Although decreased protein kinase G (PKG) activity was proposed as potential therapeutic target in heart failure with preserved ejection fraction (HFpEF), randomized clinical trials (RCTs) with type-5 phosphodiesterase inhibitors (PDE5i) showed neutral results. Whether specific subgroups of HFpEF patients may benefit from PDE5i remains to be defined. Our aim was to test chronic sildenafil therapy in the young male ZSF1 obese rat model of HFpEF with severe hypertension and metabolic syndrome. Sixteen-week-old ZSF1 obese rats were randomly assigned to receive sildenafil 100 mg·Kg⁻¹·d⁻¹ dissolved in drinking water (ZSF1 Ob SIL, n = 8), or placebo (ZSF1 Ob PL, n = 8). A group of Wistar-Kyoto rats served as control (WKY, n = 8). Four weeks later animals underwent effort tests, glucose metabolism studies, hemodynamic evaluation, and samples were collected for aortic ring preparation, left ventricular (LV) myocardial adenosine triphosphate (ATP) quantification, immunoblotting and histology. ZSF1 Ob PL rats showed systemic hypertension, aortic stiffening, impaired LV relaxation and increased LV stiffness, with preserved ejection fraction and cardiac index. Their endurance capacity was decreased as assessed by maximum workload and peak oxygen consumption (V˙O₂) and respiratory quotient were increased, denoting more reliance on anaerobic metabolism. Additionally, ATP levels were decreased. Chronic sildenafil treatment attenuated hypertension and decreased LV stiffness, modestly enhancing effort tolerance with a concomitant increase in peak, ATP levels and VASP phosphorylation. Chronic sildenafil therapy in this model of HFpEF of the young male with extensive and poorly controlled comorbidities has beneficial cardiovascular effects which support RCTs in HFpEF patient subgroups with similar features.

尽管蛋白激酶 G (PKG) 活性降低被认为是射血分数保留的心力衰竭 (HFpEF) 的潜在治疗靶点，但使用 5 型磷酸二酯酶抑制剂 (PDE5i) 进行的随机临床试验 (RCT) 显示出中性结果。HFpEF 患者的特定亚组是否可以从 PDE5i 中受益仍有待确定。我们的目的是在患有严重高血压和代谢综合征的 HFpEF 的年轻雄性 ZSF1 肥胖大鼠模型中测试慢性西地那非治疗。16 周龄 ZSF1 肥胖大鼠被随机分配接受西地那非 100 mg·Kg ^-1 ·d ^-1溶于饮用水（ZSF1 Ob SIL，n = 8）或安慰剂（ZSF1 Ob PL，n = 8）。一组 Wistar-Kyoto 大鼠作为对照 (WKY, n = 8)。4 周后，动物接受了努力测试、葡萄糖代谢研究、血流动力学评估，并收集样本用于主动脉环准备、左心室 (LV) 心肌三磷酸腺苷 (ATP) 定量、免疫印迹和组织学。ZSF1 Ob PL 大鼠表现出全身性高血压、主动脉僵硬、左室舒张受损和左室僵硬增加，射血分数和心脏指数保持不变。根据最大工作量和峰值耗氧量（V˙O ₂) 和呼吸商增加，表明更多地依赖无氧代谢。此外，ATP 水平降低。慢性西地那非治疗减轻高血压和降低 LV 僵硬度，适度提高努力耐受性，同时峰值、ATP 水平和 VASP 磷酸化增加。在患有广泛且控制不佳的合并症的年轻男性 HFpEF 模型中，慢性西地那非治疗具有有益的心血管作用，支持在具有相似特征的 HFpEF 患者亚组中进行 RCT。