Olschewski Andrea, Hong Zhigang, Peterson Douglas A, Nelson Daniel P, Porter Valerie A, Weir E Kenneth
Justus Leipzig University, Giessen, Germany.
Am J Physiol Lung Cell Mol Physiol. 2004 Jan;286(1):L15-22. doi: 10.1152/ajplung.00372.2002. Epub 2003 Jul 3.
At birth, associated with the rise in oxygen tension, the pulmonary arteries (PA) dilate and the ductus arteriosus (DA) constricts. Both PA and DA constrict with vasoconstrictors and dilate with vasodilators. They respond in a contrary manner only to changes in oxygen tension. We hypothesized that the effects of changes in oxygen are mediated by changes in redox status. Consequently, we tested whether a reducing agent, DTT, and an oxidizing agent, dithionitrobenzoic acid (DTNB), would have opposite effects on a major oxygen signaling pathway in the PA and DA smooth muscle cells (SMCs), the sequence of change in potassium current (IK), membrane potential (Em), cytosolic calcium, and vessel tone. Under normoxic conditions, DTT constricted adult and fetal resistance PA rings, whereas in DA rings DTT acted as a potent vasodilator. In normoxia, voltage-clamp measurements showed inhibition of IK by DTT in PASMCs and, in contrast, activation in DASMCs. Consequently, DTT depolarized fetal and adult PASMCs and hyperpolarized DASMCs. [Ca2+]i was increased by DTT in fetal and adult PASMCs and decreased in DASMCs. Under hypoxic conditions, DTNB constricted DA rings and caused vasodilatation in fetal PA rings. DTNB inhibited IK and depolarized the cell membrane in DASMCs. In contrast, activation of IK and hyperpolarization was seen in PASMCs. Thus the same redox signal can elicit opposite effects on IK, Em, cytosolic calcium, and vascular tone in resistance PA and the DA. These observations support the concept that redox changes could signal the opposite effects of oxygen in the PA and DA.
出生时，随着氧张力升高，肺动脉（PA）扩张，动脉导管（DA）收缩。PA和DA对血管收缩剂均产生收缩反应，对血管扩张剂均产生扩张反应。它们仅对氧张力变化产生相反的反应。我们推测氧变化的影响是由氧化还原状态的变化介导的。因此，我们测试了还原剂二硫苏糖醇（DTT）和氧化剂二硫代硝基苯甲酸（DTNB）是否会对PA和DA平滑肌细胞（SMC）中的主要氧信号通路、钾电流（IK）、膜电位（Em）、胞质钙和血管张力的变化顺序产生相反的影响。在常氧条件下，DTT使成年和胎儿阻力性PA环收缩，而在DA环中，DTT起强效血管扩张剂的作用。在常氧状态下，电压钳测量显示DTT在PASMC中抑制IK，相反，在DASMC中激活IK。因此，DTT使胎儿和成年PASMC去极化，使DASMC超极化。DTT使胎儿和成年PASMC中的[Ca2+]i升高，使DASMC中的[Ca2+]i降低。在低氧条件下，DTNB使DA环收缩，并使胎儿PA环血管扩张。DTNB抑制DASMC中的IK并使细胞膜去极化。相反，在PASMC中观察到IK激活和超极化。因此，相同的氧化还原信号可对阻力性PA和DA中的IK、Em、胞质钙和血管张力产生相反的影响。这些观察结果支持氧化还原变化可能为PA和DA中氧的相反作用提供信号的概念。
