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Coronary microvascular dysfunction contributes to the development of left ventricular (LV) diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF), a prevalent symptom that has limited targeted treatment options. Selective pharmacological inhibitors of phosphodiesterase 9A (PDE9A), such as PF04447943, have emerged as a potential therapeutic approach for the treatment of cardiometabolic diseases, in part, owing to their antioxidant effects. We hypothesized that PDE9A inhibition has beneficial effects on the coronary microvasculature, thereby improving LV diastolic function in HFpEF. In order to study this, the Obese diabetic Zucker fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF1) rat, a model of human HFpEF, was employed in which it was found that progressively developing coronary microvascular rarefaction, as quantified by an unbiased, three-dimensional reconstruction of the coronary microvascular network (Vesselucida360), as well as vasodilator coronary arteriole dysfunction are associated with the development of LV diastolic dysfunction, which were improved by the treatment with the selective PDE9A inhibitor, PF04447943 (3 mg/kg/day, oral gavage for 2 weeks). These coronary microvascular changes were accompanied by an increase in cardiac 3-nitrotyrosine, a marker of nitrosative stress, which was also mitigated by PF04447943 treatment. Furthermore, mass spectrometry-based proteomics and pathway analyses identified peroxiredoxin-5 (PRDX5) as one of the predominantly downregulated antioxidants in the heart of the obese ZSF1 rats, which was augmented after PDE9A inhibition. From this data, it was concluded that PDE9A inhibition, potentially through augmenting the PRDX-5 antioxidant mechanism, improved coronary vascular rarefaction and vasodilator function, thereby restoring LV diastolic function in obese ZSF1 rats. T32HL155011 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.