title: Natakalim Ameliorates Isoproterenol-Induced Chronic Heart Failure by Protecting against Endothelial Dysfunction.
abstract: The pharmacological effects and underlying mechanisms of natakalim, a novel SUR2B/Kir6.1-KATP channel opener, against chronic heart failure induced by isoproterenol in rats were investigated. Male Wistar rats were administered isoproterenol subcutaneously (85 mg/kg, 7 days) to induce chronic heart failure and were then treated with natakalim or saline for 6 weeks. Their blood pressure, heart rates and cardiac functions were measured using an 8-channel physiological recorder. Sophisticated technologies such as histological analysis, ELISA, radioimmunoassay, immunohistochemistry, real-time PCR and western blotting were employed for analysis. Natakalim (1, 3, 9 mg/kg/day, orally) or saline was administered for 6 weeks orally via a gastric tube to rats that had been injected with isoproterenol. Natakalim remarkably inhibited changes in left ventricular hemodynamic parameters and decreased the heart mass index, the left ventricular weight index, right ventricular weight index and lung weight index. Histological examination demonstrated no significant hypertrophy or fibrosis in the hearts of the natakalim-treated rats. Mechanistically, natakalim attenuates the elevation of plasma nitric oxide (NO) level and inducible NO synthase in cardiac tissue induced by isoproterenol. Additionally, natakalim inhibits the endothelin signaling system by decreasing both the content of endothelin-1 in the plasma and the protein levels of cardiac endothelin receptors A and B. Moreover, natakalim could augment the plasma prostacyclin concentration. In conclusion, our study provides evidence that natakalim effectively ameliorates isoproterenol-induced chronic heart failure in rats by protecting against endothelial dysfunction.
authors.affiliation: Cardiovascular Drug Research Center, Institute of Health and Environmental Medicine, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Mingli
authors.initials: M
authors.lastname: Zhong
authors.forename: Hongmin
authors.initials: H
authors.lastname: Zhou
authors.forename: Chaoliang
authors.initials: C
authors.lastname: Long
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wenyu
authors.initials: W
authors.lastname: Cui
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Hai
authors.initials: H
authors.lastname: Wang
mesh_terms: D000498:Allyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006333:Heart Failure / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007545:Isoproterenol / Q000633:toxicity*; D008297:Male; D011437:Propylamines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000498:Allyl Compounds; D002316:Cardiotonic Agents; D011437:Propylamines; C556401:natakalim; D007545:Isoproterenol