Multiple common cardiovascular comorbidities produce coronary microvascular dysfunction. We previously observed in swine that a combination of diabetes mellitus (DM), high fat diet (HFD) and chronic kidney disease (CKD) induced systemic inflammation, increased oxidative stress and produced coronary endothelial dysfunction, altering control of coronary microvascular tone via loss of NO bioavailability, which was associated with an increase in circulating endothelin (ET). In the present study, we tested the hypotheses that (1) ROS scavenging and (2) ET_A+B-receptor blockade improve myocardial oxygen delivery in the same female swine model. Healthy female swine on normal pig chow served as controls (Normal). Five months after induction of DM (streptozotocin, 3 × 50 mg kg⁻¹ i.v.), hypercholesterolemia (HFD) and CKD (renal embolization), swine were chronically instrumented and studied at rest and during exercise. Sustained hyperglycemia, hypercholesterolemia and renal dysfunction were accompanied by systemic inflammation and oxidative stress. In vivo ROS scavenging (TEMPOL + MPG) reduced myocardial oxygen delivery in DM + HFD + CKD swine, suggestive of a vasodilator influence of endogenous ROS, while it had no effect in Normal swine. In vitro wire myography revealed a vasodilator role for hydrogen peroxide (H₂O₂) in isolated small coronary artery segments from DM + HFD + CKD, but not Normal swine. Increased catalase activity and ceramide production in left ventricular myocardial tissue of DM + HFD + CKD swine further suggest that increased H₂O₂ acts as vasodilator ROS in the coronary microvasculature. Despite elevated ET-1 plasma levels in DM + HFD + CKD swine, ET_A+B blockade did not affect myocardial oxygen delivery in Normal or DM + HFD + CKD swine. In conclusion, loss of NO bioavailability due to 5 months exposure to multiple comorbidities is partially compensated by increased H₂O₂-mediated coronary vasodilation.

多种常见的心血管合并症会导致冠状动脉微血管功能障碍。我们之前在猪身上观察到，糖尿病（DM）、高脂饮食（HFD）和慢性肾病（CKD）的结合会诱发全身炎症，增加氧化应激并产生冠状动脉内皮功能障碍，通过丧失冠状动脉微血管张力来改变对冠状动脉微血管张力的控制。 NO 生物利用度，与循环内皮素 (ET) 的增加相关。在本研究中，我们在同一雌性猪模型中测试了以下假设：(1) ROS 清除和 (2) ET _A+B受体阻断可改善心肌氧输送。使用正常猪饲料的健康雌性猪作为对照（正常）。诱导 DM（链脲佐菌素，3 × 50 mg kg ^-1 iv）、高胆固醇血症（HFD）和 CKD（肾栓塞）后五个月，对猪进行长期仪器检测并在休息和运动期间进行研究。持续的高血糖、高胆固醇血症和肾功能障碍伴有全身炎症和氧化应激。体内 ROS 清除（TEMPOL + MPG）减少了 DM + HFD + CKD 猪的心肌氧输送，表明内源性 ROS 具有血管舒张作用，而对正常猪则没有影响。体外钢丝肌造影显示，过氧化氢 (H ₂ O ₂ ) 在 DM + HFD + CKD 分离的小冠状动脉段中具有血管扩张作用，但在正常猪中则不然。 DM + HFD + CKD 猪左心室心肌组织中过氧化氢酶活性和神经酰胺产生的增加进一步表明，增加的 H ₂ O ₂在冠状微脉管系统中充当血管扩张剂 ROS。 尽管 DM + HFD + CKD 猪的 ET-1 血浆水平升高，但 ET _A+B阻断并不影响正常或 DM + HFD + CKD 猪的心肌氧输送。总之，由于 5 个月暴露于多种合并症而导致的 NO 生物利用度损失可通过增加 H ₂ O ₂介导的冠状血管舒张来部分补偿。