BAY 41-2272, a direct activator of soluble guanylate cyclase, reduces right ventricular hypertrophy and prevents pulmonary vascular remodeling during chronic hypoxia in neonatal rats.
Exposure to hypoxia during the first weeks of life in newborn rats decreases vascular growth and alveolarization and causes pulmonary hypertension (PH). BAY 41-2272 is a novel direct activator of soluble guanylate cyclase independent of nitric oxide, effective as an acute pulmonary vasodilator in an animal model of persistent pulmonary hypertension of the newborn, but whether prolonged BAY 41-2272 therapy is effective in the setting of chronic PH is unknown. We hypothesize that BAY 41-2272 would prevent PH induced by chronic exposure to neonatal hypoxia. At 2 days of age, newborn rats were randomly exposed to hypoxia (FiO2, 0.12) or room air, and received daily intramuscular treatment with BAY 41-2272 (1 mg/kg) or saline. After 2 weeks, rats were killed for assessment of right ventricular hypertrophy (RVH), wall thickness of small pulmonary arteries, vessels density, radial alveolar counts and mean linear intercepts. In comparison with control, hypoxia increased RVH and artery wall thickness, reduced vessels density, decreased radial alveolar counts and increased mean linear intercepts. In comparison with hypoxic controls, prolonged BAY 41-2272 treatment during chronic hypoxia reduced RVH (0.67 +/- 0.03 vs. 0.52 +/- 0.05; p < 0.05), and attenuated artery wall thickness (48.2 +/- 2.8% vs. 35.7 +/- 4.1 microm; p < 0.01). However, BAY 41-2272 did not change vessels density, radial alveolar counts or mean linear intercepts. We conclude that BAY 41-2272 prevents the vascular structural effects of PH and reduces RVH but does not protect from hypoxia-induced inhibition of alveolarization and vessel growth. We speculate that BAY 41-2272 may provide a new therapy for chronic PH.
Department of Pediatrics, Pediatric Heart Lung Center, University of Colorado School of Medicine, Denver, Colo., USA. p-deruelle@chru-lille.fr
Philippe
P
Deruelle
Vivek
V
Balasubramaniam
Anette M
AM
Kunig
Gregory J
GJ
Seedorf
Neil E
NE
Markham
Steven H
SH
Abman
D000818:Animals; D000831:Animals, Newborn; D002908:Chronic Disease; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000473:pathology* / Q000503:physiopathology / Q000517:prevention & control; D000860:Hypoxia / Q000150:complications / Q000473:pathology* / Q000503:physiopathology; D008168:Lung / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D009929:Organ Size; D011247:Pregnancy; D011651:Pulmonary Artery / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects
C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D011720:Pyrazoles; D011725:Pyridines; D006162:Guanylate Cyclase