Ranolazine combined with enalapril or metoprolol prevents progressive LV dysfunction and remodeling in dogs with moderate heart failure
- 1 November 2008
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 295 (5), H2149-H2155
- https://doi.org/10.1152/ajpheart.00728.2008
Abstract
Acute intravenous infusion of ranolazine (Ran), an anti-ischemic/antiangina drug, was previously shown to improve left ventricular (LV) ejection fraction (EF) without a concomitant increase in myocardial oxygen consumption in dogs with chronic heart failure (HF). This study examined the effects of treatment with Ran alone and in combination with metoprolol (Met) or enalapril (Ena) on LV function and remodeling in dogs with HF. Dogs ( n = 28) with microembolization-induced HF were randomized to 3 mo oral treatment with Ran alone [375 mg twice daily (bid); n = 7], Ran (375 mg bid) in combination with Met tartrate (25 mg bid; n = 7), Ran (375 mg bid) in combination with Ena (10 mg bid; n = 7), or placebo (PL; Ran vehicle bid; n = 7). Ventriculographic measurements of LV end-diastolic volume (EDV) and end-systolic volume (ESV) and LV EF were obtained before treatment and after 3 mo of treatment. In PL-treated dogs, EDV and ESV increased significantly. Ran alone prevented the increase in EDV and ESV seen in the PL group and significantly increased EF, albeit modestly, from 35 ± 1% to 37 ± 2%. When combined with either Ena or Met, Ran prevented the increase in EDV, significantly decreased ESV, and markedly increased EF compared with those of PL. EF increased from 35 ± 1% to 40 ± 1% with Ran + Ena and from 34 ± 1% to 41 ± 1% with Ran + Met. Ran alone or in combination with Ena or Met was also associated with beneficial effects at the cellular level on histomorphometric parameters such as hypertrophy, fibrosis, and capillary density as well as the expression for pathological hypertrophy and Ca2+ cycling genes. In conclusion, Ran prevented progressive LV dysfunction and global and cellular myocardial remodeling, and Ran in combination with Ena or Met improved LV function beyond that observed with Ran alone.Keywords
This publication has 50 references indexed in Scilit:
- Chronic heart failure slows late sodium current in human and canine ventricular myocytes: Implications for repolarization variabilityEuropean Journal of Heart Failure, 2007
- Global Risk Management in Patients with Type 2 Diabetes MellitusThe American Journal of Cardiology, 2007
- Hemodynamic Properties of a New-Generation Positive Luso-Inotropic Agent for the Acute Treatment of Advanced Heart FailureThe American Journal of Cardiology, 2007
- Inhibition of the late sodium current as a potential cardioprotective principle: effects of the late sodium current inhibitor ranolazineHeart, 2006
- Ranolazine Improves Abnormal Repolarization and Contraction in Left Ventricular Myocytes of Dogs with Heart Failure by Inhibiting Late Sodium CurrentJournal of Cardiovascular Electrophysiology, 2006
- Comparative efficacy of ranolazine versus atenolol for chronic angina pectorisThe American Journal of Cardiology, 2005
- Na+−Ca2+ exchange and sarcoplasmic reticular Ca2+ regulation in ventricular myocytes from transgenic mice overexpressing the Na+−Ca2+ exchangerThe Journal of Physiology, 1998
- Progression of heart failure: A role for interstitial fibrosisMolecular and Cellular Biochemistry, 1995
- Mitochondrial abnormalities in myocardium of dogs with chronic heart failureJournal of Molecular and Cellular Cardiology, 1992
- Left ventricular shape: A factor in the etiology of functional mitral regurgitation in heart failureAmerican Heart Journal, 1992