The Role of Endothelin and Endothelin Receptor Subtypes in Regulation of Fetal Pulmonary Vascular Tone

Abstract

ABSTRACT: The physiologic role of endothelin-1 (ET-1) and its receptors in regulating fetal pulmonary vascular tone is unknown. We therefore investigated the role of ET-1 and its receptors in the regulation of fetal pulmonary vascular tone using BQ 123 (an ET. receptor antagonist) and 4 Ala ET-1 (an ET_b receptor agonist). In six fetal sheep in utero, we found that injections of ET-1 (250 ng/kg fetal weight) into the left pulmonary artery increased left pulmonary blood flow (21.0 ± 17.5 to 74.7 ± 32.9 mL/kg/min, p < 0.05) and decreased left pulmonary vascular resistance (6.02 ± 7.00 to 0.84 ± 0.48 mm Hg/kg/min/mL, p < 0.05). BQ 123 (5 mg) increased pulmonary blood flow (24.6 ± 28.7 to 47.7 ± 27.4 mL/kg/min, p < 0.05) and decreased pulmonary vascular resistance (8.84 ± 10.32 to 1.43 ± 0.80 mm Hg/kg/min/mL, p < 0.05); 4 Ala ET-1 (1725 ng/kg) markedly increased pulmonary blood flow (8.6 ± 6.8 to 69.4 ± 23.1 mL/kg/min, p < 0.05) and decreased pulmonary vascular resistance (12.02 ± 10.2 to 0.78 ± 0.44 mm Hg/kg/min/mL, p < 0.05). The absolute increase in pulmonary blood flow produced by ET-1 was attenuated by glibenclamide (an ATP-dependent potassium channel blocker) (flow increase of 73.4 ± 34.1 versus 49.3 ± 16.8 mL/kg/min, p < 0.05). This study demonstrates that ET. receptor activation has a small role in maintaining basal fetal pulmonary vascular tone, and that specific ET_b receptor activation produces marked pulmonary vasodilation. The increase in pulmonary flow produced by ET-1 in fetuses is partly mediated by ATP-dependent potassium channels.

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