title: Acute vasodilator effects of Rho-kinase inhibitors in neonatal rats with pulmonary hypertension unresponsive to nitric oxide.
abstract: 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 Fi(O(2)), or 1 mg.kg(-1).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 mug/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.
authors.affiliation: Department of Newborn and Developmental Paediatrics, Sunnybrook Health Sciences Centre, 76 Grenville Street, Toronto, Ontario, Canada.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: McNamara
authors.forename: Prashanth
authors.initials: P
authors.lastname: Murthy
authors.forename: Crystal
authors.initials: C
authors.lastname: Kantores
authors.forename: Lilian
authors.initials: L
authors.lastname: Teixeira
authors.forename: Doreen
authors.initials: D
authors.lastname: Engelberts
authors.forename: Todd
authors.initials: T
authors.lastname: van Vliet
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kavanagh
authors.forename: Robert P
authors.initials: RP
authors.lastname: Jankov
mesh_terms: D000280:Administration, Inhalation; D000577:Amides / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001761:Bleomycin; D002465:Cell Movement / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D000860:Hypoxia; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D009569:Nitric Oxide / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014655:Vascular Resistance / Q000187:drug effects; D014665:Vasodilator Agents / Q000627:therapeutic use*; D016278:Ventricular Function, Right / Q000187:drug effects; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D000577:Amides; D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; D011725:Pyridines; D014665:Vasodilator Agents; D001761:Bleomycin; C108830:Y 27632; D009569:Nitric Oxide; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein