Chen Mei-Jung, Lai Yih-Loong
Department of Physiology, National Taiwan University College of Medicine, 100, Taipei, Taiwan.
Toxicol Appl Pharmacol. 2003 Mar 15;187(3):178-85. doi: 10.1016/s0041-008x(02)00070-4.
We explored the dysfunction of tachykinins on monocrotaline (MCT)-induced pulmonary hypertension by using double-stranded preprotachykinin (ds PPT) RNA and neurokinin receptor (NK) antagonists. Here, we showed the possibility to attenuate the PPT gene expression by ds RNA, RNA interference (RNAi), in fully developed tissue of rats. We designed four groups (control, MCT, RNAi + MCT, and solvent + MCT) of experiments in series 1 and seven groups (control, MCT, MCT + CP-96345-3.4, MCT + CP-96345-10, MCT + CP-96344-10, MCT + SR-48968, and MCT + SR-48965) of experiments in series 2. Rats in the control groups received saline injection. MCT-treated rats received a single MCT injection (60 mg/kg sc). One day prior to MCT, bilateral nodose ganglia were microinjected with ds PPT RNA in rats of the RNAi + MCT group or with solvent in the solvent + MCT group. Beginning from 1 day post-MCT, MCT-treated rats received a daily injection of the NK(1) receptor antagonist, CP-96345 (3.4 or 10 mg/kg ip) or its inactive enantiomer CP-96344 (10 mg/kg ip). The NK(2) receptor antagonist SR-48968 (3 mg/kg ip) or its inactive enantiomer SR-48965 (3 mg/kg ip) was injected to MCT-treated rats every other day starting 1 day post-MCT. Functional study was carried out 2 weeks (series 1) or 3 weeks (series 2) after MCT. MCT induced right ventricular hypertrophy, as well as increases in pulmonary arterial pressure, PPT mRNA (nodose ganglia and lung tissue), and lung tissue substance P level. All of the above MCT-induced alterations were attenuated by either RNAi or NK receptor antagonists. We conclude that tachykinins play an important role in MCT-induced pulmonary hypertension.
我们通过使用双链前速激肽原（ds PPT）RNA和神经激肽受体（NK）拮抗剂，探讨了速激肽在野百合碱（MCT）诱导的肺动脉高压中的功能障碍。在此，我们展示了在大鼠完全发育的组织中，通过ds RNA（RNA干扰，RNAi）减弱PPT基因表达的可能性。我们在系列1中设计了四组实验（对照组、MCT组、RNAi + MCT组和溶剂 + MCT组），在系列2中设计了七组实验（对照组、MCT组、MCT + CP - 96345 - 3.4组、MCT + CP - 96345 - 10组、MCT + CP - 96344 - 10组、MCT + SR - 48968组和MCT + SR - 48965组）。对照组大鼠接受盐水注射。MCT处理组大鼠接受单次MCT注射（60 mg/kg皮下注射）。在注射MCT前一天，RNAi + MCT组大鼠双侧结状神经节显微注射ds PPT RNA，溶剂 + MCT组大鼠注射溶剂。从MCT注射后1天开始，MCT处理组大鼠每天注射NK(1)受体拮抗剂CP-96345（3.4或10 mg/kg腹腔注射）或其无活性对映体CP-96344（10 mg/kg腹腔注射）。从MCT注射后1天开始，每隔一天给MCT处理组大鼠注射NK(2)受体拮抗剂SR-48968（3 mg/kg腹腔注射）或其无活性对映体SR-48965（3 mg/kg腹腔注射）。在MCT注射后2周（系列1）或3周（系列2）进行功能研究。MCT诱导右心室肥大，以及肺动脉压、PPT mRNA（结状神经节和肺组织）和肺组织P物质水平升高。上述所有MCT诱导的改变均被RNAi或NK受体拮抗剂减弱。我们得出结论，速激肽在MCT诱导的肺动脉高压中起重要作用。
