Lockwood Francesca, Lachaux Marianne, Harouki Najah, Soulié Matthieu, Nicol Lionel, Renet Sylvanie, Dumesnil Anaïs, Vercauteren Magali, Bellien Jeremy, Iglarz Marc, Richard Vincent, Mulder Paul
Univ Rouen Normandie, INSERM U1096, EnVI, Rouen, France.
Institute for Clinical Medicine, Medical Faculty, University of Oslo, Oslo, Norway.
Fundam Clin Pharmacol. 2025 Jun;39(3):e70006. doi: 10.1111/fcp.70006.
Metabolic syndrome (MetS) is a multifaceted disease associated with heart failure (HF), which affects the vascular system. The endothelin (ET) system is a key player in MetS and HF; therefore, targets for ET receptors are of therapeutic interest.
This study sought to evaluate the effects of macitentan, a dual endothelin receptor antagonist (ERA), in a rat model of MetS-induced heart failure with preserved ejection fraction (HFpEF).
We assessed in 12-week-old Zucker fa/fa rats the effects of macitentan (10 mg/kg/day as a food additive for short-term/7- or long-term/90-day treatment) on right ventricular (RV) and left ventricular (LV) function/remodelling (MRI), RV and LV haemodynamics (catheterization) and RV and LV coronary function (myograph).
After 7- and 90-days, untreated Zucker fa/fa rats presented isolated LV diastolic dysfunction (illustrated by elevated LV end-diastolic pressure [EDP] and LV end-diastolic pressure-volume relationship [EDPVR] without changes in LV EDPVR). This was associated with increased collagen deposition and impaired endothelium-dependent coronary artery relaxation. Macitentan 7- and 90-day treatment significantly decreased blood pressure and prevented LV, RV and coronary dysfunctions and long-term treatment reduced LV collagen density. Moreover, 7- and 90-day macitentan treatment significantly reduced cardiac inflammation and reactive oxygen species (ROS) production.
Dual ERA macitentan improved both LV and RV diastolic dysfunction. This was associated with improved coronary vasodilation, diminished cardiac oxidative stress and improved blood composition. These results suggest that antagonizing the ET system with macitentan is a promising approach to treat HFpEF and its complications.
代谢综合征（MetS）是一种与心力衰竭（HF）相关的多方面疾病，会影响血管系统。内皮素（ET）系统在MetS和HF中起关键作用；因此，ET受体的靶点具有治疗意义。
本研究旨在评估双重内皮素受体拮抗剂（ERA）马昔腾坦在射血分数保留的MetS诱导的心力衰竭（HFpEF）大鼠模型中的作用。
我们评估了在12周龄的Zucker fa/fa大鼠中，马昔腾坦（10mg/kg/天作为食品添加剂用于短期/7天或长期/90天治疗）对右心室（RV）和左心室（LV）功能/重塑（MRI）、RV和LV血流动力学（导管插入术）以及RV和LV冠状动脉功能（肌动描记法）的影响。
7天和90天后，未经治疗的Zucker fa/fa大鼠出现孤立的左心室舒张功能障碍（表现为左心室舒张末期压力[EDP]升高和左心室舒张末期压力-容积关系[EDPVR]升高，而左心室EDPVR无变化）。这与胶原沉积增加和内皮依赖性冠状动脉舒张受损有关。马昔腾坦7天和90天治疗显著降低血压，并预防左心室、右心室和冠状动脉功能障碍，长期治疗降低左心室胶原密度。此外，7天和90天马昔腾坦治疗显著减轻心脏炎症和活性氧（ROS）产生。
双重ERA马昔腾坦改善了左心室和右心室舒张功能障碍。这与冠状动脉舒张改善、心脏氧化应激减轻和血液成分改善有关。这些结果表明，用马昔腾坦拮抗ET系统是治疗HFpEF及其并发症的一种有前景的方法。
