Department of Biomedical Sciences, University of Missouri-Columbia , Columbia, Missouri.
Dalton Cardiovascular Research Center, University of Missouri-Columbia , Columbia, Missouri.
J Appl Physiol (1985). 2018 Jul 1;125(1):86-96. doi: 10.1152/japplphysiol.01138.2017. Epub 2018 Mar 29.
Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Thus, the purpose of this study was to determine the therapeutic efficacy of chronic interval exercise training (IT) on large-conductance Ca-activated K (BK) channel-mediated coronary vascular function in heart failure. We hypothesized that chronic interval exercise training would attenuate pressure overload-induced impairments to coronary BK channel-mediated function. A translational large-animal model with cardiac features of HFpEF was used to test this hypothesis. Specifically, male Yucatan miniswine were divided into three groups ( n = 7/group): control (CON), aortic banded (AB)-heart failure (HF), and AB-interval trained (HF-IT). Coronary blood flow, vascular conductance, and vasodilatory capacity were measured after administration of the BK channel agonist NS-1619 both in vivo and in vitro in the left anterior descending coronary artery and isolated coronary arterioles, respectively. Skeletal muscle citrate synthase activity was decreased and left ventricular brain natriuretic peptide levels increased in HF vs. CON and HF-IT animals. A parallel decrease in NS-1619-dependent coronary vasodilatory reserve in vivo and isolated coronary arteriole vasodilatory responsiveness in vitro were observed in HF animals compared with CON, which was prevented in the HF-IT group. Although exercise training prevented BK channel-mediated coronary vascular dysfunction, it did not change BK channel α-subunit mRNA, protein, or cellular location (i.e., membrane vs. cytoplasm). In conclusion, these results demonstrate the viability of chronic interval exercise training as a therapy for central and peripheral adaptations of experimental heart failure, including BK channel-mediated coronary vascular dysfunction. NEW & NOTEWORTHY Conventional treatments have failed to improve the prognosis of heart failure with preserved ejection fraction (HFpEF) patients. Our findings show that chronic interval exercise training can prevent BK channel-mediated coronary vascular dysfunction in a translational swine model of chronic pressure overload-induced heart failure with relevance to human HFpEF.
传统治疗未能改善射血分数保留型心力衰竭（HFpEF）患者的预后。因此，本研究旨在确定慢性间歇运动训练（IT）对心力衰竭中大电导钙激活钾（BK）通道介导的冠状动脉血管功能的治疗效果。我们假设慢性间歇运动训练会减轻压力超负荷引起的冠状动脉 BK 通道介导功能障碍。使用具有 HFpEF 心脏特征的转化大型动物模型来检验这一假设。具体来说，雄性尤卡坦小型猪分为三组（每组 n = 7）：对照组（CON）、主动脉缩窄（AB）-心力衰竭（HF）和 AB-间歇训练（HF-IT）。在左前降支冠状动脉和分离的冠状动脉小动脉中，分别给予 BK 通道激动剂 NS-1619 后，在体内和体外测量冠状动脉血流、血管传导性和血管舒张能力。HF 与 CON 和 HF-IT 动物相比，心肌柠檬酸合酶活性降低，左心室脑钠肽水平升高。与 CON 相比，HF 动物体内 NS-1619 依赖性冠状动脉舒张储备和体外分离的冠状动脉小动脉舒张反应性平行下降，HF-IT 组则得到预防。尽管运动训练预防了 BK 通道介导的冠状动脉血管功能障碍，但它并没有改变 BK 通道α亚基的 mRNA、蛋白或细胞位置（即膜与细胞质）。总之，这些结果表明慢性间歇运动训练作为一种治疗实验性心力衰竭的中央和外周适应的疗法是可行的，包括 BK 通道介导的冠状动脉血管功能障碍。
