Pulmonary hypertension is common in heart failure with preserved ejection fraction (HFpEF). Here, we tested the hypothesis that comorbidities [diabetes mellitus (DM, streptozotocin), hypercholesterolemia (HC, high-fat diet) and chronic kidney disease (CKD, renal microembolization)] directly impair pulmonary vasomotor control in a DM + HC + CKD swine model. 6 months after induction of DM + HC + CKD, pulmonary arterial pressure was similar in chronically instrumented female DM + HC + CKD (n = 19) and Healthy swine (n = 18). However, cardiac output was lower both at rest and during exercise, implying an elevated pulmonary vascular resistance (PVR) in DM + HC + CKD swine (153 ± 10 vs. 122 ± 9 mmHg∙L⁻¹∙min∙kg). Phosphodiesterase 5 inhibition and endothelin receptor antagonism decreased PVR in DM + HC + CKD (− 12 ± 12 and − 22 ± 7 mmHg∙L⁻¹∙min∙kg) but not in Healthy swine (− 1 ± 12 and 2 ± 14 mmHg∙L⁻¹∙min∙kg), indicating increased vasoconstrictor influences of phosphodiesterase 5 and endothelin. Inhibition of nitric oxide synthase produced pulmonary vasoconstriction that was similar in Healthy and DM + HC + CKD swine, but unmasked a pulmonary vasodilator effect of endothelin receptor antagonism in Healthy (− 56 ± 26 mmHg∙L⁻¹∙min∙kg), whereas it failed to significantly decrease PVR in DM + HC + CKD, indicating loss of nitric oxide mediated inhibition of endothelin in DM + HC + CKD. Scavenging of reactive oxygen species (ROS) had no effect on PVR in either Healthy or DM + HC + CKD swine. Cardiovascular magnetic resonance imaging, under anesthesia, showed no right ventricular changes. Finally, despite an increased contribution of endogenous nitric oxide to vasomotor tone regulation in the systemic vasculature, systemic vascular resistance at rest was higher in DM + HC + CKD compared to Healthy swine (824 ± 41 vs. 698 ± 35 mmHg∙L⁻¹∙min∙kg). ROS scavenging induced systemic vasodilation in DM + HC + CKD, but not Healthy swine. In conclusion, common comorbidities directly alter pulmonary vascular control, by enhanced PDE5 and endothelin-mediated vasoconstrictor influences, well before overt left ventricular backward failure or pulmonary hypertension develop.

肺动脉高压在射血分数保留的心力衰竭 (HFpEF) 中很常见。在这里，我们检验了合并症 [糖尿病（DM，链脲佐菌素）、高胆固醇血症（HC，高脂肪饮食）和慢性肾脏疾病（CKD，肾微栓塞）] 直接损害 DM + HC + CKD 猪的肺血管舒缩控制的假设模型。DM + HC + CKD 诱导后 6 个月，长期使用仪器仪表的女性 DM + HC + CKD ( n  = 19) 和健康猪 ( n  = 18)的肺动脉压相似。然而，静息和运动时心输出量均较低，这意味着 DM + HC + CKD 猪的肺血管阻力 (PVR) 升高（153 ± 10 vs. 122 ± 9 mmHg∙L ^-1∙min∙kg)。磷酸二酯酶 5 抑制和内皮素受体拮抗作用降低了 DM + HC + CKD（- 12 ± 12 和 - 22 ± 7 mmHg∙L ^-1 ∙min∙kg）的 PVR，但在健康猪中没有降低（- 1 ± 12 和 2 ± 14 mmHg ∙L ^-1 ∙min∙kg)，表明磷酸二酯酶 5 和内皮素对血管收缩的影响增加。一氧化氮合酶的抑制产生的肺血管收缩在健康猪和 DM + HC + CKD 猪中相似，但在健康猪中揭示了内皮素受体拮抗作用的肺血管扩张作用 (− 56 ± 26 mmHg∙L ^-1∙min∙kg)，而它未能显着降低 DM + HC + CKD 中的 PVR，表明在 DM + HC + CKD 中一氧化氮介导的内皮素抑制作用丧失。清除活性氧 (ROS) 对健康或 DM + HC + CKD 猪的 PVR 没有影响。麻醉下的心血管磁共振成像显示右心室无变化。最后，尽管内源性一氧化氮对全身脉管系统血管舒缩张力调节的贡献增加，但与健康猪相比，DM + HC + CKD 的静息时全身血管阻力更高（824 ± 41 vs. 698 ± 35 mmHg∙L ^-1∙min∙kg)。ROS 清除在 DM + HC + CKD 中诱导全身血管舒张，但对健康猪无影响。总之，常见的合并症直接改变肺血管控制，通过增强 PDE5 和内皮素介导的血管收缩剂的影响，早在明显的左心室后向衰竭或肺动脉高压发展之前。