Tachykinin dysfunction attenuates monocrotaline-induced pulmonary hypertension.
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.
Chen
Mei-Jung
MJ
Department of Physiology, National Taiwan University College of Medicine, 100, Taipei, Taiwan.
Lai
Yih-Loong
YL
D000818:Animals; D001794:Blood Pressure; D001835:Body Weight; D006339:Heart Rate; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000378:metabolism* / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000503:physiopathology; D008297:Male; D016686:Monocrotaline / Q000633:toxicity*; D009929:Organ Size; D034622:RNA Interference; D012330:RNA, Double-Stranded / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018039:Receptors, Tachykinin / Q000037:antagonists & inhibitors / Q000378:metabolism; D013373:Substance P / Q000032:analysis; D015320:Tachykinins / Q000235:genetics / Q000378:metabolism*
D012330:RNA, Double-Stranded; D018039:Receptors, Tachykinin; D015320:Tachykinins; D013373:Substance P; D016686:Monocrotaline