Effect of CGS 26303, an endothelin-converting enzyme-neutral endopeptidase inhibitor, on nitrofen-induced congenital diaphragmatic hernia in the rat.
OBJECTIVE
The pathophysiology of congenital diaphragmatic hernia (CDH) associated with lung hypoplasia and pulmonary hypertension is not understood fully. Endothelins (ETs) are the most potent vasoconstrictors that also act as promitogenic agents. They may play a role during pregnancy in leading to the condition found at birth and ongoing mortality in CDH. Therefore, the authors studied the effect of CGS 26303, a nonselective endothelin-converting enzyme and neutral endopeptidase inhibitor, in the rat model of CDH.


METHODS
Pregnant Sprague-Dawley rats were divided into 3 groups: group 1 (n = 4) received CGS 26303 (50 mg/kg, subcutaneously, twice a day), from gestational day 12 until term (21 to 23 days); group 2 (n = 8) received nitrofen (100 mg/kg, orally) at gestational day 11.5; group 3 (n = 8) received both nitrofen and CGS 26303. The survival of the newborn rats was monitored up to 240 minutes. After natural death or euthanasia, they were weighed and microdissected. The degree of hernia was quantified as small, moderate, or severe, and lungs and liver were harvested and weighed.


RESULTS
Newborn rats from mothers of group 3 (n = 81) survived 196 +/- 8 minutes compared with 173 +/- 9 minutes of those of group 2 (n = 97). Severe CDH from group 3 (n = 20) had a mean survival time of 66 +/- 13 minutes compared with 26 +/- 4 minutes for those of group 2 (n = 27). Lung index in severe CDH pups of group 3 was increased by 13% compared with those from group 2 (P < .0001), whereas their liver index went down by 8% (P < .05).


CONCLUSIONS
These results suggest that CGS 26303 might have a beneficial effect when given during pregnancy in increasing survival at birth and reducing the severity of the pulmonary hypoplasia in newborn rats with nitrofen-induced CDH.
Kavanagh
M
M
Anaesthesiology and Neonatal Investigation Laboratory, Laval University Hospital Centre, CHUQ/CHUL, Sainte-Foy, Quebec, Canada.
Battistini
B
B
Kluth
D
D
Jean
S
S
Fournier
L
L
Jeng
A Y
AY
Major
D
D
Cloutier
R
R
D000818:Animals; D000831:Animals, Newborn; D016282:Aspartic Acid Endopeptidases / Q000187:drug effects* / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D004195:Disease Models, Animal; D000072396:Endothelin-Converting Enzymes; D005260:Female; D006548:Hernia, Diaphragmatic / Q000139:chemically induced / Q000145:classification / Q000188:drug therapy*; D065630:Hernias, Diaphragmatic, Congenital; D007279:Injections, Subcutaneous; D016014:Linear Models; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D008666:Metalloendopeptidases; D009929:Organ Size / Q000187:drug effects; D063065:Organophosphonates / Q000494:pharmacology*; D010647:Phenyl Ethers; D011247:Pregnancy; D016016:Proportional Hazards Models; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D012016:Reference Values; D016019:Survival Analysis; D013777:Tetrazoles / Q000494:pharmacology*
D063065:Organophosphonates; D010647:Phenyl Ethers; D011480:Protease Inhibitors; D013777:Tetrazoles; C089987:CGS 26303; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; C007350:nitrofen