Hashimoto M, Close L A, Ishida Y, Paul R J
Department of Physiology and Biophysics, College of Medicine, University of Cincinnati, Ohio 45267-0576.
Am J Physiol. 1993 Jul;265(1 Pt 2):H299-306. doi: 10.1152/ajpheart.1993.265.1.H299.
Hypoxia has major effects on endothelium-dependent relaxation. To further understand the underlying mechanism(s), we investigated the O2 dependence of the endothelium-dependent relaxations elicited by ionophore A-23187 or agonists substance P (SP) or thrombin (TB) in porcine coronary arteries. A-23187 elicits an endothelium-dependent relaxation of KCl- or U-46619-induced contractures that can be described in terms of a rapid and slow phase. The duration of the relaxation was dose dependent. SP (10 nM) and TB (0.1 U/ml) also elicited endothelium-dependent relaxations that were rapid but transient. Hypoxic conditions (95% N2-5% CO2 instead of 95% O2-5% CO2; PO2 < 1%) abolished the A-23187 rapid phase and the SP and TB transient relaxation but not the A-23187 slow phase. Threshold PO2 for the rapid phase was approximately 35 mmHg. Pretreatment with cyanide (5 mM), to inhibit respiration, or 2-deoxy-D-glucose, to inhibit glycolysis, had little effect. Similarly, propranolol (10 microM) or indomethacin (10 microM) had no effect on the relaxation to A-23187, TB, or SP. In contrast, both NO synthesis inhibitors and ouabain blunted all endothelium-dependent relaxations studied. Our results suggest that the rapid relaxations to A-23187, SP, and TB are sensitive to O2 but not mitochondrial respiration. The slow sustained relaxation induced by A-23187, however, is characterized by a sensitivity to O2 that is distinct from that of the rapid phase, yet is dependent on an intact endothelium and is affected by NO synthesis inhibitors. Thus the endothelium-dependent relaxation to A-23187 is probably mediated by NO, but its sensitivity to O2 suggests that two distinct mechanisms may be involved.
缺氧对内皮依赖性舒张有重大影响。为了进一步了解其潜在机制，我们研究了离子载体A - 23187或激动剂P物质（SP）或凝血酶（TB）在猪冠状动脉中引发的内皮依赖性舒张的氧依赖性。A - 23187可引发对氯化钾或U - 46619诱导的收缩的内皮依赖性舒张，这可以用快速和缓慢两个阶段来描述。舒张的持续时间呈剂量依赖性。SP（10 nM）和TB（0.1 U/ml）也引发快速但短暂的内皮依赖性舒张。缺氧条件（用95% N₂ - 5% CO₂代替95% O₂ - 5% CO₂；PO₂ < 1%）消除了A - 23187的快速阶段以及SP和TB的短暂舒张，但未消除A - 23187的缓慢阶段。快速阶段的阈值PO₂约为35 mmHg。用氰化物（5 mM）抑制呼吸或用2 - 脱氧 - D - 葡萄糖抑制糖酵解，影响很小。同样，普萘洛尔（10 μM）或吲哚美辛（10 μM）对A - 23187、TB或SP引起的舒张无影响。相比之下，一氧化氮合成抑制剂和哇巴因均减弱了所研究的所有内皮依赖性舒张。我们的结果表明，对A - 23187、SP和TB的快速舒张对氧敏感，但对线粒体呼吸不敏感。然而，A - 23187诱导的缓慢持续舒张的特点是对氧的敏感性与快速阶段不同，但依赖于完整的内皮且受一氧化氮合成抑制剂影响。因此，对A - 23187的内皮依赖性舒张可能由一氧化氮介导，但其对氧的敏感性表明可能涉及两种不同机制。
