Baba T, Kanda T, Kobayashi I
Department of Laboratory Medicine, Gunma University School of Medicine, Maebashi, Japan.
Life Sci. 2000 Jun 23;67(5):587-97. doi: 10.1016/s0024-3205(00)00654-8.
Renin angiotensin system contributes to activation of circulating endothelin in congestive heart failure. To investigate the effects of angiotensin II receptor antagonist and angiotensin converting enzyme inhibitors (ACEI) on the levels of endothelin-1 (ET-1), we administered orally angiotensin II type 1 receptor (AT1) antagonist, L-158,809 (ATA) (6, 1.2 and 0.12 mg/kg/day), enalapril (1 mg/kg/day) and captopril (7.5 mg/kg/day) for 14 days to mice with viral myocarditis, beginning 7 days after encephalomyocarditis virus (500 pfu/mouse) inoculation. Plasma ET-1, cardiac ET-1, heart weight (HW) and HW/ body weight (BW) ratio were examined and compared with infected untreated mice. Moreover, the HW (mg) and HW/BW (x 10(-3)) ratio were significantly (P<0.05) reduced in mice treated with ATA and ACEIs in comparison with infected control. ACEIs and higher dosed of ATA reduced myofiber hypertrophy. Both of plasma and cardiac ET-1 proteins were significantly elevated in infected control compared with uninfected normal mice. Plasma ET-1 was significantly (P<0.01) reduced in mice with three different concentrations of ATA but were not decreased in mice with captopril or enalapril compared with infected control. The expression of endothelin-1 mRNA was significantly reduced in mice with ATA in comparison with infected untreated mice by competitive RT-PCR. ATA reduced ET-1 protein and mRNA in the myocardium of mice with myocarditis, improving congestive heart failure and myofiber hypertrophy. We suggest the effect of ATA on the reduction of endothelin has a different pathway from angiotensin converting inhibitor and that ATA seems to be a useful agents for congestive heart failure due to viral myocarditis.
肾素血管紧张素系统参与充血性心力衰竭时循环内皮素的激活。为研究血管紧张素II受体拮抗剂和血管紧张素转换酶抑制剂（ACEI）对内皮素-1（ET-1）水平的影响，我们于脑心肌炎病毒（500 pfu/小鼠）接种后7天开始，对患有病毒性心肌炎的小鼠口服给予1型血管紧张素II受体（AT1）拮抗剂L-158,809（ATA）（6、1.2和0.12 mg/kg/天）、依那普利（1 mg/kg/天）和卡托普利（7.5 mg/kg/天），持续14天。检测血浆ET-1、心脏ET-1、心脏重量（HW）和心脏重量/体重（BW）比值，并与未治疗的感染小鼠进行比较。此外，与感染对照组相比，接受ATA和ACEI治疗的小鼠的HW（mg）和HW/BW（×10⁻³）比值显著降低（P<0.05）。ACEI和高剂量的ATA可减轻肌纤维肥大。与未感染的正常小鼠相比，感染对照组的血浆和心脏ET-1蛋白均显著升高。与感染对照组相比，三种不同浓度ATA处理的小鼠血浆ET-1显著降低（P<0.01），但卡托普利或依那普利处理的小鼠血浆ET-1未降低。通过竞争性逆转录-聚合酶链反应（RT-PCR）检测，与未治疗的感染小鼠相比，ATA处理的小鼠内皮素-1 mRNA表达显著降低。ATA可降低心肌炎小鼠心肌中的ET-1蛋白和mRNA水平，改善充血性心力衰竭和肌纤维肥大。我们认为ATA降低内皮素的作用途径与血管紧张素转换抑制剂不同，ATA似乎是治疗病毒性心肌炎所致充血性心力衰竭的有效药物。
