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 10-12 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 ≤ 0.05). Conclusions. Exaggerated vasoconstrictor responses to endothelin-1 may contribute to pulmonary hypertension in CDH.