Hacker A D
Department of Medicine, University of California, Los Angeles.
Biochem Pharmacol. 1993 Jun 22;45(12):2475-81. doi: 10.1016/0006-2952(93)90229-p.
Dietary restriction (DR), i.e. reduction of total caloric intake, has been shown to result in protection against monocrotaline (MCT)-induced pulmonary hypertension (PH). Restriction of the diet to 8 g/rat/day instead of the usual intake (18 g/rat/day), inhibits the progression of cardiopulmonary changes and prolongs survival after a single dose of MCT. We have shown previously that the development of MCT-induced pulmonary hypertension is associated with inhibition of polyamine biosynthesis in the lungs of MCT-treated rats. In the present study, we tested the hypothesis that DR provides protection against the development of chronic PH in the rat by limiting increases in polyamine and DNA synthesis. We randomly divided animals into four groups each (MCT, MCT + DR, control, and control + DR). We injected rats with a single dose of MCT (60 mg/kg, s.c.) and a corresponding number of control rats with vehicle. Animals in all groups were given free access to food and water prior to administration of MCT. Immediately following injection of MCT both the MCT and control groups were given free access to food and water, while the other groups (MCT + DR and control + DR) we given the restricted diet (8 g/rat/day). Daily measurements were made of body weight and of water and food intake. Animals were killed in each group at 1, 4, 7, 14, and 21 days post MCT to determine right ventricular hypertrophy (RVH), lung wet weight, ornithine decarboxylase (ODC) activity, and polyamine and DNA contents. We measured DNA synthesis 7 days after MCT by determining [3H]thymidine incorporation into the whole lung DNA. We found that 7 days after MCT treatment DNA synthesis increased compared to control. However, DR (MCT + DR) treatmen prevented the increase in DNA synthesis following MCT. Right ventricular hypertrophy, lung wet weight, ODC activity and lung polyamine levels were increased following MCT. Treatment with DR (MCT + DR) prevented increases in RVH, lung wet weight, ODC activity and lung polyamine levels. We conclude that DR to 8 g/day/rat protects against MCT-induced PH and is associated with an inhibition of increased lung polyamine and DNA synthesis that occur in the lung during the development of MCT-induced PH. These results are consistent with a recent report which suggests that increased lung polyamine biosynthesis is required for the development of MCT-induced PH. The data are also consistent with the hypothesis that inhibition of polyamine biosynthesis influences the development of MCT-induced PH in part by regulating DNA synthesis in key lung cells.
饮食限制（DR），即减少总热量摄入，已被证明可预防野百合碱（MCT）诱导的肺动脉高压（PH）。将饮食限制为8克/大鼠/天，而不是通常的摄入量（18克/大鼠/天），可抑制心肺变化的进展，并延长单次注射MCT后的生存期。我们之前已经表明，MCT诱导的肺动脉高压的发展与MCT处理的大鼠肺中多胺生物合成的抑制有关。在本研究中，我们测试了以下假设：DR通过限制多胺和DNA合成的增加来预防大鼠慢性PH的发展。我们将动物随机分为四组（MCT组、MCT + DR组、对照组和对照组 + DR组）。我们给大鼠单次注射MCT（60毫克/千克，皮下注射），并给相应数量的对照大鼠注射赋形剂。在注射MCT之前，所有组的动物均可自由获取食物和水。注射MCT后，MCT组和对照组可立即自由获取食物和水，而其他组（MCT + DR组和对照组 + DR组）给予限制饮食（8克/大鼠/天）。每天测量体重、水摄入量和食物摄入量。在注射MCT后的第1、4、7、14和21天，处死每组动物，以确定右心室肥大（RVH）、肺湿重、鸟氨酸脱羧酶（ODC）活性以及多胺和DNA含量。我们通过测定[3H]胸苷掺入全肺DNA来测量MCT处理7天后的DNA合成。我们发现，与对照组相比，MCT处理7天后DNA合成增加。然而，DR（MCT + DR）处理可防止MCT后DNA合成的增加。MCT后右心室肥大、肺湿重、ODC活性和肺多胺水平增加。DR（MCT + DR）处理可防止RVH、肺湿重、ODC活性和肺多胺水平的增加。我们得出结论，将饮食限制为8克/天/大鼠可预防MCT诱导的PH，并且与抑制MCT诱导的PH发展过程中肺中多胺和DNA合成的增加有关。这些结果与最近的一份报告一致，该报告表明MCT诱导的PH发展需要肺中多胺生物合成增加。这些数据也与以下假设一致，即多胺生物合成的抑制部分通过调节关键肺细胞中的DNA合成来影响MCT诱导的PH的发展。
