Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
Hypertens Res. 2012 Nov;35(11):1093-101. doi: 10.1038/hr.2012.94. Epub 2012 Jul 12.
Arteries from young healthy animals respond to chronic changes in blood flow and blood pressure by structural remodeling. We tested whether the ability to respond to decreased (-90%) or increased (+100%) blood flow is impaired during the development of deoxycorticosterone acetate (DOCA)-salt hypertension in rats, a model for an upregulated endothelin-1 system. Mesenteric small arteries (MrA) were exposed to low blood flow (LF) or high blood flow (HF) for 4 or 7 weeks. The bioavailability of vasoactive peptides was modified by chronic treatment of the rats with the dual neutral endopeptidase (NEP)/endothelin-converting enzyme (ECE) inhibitor SOL1. After 3 or 6 weeks of hypertension, the MrA showed hypertrophic arterial remodeling (3 weeks: media cross-sectional area (mCSA): 10±1 × 10(3) to 17±2 × 10(3) μm(2); 6 weeks: 13±2 × 10(3) to 24±3 × 10(3) μm(2)). After 3, but not 6, weeks of hypertension, the arterial diameter was increased (Ø: 385±13 to 463±14 μm). SOL1 reduced hypertrophy after 3 weeks of hypertension (mCSA: 6 × 10(3)±1 × 10(3) μm(2)). The diameter of the HF arteries of normotensive rats increased (Ø: 463±22 μm) but no expansion occurred in the HF arteries of hypertensive rats (Ø: 471±16 μm). MrA from SOL1-treated hypertensive rats did show a significant diameter increase (Ø: 419±13 to 475±16 μm). Arteries exposed to LF showed inward remodeling in normotensive and hypertensive rats (mean Ø between 235 and 290 μm), and infiltration of monocyte/macrophages. SOL1 treatment did not affect the arterial diameter of LF arteries but reduced the infiltration of monocyte/macrophages. We show for the first time that flow-induced remodeling is impaired during the development of DOCA-salt hypertension and that this can be prevented by chronic NEP/ECE inhibition.
动脉的结构会发生重塑，以适应血流和血压的慢性变化。我们检测了在去氧皮质酮醋酸盐（DOCA）-盐性高血压大鼠模型（内皮素-1 系统上调的模型）中，动脉对血流量减少（-90%）或增加（+100%）的反应能力是否会在发展过程中受损。肠系膜小动脉（MrA）接受低血流（LF）或高血流（HF）处理 4 或 7 周。大鼠慢性接受双重中性内肽酶（NEP）/内皮素转换酶（ECE）抑制剂 SOL1 治疗，可改变血管活性肽的生物利用度。高血压 3 或 6 周后，MrA 显示出血管肥厚性重塑（3 周：中膜横截面积（mCSA）：10±1×103 至 17±2×103μm2；6 周：13±2×103 至 24±3×103μm2）。高血压 3 周后，动脉直径增大（Ø：385±13 至 463±14μm），但高血压 6 周后没有增大。3 周高血压时，SOL1 减少了肥厚（mCSA：6×103±1×103μm2）。正常血压大鼠的 HF 动脉直径增大（Ø：463±22μm），但高血压大鼠的 HF 动脉没有扩张（Ø：471±16μm）。接受 SOL1 治疗的高血压大鼠的 MrA 确实显示出显著的直径增大（Ø：419±13 至 475±16μm）。正常血压和高血压大鼠 LF 动脉出现内向重塑（平均 Ø 为 235 至 290μm），并发生单核细胞/巨噬细胞浸润。SOL1 治疗不影响 LF 动脉的动脉直径，但减少单核细胞/巨噬细胞的浸润。我们首次表明，在 DOCA-盐性高血压的发展过程中，流量诱导的重塑受损，而慢性 NEP/ECE 抑制可预防这种情况。
