Decreased coronary arteriolar response to KCa channel opener after cardioplegic arrest in diabetic patients

Abstract

We have recently found that diabetes is associated with the inactivation of the calcium-activated potassium channels (KCa) in endothelial cells, which may contribute to endothelial dysfunction in diabetic patients at baseline. In the current study, we further investigated the effects of diabetes on coronary arteriolar responses to the small (SK) and intermediate (IK) KCa opener NS309 in diabetic and non-diabetic patients and correlated that data with the changes in the SK/IK protein expression/distribution in the setting of cardioplegic ischemia and reperfusion (CP) and cardiopulmonary bypass (CPB). Coronary arterioles from the harvested right atrial tissue samples from diabetic and non-diabetic patients (n = 8/group) undergoing cardiac surgery were dissected pre- and post-CP/CPB. The in vitro relaxation response of pre-contracted arterioles was examined in the presence of the selective SK/IK opener NS309 (10−9–10−5 M). The protein expression/localization of KCa channels in the harvested atrial tissue samples, coronary microvessels, and primary cultured human coronary endothelial cells were assayed by Western blotting and immunohistochemistry. The relaxation response to NS309 post-CP/CPB was significantly decreased in diabetic and non-diabetic groups compared to their pre-CP/CPB responses, respectively (P < 0.05). Furthermore, this decrease was greater in the diabetic group than that of the non-diabetic group (P < 0.05). There were no significant differences in the total protein expression/distribution of SK/IK in the human myocardium, coronary microvessels or coronary endothelial cells between diabetic and non-diabetic groups or between pre- and post-CP/CPB (P > 0.05). Our results suggest that diabetes further inactivates SK/IK channels of coronary microvasculature early after CP/CPB and cardiac surgery. The lack of diabetic changes in SK/IK protein abundances in the setting of CP/CPB suggests that the effect is post-translational. This alteration may contribute to post-operative endothelial dysfunction in the diabetic patients early after CP/CPB and cardiac surgery.