Left ventricular (LV) hypertrophy is a common characteristic of heart failure with preserved ejection fraction (HFpEF). Our lab recently characterized a mini-swine model of LV hypertrophy induced by aortic banding (AB) that displays clinical features associated with HFpEF including LV hypertrophy, diastolic dysfunction, and depressed contractile reserve. Disrupted cGMP signaling, a result of impaired production or enhanced catabolism, may play a role in development of HFpEF. We hypothesized preservation of cGMP signaling would attenuate pathological remodeling and improve cardiac function. The purpose of this study was to promote cGMP signaling via two mechanisms: 1) the DPP4 inhibitor saxagliptin; and 2) the PDE5 inhibitor tadalafil. We assessed whole heart and individual cardiomyocyte function 6 months post-AB in: control non-banded (CON; n=6), AB-control (AB; n=7), AB saxagliptin-treated (AB-SAX; n=7), and AB tadalafil-treated (AB-TAD; n=8) swine. Heart weight:body weight ratio increased to a similar extent in all AB groups. However, changes in cardiomyocyte morphology were variable. Cardiomyocyte length was increased only in the AB-TAD group, while cell width increased in both AB and AB-TAD animals. Cardiomyocyte length:width ratio decreased in the AB and AB-TAD groups, commensurate with decreased LV end diastolic (ED) and end systolic (ES) volumes. These changes were prevented in AB-SAX animals, as LV volumes and cell morphology were similar to CON. Pressure-volume analysis showed resting LV wall stiffness (ED pressure volume relationship [EDPVR] slope) was increased similarly in all AB groups. Increased resting LV contractility (ESPVR and preload recruitable stroke work) was observed in AB and AB-TAD animals. Interestingly, cardiomyocyte shortening was reduced in the AB-TAD group contrasting findings observed at the whole heart level. Saxaglitpin attenuated hypercontractile LV function at rest and preserved normal cardiomyocyte shortening. In conclusion, LV and cardiomyocyte function was distinctly altered in response to separate methods of pharmacological cGMP regulation. Our data suggest different pharmacological approaches to augment cGMP signaling promote distinct LV functional adaptations to developing HF.