Acute vasodilator effects of Rho-kinase inhibitors in neonatal rats with pulmonary hypertension unresponsive to nitric oxide.
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.
McNamara
Patrick J
PJ
Department of Newborn and Developmental Paediatrics, Sunnybrook Health Sciences Centre, 76 Grenville Street, Toronto, Ontario, Canada.
Murthy
Prashanth
P
Kantores
Crystal
C
Teixeira
Lilian
L
Engelberts
Doreen
D
van Vliet
Todd
T
Kavanagh
Brian P
BP
Jankov
Robert P
RP
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
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