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1 Paediatrics, Hospital for Sick Children, Toronto, Canada
2 Newborn and Developmental Paediatrics, Sunnybrook Health Sciences Centre, Toronto, Canada
3 Clinical Integrative Biology, Sunnybrook Research Institute, Toronto, Canada
4 Physiology & Experimental Medicine, Hospital for Sick Children Research Institute, Toronto, Canada
5 Newborn and Developmental Paediatrics, Sunnybrook Health Sciences Centre, United States
* To whom correspondence should be addressed. E-mail: robert.jankov{at}sunnybrook.ca.
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 (Y-27632 15 mg/kg or fasudil 30 mg/kg i.p.) in two neonatal rat models of chronic PHT with pulmonary vascular remodeling (chronic hypoxia, FiO2 0.13, or chronic i.p. bleomycin 1 mg/kg/d for 14 d 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 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, SIN-1 (2 µg/kg i.p.). In contrast, a single i.p. 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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