Dept. of Cellular and Integrative Physiology, Indiana Univ. School of Medicine, Indianapolis, 46202, USA.
Am J Physiol Heart Circ Physiol. 2010 Apr;298(4):H1182-9. doi: 10.1152/ajpheart.00888.2009. Epub 2010 Jan 29.
This investigation tested the hypothesis that metabolic syndrome decreases the relative contribution of specific K(+) channels to coronary reactive hyperemia. Ca(2+)-activated (BK(Ca)), voltage-activated (K(V)), and ATP-dependent (K(ATP)) K(+) channels were investigated. Studies were conducted in anesthetized miniature Ossabaw swine fed a normal maintenance diet (11% kcal from fat) or an excess calorie atherogenic diet (43% kcal from fat, 2% cholesterol, 20% kcal from fructose) for 20 wk. The latter diet induces metabolic syndrome, increasing body weight, fasting glucose, total cholesterol, and triglyceride levels. Ischemic vasodilation was determined by the coronary flow response to a 15-s occlusion before and after cumulative administration of antagonists for BK(Ca) (penitrem A; 10 microg/kg iv), K(V) (4-aminopyridine; 0.3 mg/kg iv) and K(ATP) (glibenclamide; 1 mg/kg iv) channels. Coronary reactive hyperemia was diminished by metabolic syndrome as the repayment of flow debt was reduced approximately 30% compared with lean swine. Inhibition of BK(Ca) channels had no effect on reactive hyperemia in either lean or metabolic syndrome swine. Subsequent inhibition of K(V) channels significantly reduced the repayment of flow debt ( approximately 25%) in both lean and metabolic syndrome swine. Additional blockade of K(ATP) channels further diminished ( approximately 45%) the repayment of flow debt in lean but not metabolic syndrome swine. These data indicate that the metabolic syndrome impairs coronary vasodilation in response to cardiac ischemia via reductions in the contribution of K(+) channels to reactive hyperemia.
本研究旨在验证以下假设，即代谢综合征会降低特定 K(+)通道对冠状动脉反应性充血的相对贡献。研究中检测了钙激活（BK(Ca)）、电压激活（K(V)）和 ATP 依赖性（K(ATP)）K(+)通道。研究采用麻醉小型 Ossabaw 猪，给予正常维持饮食（11%的热量来自脂肪）或过量热量致动脉粥样硬化饮食（43%的热量来自脂肪、2%的胆固醇、20%的热量来自果糖）喂养 20 周。后者的饮食会导致代谢综合征，增加体重、空腹血糖、总胆固醇和甘油三酯水平。通过在累积给予 BK(Ca)（penitrem A；10μg/kg 静脉内）、K(V)（4-氨基吡啶；0.3mg/kg 静脉内）和 K(ATP)（格列本脲；1mg/kg 静脉内）通道拮抗剂前后，测量缺血性血管舒张作用，以冠状动脉对 15 秒闭塞的血流反应来确定。与瘦猪相比，代谢综合征使冠状动脉反应性充血减少约 30%，从而导致缺血后血流恢复减少。在瘦猪和代谢综合征猪中，抑制 BK(Ca)通道对反应性充血均无影响。随后抑制 K(V)通道可显著减少瘦猪和代谢综合征猪的血流恢复（约 25%）。进一步阻断 K(ATP)通道可进一步减少（约 45%）瘦猪但不减少代谢综合征猪的血流恢复。这些数据表明，代谢综合征通过降低 K(+)通道对反应性充血的贡献，损害了对缺血性心脏的冠状动脉血管舒张作用。
