Inhibition of late Na+ current, a novel target to improve diastolic function and electrical abnormalities in Dahl salt-sensitive rats

Late Na+ current (I-NaL) is enhanced in myocytes of animals with chronic heart failure and patients with hypertrophic cardiomyopathy. To define the role of I-NaL in diastolic heart failure, the effects of GS-458967 (GS-967), a potent I-NaL 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]. I-NaL 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 I-NaL 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 I-NaL 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.