Pharmacological evidence： a new therapeutic approach to the treatment of chronic heart failure through SUR2B/Kir6.1 channel in endothelial cells

• Published in: Acta pharmacologica Sinica Vol. 38; no. 1; pp. 41 - 55
• Main Authors: Wang, Shang, Long, Chao-liang, Chen, Jun, Cui, Wen-yu, Zhang, Yan-fang, Zhang, Hao, Wang, Hai
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2017; Nature Publishing Group
• Subjects: Allyl Compounds - antagonists & inhibitors; Allyl Compounds - pharmacology; Allyl Compounds - therapeutic use; Animals; ATP敏感性钾通道; Biomedical and Life Sciences; Biomedicine; Dose-Response Relationship, Drug; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Glyburide - analogs & derivatives; Glyburide - pharmacology; Heart Failure - chemically induced; Heart Failure - drug therapy; Immunology; Internal Medicine; Isoproterenol; KATP Channels - agonists; Medical Microbiology; Natriuretic Peptide, Brain - metabolism; Original; original-article; Pharmacology/Toxicology; Propylamines - antagonists & inhibitors; Propylamines - pharmacology; Propylamines - therapeutic use; Proteomics; Rats; Sulfonylurea Receptors - agonists; Vaccine; Ventricular Remodeling - drug effects; 充血性心力衰竭; 内皮细胞; 慢性; 治疗效果; 药理学; 蛋白质组学; 证据; endothelial function; eNOS/VASP pathways; iptakalim; chronic heart failure; isoproterenol; glibenclamide; natakalim; ATP-sensitive potassium channel
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2016.118

Both iptakalim （Ipt） and natakalim （Nat） activate the SUR2B/Kir6.1 channel, an ATP-sensitive potassium channel （KATp） subtype, with high selectivity. In this study we investigated the therapeutic effects of Ipt and Nat against isoproterenol-induced chronic heart failure （ISO-CHF） in rats, and demonstrated a new therapeutic approach to the treatment of CHF through activation of the SUR2B/Kir6.1 channel in endothelial cells. In ISO-CHF rats, oral administration of Nat （1, 3, 9 mg.kg^-1.d^-1） or Ipt （3 mg.kg^-1.d^-1） for 60 days significantly improved cardiac dysfunction, reversed cardiac remodeling, significantly attenuated the pathological increases in BNP levels, and improved endothelial dysfunction by adjusting the balance between endothelin and NO systems. The therapeutic effects of Nat were prevented by the selective KATp blocker glibenclamine （Gli, 50 mg.kg^-1.d^-1）, confirming that these effects were mediated through activation of the SUR2B/Kir6.1 channel in endothelial cells. The molecular mechanisms underlying the therapeutic effects of Nat were further addressed using proteomic methods. We identified 724 proteins in the plasma of ISO-CHF rats; 55 proteins were related to Nat. These differentially expressed proteins were mainly involved in single-organism processes and the regulation of biological quality relative to CHF, including proteasome （Psm） and ATP protein clusters. We screened out PRKAR213, GAS6/eNOS/NO and NO/Pt~/VASP pathways involved in the amelioration of CHF among the 24 enriched pathways. We further confirmed 6 protein candidates, including PRKAR2~, GAS6 and VASP, which were involved in the endothelial mechanisms, and ATP, TIMP3 and AGT, which contributed to its cardiovascular actions. This study demonstrates a new pharmacological approach to the treatment of CHF through activation of the SUR2B/Kir6.1 channel in endothelial cells, and that the eNOS/VASP pathways are involved in its signaling mechanisms.