Kobayashi N, Higashi T, Hara K, Shirataki H, Matsuoka H
Department of Medicine, Dokkyo University School of Medicine, Tochigi, Japan.
Cardiovasc Res. 1999 Dec;44(3):518-26. doi: 10.1016/s0008-6363(99)00237-0.
To elucidate the relationship between renin-angiotensin system and nitric oxide in hypertensive heart failure, we evaluated the effects of long-term treatment with imidapril, angiotensin-converting enzyme inhibitor, on endothelial-cell nitric oxide synthase (eNOS) and inducible NOS (iNOS) expression in the left ventricle (LV) and its relation to myocardial remodelling in failing heart of Dahl salt-sensitive hypertensive rats (DS) fed a high-salt diet.
In DS rats fed an 8% NaCl diet after the age of 6 weeks, a stage of concentric left ventricular hypertrophy at 11 weeks (DSLVH) was followed by a distinct stage of fatal left ventricular failure with chamber dilatation at 18 weeks (DSCHF). Imidapril (DSCHF-I, n = 7, 1 mg/kg/day, subdepressor dose) or vehicle (DSCHF-V, n = 7) were given from DSLVH to DSCHF stage for 7 weeks, and age-matched (18 weeks) Dahl salt-resistant rats fed the same diet were served as control group (DR-C, n = 7).
Markedly increased left ventricular end-diastolic diameter and reduced fractional shortening in DSCHF-V was significantly ameliorated in DSCHF-I using transthoracic echocardiography. The level of eNOS mRNA and protein in the LV was significantly suppressed in DSCHF-V compared with DR-C, and significantly increased in DSCHF-I compared with DR-C and DSCHF-V. The iNOS mRNA and protein and the fibrosis factor expression of type I collagen mRNA were significantly increased in DSCHF-V compared with DR-C, and significantly decreased in DSCHF-I compared with DSCHF-V. DSCHF-V demonstrated a significant increase in wall-to-lumen ratio, perivascular fibrosis, and myocardial fibrosis. These changes in the microvasculature were improved significantly by imidapril.
Subdepressor dose of imidapril may ameliorate the endothelial damage not only by inhibiting production of angiotensin II but also by promoting eNOS and inhibiting iNOS mRNA and protein expression in the LV, and this increased eNOS mRNA and protein level may have a role in the improvement of congestive heart failure and myocardial remodelling.
为阐明高血压性心力衰竭中肾素-血管紧张素系统与一氧化氮之间的关系，我们评估了血管紧张素转换酶抑制剂咪达普利长期治疗对高盐饮食喂养的 Dahl 盐敏感高血压大鼠（DS）衰竭心脏左心室（LV）中内皮细胞一氧化氮合酶（eNOS）和诱导型一氧化氮合酶（iNOS）表达的影响，及其与心肌重塑的关系。
6 周龄后喂食 8%氯化钠饮食的 DS 大鼠，11 周时处于同心性左心室肥厚阶段（DSLVH），18 周时发展为明显的伴有心室扩张的致命性左心室衰竭阶段（DSCHF）。从 DSLVH 到 DSCHF 阶段，给咪达普利（DSCHF-I，n = 7，1 mg/kg/天，亚降压剂量）或赋形剂（DSCHF-V，n = 7），持续 7 周，将喂食相同饮食的年龄匹配（18 周）的 Dahl 盐抵抗大鼠作为对照组（DR-C，n = 7）。
经胸超声心动图显示，DSCHF-V 组左心室舒张末期直径显著增加，缩短分数降低，而 DSCHF-I 组这些情况得到显著改善。与 DR-C 相比，DSCHF-V 组 LV 中 eNOS mRNA 和蛋白水平显著降低，与 DR-C 和 DSCHF-V 相比，DSCHF-I 组显著升高。与 DR-C 相比，DSCHF-V 组 iNOS mRNA 和蛋白以及 I 型胶原 mRNA 的纤维化因子表达显著增加，与 DSCHF-V 相比，DSCHF-I 组显著降低。DSCHF-V 组血管壁与管腔比值、血管周围纤维化和心肌纤维化显著增加。咪达普利显著改善了这些微血管的变化。
亚降压剂量的咪达普利可能不仅通过抑制血管紧张素 II 的产生，还通过促进 eNOS 和抑制 LV 中 iNOS mRNA 和蛋白表达来改善内皮损伤，这种 eNOS mRNA 和蛋白水平的升高可能在改善充血性心力衰竭和心肌重塑中发挥作用。
