Endothelin-1 Pulmonary Vasoconstriction in Rats with Diaphragmatic Hernia

Abstract

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.Materials and 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 10−12to 10−8M were compared by Student'sttest.Results.CDH arterioles constricted more than controls in response to endothelin-1 at concentrations of 10−11M (29 ± 11% vs 5 ± 3%,P= 0.02) and 10−10M (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≥ 0.05).Conclusions.Exaggerated vasoconstrictor responses to endothelin-1 may contribute to pulmonary hypertension in CDH.