activation is cardioprotective in rodent isolated heart model of myocardial infarction and ischemia/reperfusion. In the current study, we investigated the impact of SK activation on myocardial protection in a clinically relevant large animal model of pigs subjected to cardioplegic ischemia/reperfusion and CPB. Methods and Results: Ten Yorkshire pigs were subjected to 1 hour of CP/CPB followed by 1 hour of reperfusion. Pigs received either cold blood hyperkalemic CP alone (CP control) or CP containing the selective SK channel activator NS309 (10 -6 M, n = 5/group). Left ventricular (LV) function was assessed by using pressure-volume loop analysis. Coronary arteriolar relaxation response (in-vitro) to the endothelium-dependent vasodilators adenosine diphosphate (ADP, 10 -9 -10 -4 M) and substance P (10 -12 -10 -7 M) and independent vasodilator sodium nitroprusside (SNP) was evaluated with video-microscopy. Inclusion of NS309 in cold blood CP tends to improve the recovery of LV function compared with the CP controls. CP/CPB and reperfusion significantly reduced endothelium-dependent relaxation response to ADP, 10 -5 M) and substance P (10 -8 M) as compared to control (p<0.05). In contrast, CP-containing NS309 significant improved the recovery of endothelium-dependent relaxation response to ADP and substance P as compared with the control group (p<0.05, respectively). Conclusion: In pig model of CP/CPB, inclusion of the selective SK channel activator in the cold blood cardioplegia improves recovery of coronary arteriolar endothelial function and microvascular relaxation, which may contribute to increased myocardial perfusion and improved LV function.
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