Effects of rho-kinase inhibition on pulmonary hypertension, lung growth, and structure in neonatal rats chronically exposed to hypoxia.
Rho-kinase (ROCK) inhibitors prevent pulmonary hypertension (PHT) in adult rodents, but little is known about their effects on the neonatal lung. Our objective was to examine the effects of ROCK inhibition on chronic hypoxia (CH)-induced PHT and abnormal lung structure in the neonatal rat. Pups were exposed to air or CH from postnatal d 1-14 while receiving Y-27632 (5 or 10 mg x kg(-1) x d(-1)), fasudil (20 mg x kg(-1) x d(-1)), or saline intraperitoneally. Relative to air, CH-exposed pups had increased pulmonary vascular resistance, right ventricular hypertrophy, arterial medial wall thickening, and abnormal distal airway morphology characterized by septal thinning and decreased secondary septation. Treatment with 10 mg/kg Y-27632 or fasudil attenuated the structural and hemodynamic changes of PHT while having no effect on septal thinning or inhibited secondary septation. In addition, Y-27632 (10 mg/kg) and fasudil augmented CH-induced somatic growth restriction. Pulmonary arteries of CH-exposed pups had increased ROCK activity, up-regulated expression of PDGF-BB and increased smooth muscle DNA synthesis, all of which were attenuated by treatment with 10 mg/kg Y-27632. Systemically administered ROCK inhibitors prevented PHT in the CH-exposed neonatal rat but at the cost of inhibited somatic growth. Limiting effects on vascular remodeling likely resulted, in major part, from attenuated vascular PDGF-BB/beta-receptor signaling.
Clinical Integrative Biology, Sunnybrook Research Institute, Toronto, Ontario, Canada M4N 3M5.
Adrian J A
AJ
Ziino
Julijana
J
Ivanovska
Rosetta
R
Belcastro
Crystal
C
Kantores
Emily Z
EZ
Xu
Mandy
M
Lau
Patrick J
PJ
McNamara
A Keith
AK
Tanswell
Robert P
RP
Jankov
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D056151:Airway Remodeling / Q000187:drug effects; D000577:Amides / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D000959:Antihypertensive Agents / Q000494:pharmacology*; D000077214:Becaplermin; D001835:Body Weight; D002908:Chronic Disease; D004261:DNA Replication; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018496:Hyperoxia / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D017380:Hypertrophy, Right Ventricular / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009929:Organ Size; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020574:Proto-Oncogene Proteins c-sis; D011651:Pulmonary Artery / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D014655:Vascular Resistance / Q000187:drug effects; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000577:Amides; D000959:Antihypertensive Agents; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D020574:Proto-Oncogene Proteins c-sis; D011725:Pyridines; C108830:Y 27632; D000077214:Becaplermin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D020797:Receptor, Platelet-Derived Growth Factor beta; D054460:rho-Associated Kinases; C049347:fasudil