Impaired coronary microvascular function (e.g., reduced dilation and coronary flow reserve) predicts cardiac mortality in obesity, yet underlying mechanisms and potential therapeutic strategies remain poorly understood. Mineralocorticoid receptor (MR) antagonism improves coronary microvascular function in obese humans and animals. Whether MR blockade improves in vivo regulation of coronary flow, a process involving voltage-dependent K⁺ (K_v) channel activation, or reduces coronary structural remodeling in obesity is unclear. Thus, the goals of this investigation were to determine the effects of obesity on coronary responsiveness to reductions in arterial PO₂ and potential involvement of K_v channels and whether the benefit of MR blockade involves improved coronary K_v function or altered passive structural properties of the coronary microcirculation. Hypoxemia increased coronary blood flow similarly in lean and obese swine; however, baseline coronary vascular resistance was significantly higher in obese swine. Inhibition of K_v channels reduced coronary blood flow and augmented coronary resistance under baseline conditions in lean but not obese swine and had no impact on hypoxemic coronary vasodilation. Chronic MR inhibition in obese swine normalized baseline coronary resistance, did not influence hypoxemic coronary vasodilation, and did not restore coronary K_v function (assessed in vivo, ex vivo, and via patch clamping). Lastly, MR blockade prevented obesity-associated coronary arteriolar stiffening independent of cardiac capillary density and changes in cardiac function. These data indicate that chronic MR inhibition prevents increased coronary resistance in obesity independent of K_v channel function and is associated with mitigation of obesity-mediated coronary arteriolar stiffening.

受损的冠状动脉微血管功能（例如，减少的扩张和冠状动脉血流储备）可预测肥胖患者的心脏死亡率，但潜在的机制和潜在的治疗策略仍然知之甚少。盐皮质激素受体 (MR) 拮抗剂可改善肥胖人和动物的冠状动脉微血管功能。MR 阻断是否改善了体内冠状动脉血流调节（涉及电压依赖性 K ⁺ (K _v ) 通道激活的过程，或减少肥胖症中的冠状动脉结构重塑）尚不清楚。因此，本研究的目的是确定肥胖对冠状动脉对动脉 PO _{2减少的反应和 K v}潜在参与的影响。通道以及 MR 阻断的益处是否涉及改善冠状动脉 K _v功能或改变冠状动脉微循环的被动结构特性。在瘦猪和肥胖猪中，低氧血症同样增加了冠状​​动脉血流量；然而，肥胖猪的基线冠状动脉血管阻力明显更高。_{在瘦但不肥胖的猪的基线条件下，K v}通道的抑制降低了冠状动脉血流量并增加了冠状​​动脉阻力，并且对低氧性冠状动脉血管舒张没有影响。肥胖猪的慢性 MR 抑制使基线冠状动脉阻力正常化，不影响低氧性冠状动脉血管舒张，并且不恢复冠状动脉_Kv功能（在体内、体外和通过膜片钳进行评估）。最后，MR 阻断可防止肥胖相关的冠状动脉硬化，而与心脏毛细血管密度和心脏功能的变化无关。这些数据表明，慢性 MR 抑制可防止肥胖患者冠状动脉阻力增加，而与 K _v通道功能无关，并且与减轻肥胖介导的冠状动脉硬化有关。