Endothelin-1 pulmonary vasoconstriction in rats with diaphragmatic hernia.
BACKGROUND
Pulmonary hypertension is an important cause of mortality in infants with congenital diaphragmatic hernia (CDH). Endothelin-1 has been implicated as a mediator of pulmonary hypertension. ET-A receptors are increased in the nitrofen model of CDH in rats. We hypothesized that vasoconstrictor responses to endothelin-1 are increased in pulmonary arterioles of rats with nitrofen-induced CDH.


METHODS
CDH was induced in fetal rats by feeding nitrofen (2,4-dichlorophenyl-p-nitrophenyl ether) to pregnant rats at midgestation. Third-generation pulmonary arterioles were isolated on the final day of gestation. Arterioles were cannulated and perfused at constant pressure with a physiologic salt solution. Diameters of arterioles from control animals (n = 8), CDH animals (n = 5), and animals exposed to nitrofen but without CDH (n = 4) were measured. Responses to endothelin-1 concentrations of 10(-12) to 10(-8) M were compared by Student's t test.


RESULTS
CDH arterioles constricted more than controls in response to endothelin-1 at concentrations of 10(-11) M (29 +/- 11% vs 5 +/- 3%, P = 0.02) and 10(-10) M (40 +/- 14% vs 9 +/- 6%, P = 0.04). The log concentration of endothelin-1 that induced half-maximal response (ED50) was lower for CDH arterioles than for control arterioles (-10.3 +/- 0.6 vs -9.1 +/- 0.2, P = 0.03). Responses of arterioles from animals exposed to nitrofen but without CDH were not different from controls (P > or = 0.05).


CONCLUSIONS
Exaggerated vasoconstrictor responses to endothelin-1 may contribute to pulmonary hypertension in CDH.
Section of Pediatric Surgery, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
C P
CP
Coppola
M
M
Au-Fliegner
J R
JR
Gosche
D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000494:pharmacology*; D005260:Female; D006540:Herbicides; D065630:Hernias, Diaphragmatic, Congenital; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism*; D008168:Lung / Q000098:blood supply* / Q000378:metabolism; D010647:Phenyl Ethers; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
D019332:Endothelin-1; D006540:Herbicides; D010647:Phenyl Ethers; C007350:nitrofen