Abstract—Hypertension-induced diastolic heart failure accounts for a large proportion of all heart failure presentations. Hypertension also induces left ventricular (LV) hypertrophy. Fixed-dose isosorbide dinitrate/hydralazine (HISDN) decreased mortality in human systolic heart failure but it is unknown whether it improves maladaptive myocardial remodeling. We sought to test the hypothesis that chronic HISDN modulates LV hypertrophy and myocardial remodeling in hypertension-induced diastolic heart failure. FVB mice underwent either saline (n=18) or aldosterone (n=28) infusion. All underwent uninephrectomy and drank 1% salt water for 4 weeks. Mice were randomized after surgery to regular chow or chow containing HISDN (isosorbide dinitrate: 26 mg/kg per day; hydralazine: 50 mg/kg per day) for 4 weeks. Aldosterone infusion increased tail-cuff blood pressure (161±3 mm Hg) versus saline-infused mice (129±2 mm Hg). Aldosterone induced LV hypertrophy versus saline-infused mice (LV:body weight ratio: 4.2±0.1 versus 3.6±0.1 mg/g). HISDN attenuated the aldosterone-induced increased in systolic blood pressure (137±5 mm Hg) and also lowered blood pressure in saline-infused mice (114±2 mm Hg). However, HISDN did not cause LV hypertrophy regression in aldosterone-infused mice. Aldosterone increased LV end-diastolic dimensions that were not attenuated by HISDN. Similarly, neither aldosterone infusion nor HISDN affected LV end-systolic dimensions. LV ejection fraction and wet:dry lung ratio were not different between aldosterone-untreated and aldosterone-HISDN mice. However, mitral Doppler E/A ratio (a measure of diastolic function), exercise capacity, and plasma soluble vascular cell adhesion molecule 1 levels were improved in aldosterone-HISDN hearts. In conclusion, fixed-dose HISDN improved hypertension, diastolic function, and exercise capacity and reduced soluble vascular cell adhesion molecule 1 levels. There were no reductions in LV hypertrophy, cardiac fibrosis, or pulmonary congestion. These functional improvements are likely related to extracardiac effects, such as effects on the vasculature.