Ivy D, McMurtry I F, Yanagisawa M, Gariepy C E, Le Cras T D, Gebb S A, Morris K G, Wiseman R C, Abman S H
Pediatric Heart Lung Center, University of Colorado School of Medicine and The Children's Hospital, Denver, Colorado 80218, USA.
Am J Physiol Lung Cell Mol Physiol. 2001 May;280(5):L1040-8. doi: 10.1152/ajplung.2001.280.5.L1040.
Endothelin (ET)-1 contributes to the regulation of pulmonary vascular tone by stimulation of the ET(A) and ET(B) receptors. Although activation of the ET(A) receptor causes vasoconstriction, stimulation of the ET(B) receptors can elicit either vasodilation or vasoconstriction. To examine the physiological role of the ET(B) receptor in the pulmonary circulation, we studied a genetic rat model of ET(B) receptor deficiency [transgenic(sl/sl)]. We hypothesized that deficiency of the ET(B) receptor would predispose the transgenic(sl/sl) rat lung circulation to enhanced pulmonary vasoconstriction. We found that the lungs of transgenic(sl/sl) rats are ET(B) deficient because they lack ET(B) mRNA in the pulmonary vasculature, have minimal ET(B) receptors as determined with an ET-1 radioligand binding assay, and lack ET-1-mediated pulmonary vasodilation. The transgenic(sl/sl) rats have higher basal pulmonary arterial pressure and vasopressor responses to brief hypoxia or ET-1 infusion. Plasma ET-1 levels are elevated and endothelial nitric oxide synthase protein content and nitric oxide production are diminished in the transgenic(sl/sl) rat lung. These findings suggest that the ET(B) receptor plays a major physiological role in modulating resting pulmonary vascular tone and reactivity to acute hypoxia. We speculate that impaired ET(B) receptor activity can contribute to the pathogenesis of pulmonary hypertension.
内皮素（ET）-1通过刺激ET（A）和ET（B）受体来调节肺血管张力。虽然ET（A）受体的激活会导致血管收缩，但ET（B）受体的刺激可引起血管舒张或收缩。为了研究ET（B）受体在肺循环中的生理作用，我们研究了ET（B）受体缺陷的基因大鼠模型[转基因（sl/sl）]。我们假设ET（B）受体缺陷会使转基因（sl/sl）大鼠的肺循环易于发生增强的肺血管收缩。我们发现转基因（sl/sl）大鼠的肺缺乏ET（B），因为它们在肺血管系统中缺乏ET（B）mRNA，通过ET-1放射性配体结合测定确定其ET（B）受体极少，并且缺乏ET-1介导的肺血管舒张。转基因（sl/sl）大鼠具有较高的基础肺动脉压以及对短暂缺氧或ET-1输注的升压反应。转基因（sl/sl）大鼠肺中的血浆ET-1水平升高，内皮型一氧化氮合酶蛋白含量和一氧化氮生成减少。这些发现表明ET（B）受体在调节静息肺血管张力和对急性缺氧的反应性中起主要生理作用。我们推测ET（B）受体活性受损可能导致肺动脉高压的发病机制。
