Few therapies are known to enhance diastolic function. Systemic administration of natriuretlc peptldes (NP) improves diastolic function. However, this may be due to effects on load, rather than a direct myocardlal action. We generated mice with acar-disc-specific (a-MHC promoter) gain-of-function mutation (GoF, HCAT E974A) in the natriuretic peptide A receptor (NPRA) resulting in myocyte-specific constitutive NPRA activation. We hypothesized that GoF mice would exhibit enhanced diastolic function and develop less diastolic dysfunction with pressure-overload. Methods: GoF mice (n=l2) and their wildtype (WT-/-, n=18) littermates underwent abdominal aortic banding to generate pressure-overload hypertrophy. LV structure and function (echo, catheterization, autopsy) were assessed three weeks after banding. Non-banded GoF (n=15) and Wl-/-(n=l3) groups ware controls. Results: See table (mean *SD): With aortic banding, both GoF and WT mice developed LV hypertrophy. While load and systolic function were similar between Wl and GoF mice without and with banding, the time constant of LV relaxation (Tau) was decreased in GoF mice as compared to WT indicating improved diastolic function. Conclusion: Chronic cardiac-specific NPRA activation via this GoF mutation enhanced diastolic function in mice and markedly attenuated diastolic dysfunction associated with pressure-overload hypertrophy. These data suggest that NP improve diastolic function via a direct myocardial effect