期刊
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
卷 294, 期 2, 页码 L205-L213出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajplung.00234.2007
关键词
Y-27632; fasudil; two-dimensional echocardiography; pulse wave Doppler; SIN-1
资金
- CIHR [84290, 87702] Funding Source: Medline
Pulmonary hypertension (PHT) in neonates is often refractory to the current best therapy, inhaled nitric oxide ( NO). The utility of a new class of pulmonary vasodilators, Rho-kinase ( ROCK) inhibitors, has not been examined in neonatal animals. Our objective was to examine the activity and expression of RhoA/ROCK in normal and injured pulmonary arteries and to determine the short-term pulmonary hemodynamic ( assessed by pulse wave Doppler) effects of ROCK inhibitors ( 15 mg/kg ip Y-27632 or 30 mg/kg ip fasudil) in two neonatal rat models of chronic PHT with pulmonary vascular remodeling ( chronic hypoxia, 0.13 FIO2, or 1 mg center dot kg(-1) center dot day(-1) ip chronic bleomycin for 14 days from birth). Activity of the RhoA/ROCK pathway and ROCK expression were increased in hypoxia- and bleomycin-induced PHT. In both models, severe PHT [ characterized by raised pulmonary vascular resistance (PVR) and impaired right ventricular ( RV) performance] did not respond acutely to inhaled NO ( 20 ppm for 15 min) or to a single bolus of a NO donor, 3-morpholinosydnonimine hydrochloride ( SIN-1; 2 mu g/kg ip). In contrast, a single intraperitoneal bolus of either ROCK inhibitor ( Y-27632 or fasudil) completely normalized PVR but had no acute effect on RV performance. ROCK-mediated vasoconstriction appears to play a key role in chronic PHT in our two neonatal rat models. Inhibitors of ROCK have potential as a testable therapy in neonates with PHT that is refractory to NO.
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