title: Inhibition of late Na+ current, a novel target to improve diastolic function and electrical abnormalities in Dahl salt-sensitive rats.
abstract: Late Na(+) current (INaL) is enhanced in myocytes of animals with chronic heart failure and patients with hypertrophic cardiomyopathy. To define the role of INaL in diastolic heart failure, the effects of GS-458967 (GS-967), a potent INaL inhibitor on mechanical and electrical abnormalities, were determined in an animal model of diastolic dysfunction. Dahl salt-sensitive (DSS) rats fed a high-salt (HS) diet for 8 wk, compared with a normal salt (NS) diet, had increased left ventricular (LV) mass (1,257 ± 96 vs. 891 ± 34 mg) and diastolic dysfunction [isovolumic relaxation time (IVRT): 26.8 ± 0.5 vs. 18.9 ± 0.2 ms; early transmitral flow velocity/early mitral annulus velocity (E/E') ratio: 25.5 ± 1.9 vs. 14.9 ± 0.9]. INaL in LV myocytes from HS rats was significantly increased to 0.41 ± 0.02 from 0.14 ± 0.02 pA/pF in NS rats. The action potential duration (APD) was prolonged to 136 ± 12 from 68 ± 9 ms in NS rats. QTc intervals were longer in HS vs. NS rats (267 ± 8 vs. 212 ± 2 ms). Acute and chronic treatment with GS-967 decreased the enhanced INaL to 0.24 ± 0.01 and 0.17 ± 0.02 pA/pF, respectively, vs. 0.41 ± 0.02 pA/pF in the HS group. Chronic treatment with GS-967 dose-dependently reduced LV mass, the increases in E/E' ratio, and the prolongation of IVRT by 27, 27, and 20%, respectively, at the 1.0 mg·kg(-1)·day(-1) dose without affecting blood pressure or LV systolic function. The prolonged APDs in myocytes and QTc of HS rats were significantly reduced with GS-967 treatment. These results indicate that INaL is a significant contributor to the LV diastolic dysfunction, hypertrophy, and repolarization abnormalities and thus, inhibition of this current is a promising therapeutic target for diastolic heart failure.
authors.affiliation: Department of Cardiovascular Biology, Gilead Sciences, Fremont, California.
authors.forename: Liguo
authors.initials: L
authors.lastname: Chi
authors.affiliation: Department of Cardiovascular Biology, Gilead Sciences, Fremont, California.
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.affiliation: Department of Cardiovascular Biology, Gilead Sciences, Fremont, California.
authors.forename: Aliya
authors.initials: A
authors.lastname: Zeng
authors.affiliation: Department of Cardiovascular Biology, Gilead Sciences, Fremont, California.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Hirakawa
authors.affiliation: Department of Cardiovascular Biology, Gilead Sciences, Fremont, California.
authors.forename: Sridharan
authors.initials: S
authors.lastname: Rajamani
authors.affiliation: Department of Cardiovascular Biology, Gilead Sciences, Fremont, California Haiyun.Ling@gilead.com.
authors.forename: Haiyun
authors.initials: H
authors.lastname: Ling
authors.affiliation: Department of Cardiovascular Biology, Gilead Sciences, Fremont, California.
authors.forename: Arvinder K
authors.initials: AK
authors.lastname: Dhalla
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006329:Heart Conduction System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology*; D020303:Rats, Inbred Dahl; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D017673:Sodium Chloride, Dietary; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology*; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: C578456:6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)(1,2,4)triazolo(4,3-a)pyridine; D000889:Anti-Arrhythmia Agents; D011725:Pyridines; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D017673:Sodium Chloride, Dietary; D014230:Triazoles
keywords: QT interval; cardiac function; diastolic heart failure; late sodium current