Parker J L, Adams H R
Dalton Research Center, College of Veterinary Medicine, University of Missouri, Columbia 65211.
Circ Res. 1993 Mar;72(3):539-51. doi: 10.1161/01.res.72.3.539.
Increased release of endothelium-derived relaxing factor/nitric oxide has been proposed as the final common pathway for vasodilator responses to gram-negative lipopolysaccharide (endotoxin). To test this hypothesis, we examined endothelium-dependent and endothelium-independent vasodilator agents in vascular smooth muscle isolated from guinea pigs 16 hours after injection of saline (control group) or induction of Escherichia coli endotoxemia; aortic rings (approximately 1 mm in diameter) were studied with standard isometric tension techniques. Endotoxemia resulted in a significant loss of vasodilator responses to the endothelium-dependent receptor agonists acetylcholine (10(-10)-10(-5) M) and ADP (10(-8)-10(-5) M). In contrast, endotoxemia did not affect vasodilator responses to either the endothelium-dependent receptor agonist substance P (10(-11)-10(-7) M), the endothelium-dependent and receptor-independent agonist A23187 (10(-9)-10(-6) M), or the endothelium-independent agonist nitroprusside (10(-10)-10(-4) M). The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) inhibited the vasodilator response to acetylcholine more in vessels from lipopolysaccharide-injected than control guinea pigs. Unexpectedly, L-NAME converted the endothelium-dependent vasodilator action of ADP to an endothelium-dependent vasoconstrictor response that was blocked individually by the cyclooxygenase inhibitor indomethacin, the thromboxane synthase inhibitor dazoxiben, and the thromboxane A2 receptor antagonist SQ29548. We conclude that in vivo endotoxemia inhibits the constitutive isoform of nitric oxide synthase in endothelial cells by selectively disrupting receptor-coupled activation mechanisms shared by acetylcholine and ADP. Furthermore, since L-NAME unmasks a thromboxane A2-mediated vasoconstrictor action of the endogenous purinoceptor agonist ADP, drugs that inhibit nitric oxide synthase could exacerbate sepsis-induced vasoconstriction and ischemia by synergizing with lipopolysaccharide-induced inhibition of endothelial nitric oxide synthase.
内皮源性舒张因子/一氧化氮释放增加被认为是革兰氏阴性脂多糖（内毒素）引起血管舒张反应的最终共同途径。为了验证这一假设，我们检测了在注射生理盐水（对照组）或诱导大肠杆菌内毒素血症16小时后从豚鼠分离的血管平滑肌中内皮依赖性和非内皮依赖性血管舒张剂；使用标准等长张力技术研究主动脉环（直径约1毫米）。内毒素血症导致对内皮依赖性受体激动剂乙酰胆碱（10^-10 - 10^-5 M）和ADP（10^-8 - 10^-5 M）的血管舒张反应显著丧失。相比之下，内毒素血症不影响对内皮依赖性受体激动剂P物质（10^-11 - 10^-7 M）、内皮依赖性且非受体依赖性激动剂A23187（10^-9 - 10^-6 M）或非内皮依赖性激动剂硝普钠（10^-10 - 10^-4 M）的血管舒张反应。一氧化氮合酶抑制剂NG-硝基-L-精氨酸甲酯（L-NAME）在脂多糖注射的豚鼠血管中比对照组豚鼠血管更能抑制对乙酰胆碱的血管舒张反应。出乎意料的是，L-NAME将ADP的内皮依赖性血管舒张作用转变为内皮依赖性血管收缩反应，该反应可被环氧化酶抑制剂吲哚美辛、血栓素合酶抑制剂达唑氧苯和血栓素A2受体拮抗剂SQ29548单独阻断。我们得出结论，体内内毒素血症通过选择性破坏乙酰胆碱和ADP共有的受体偶联激活机制，抑制内皮细胞中一氧化氮合酶的组成型同工型。此外，由于L-NAME揭示了内源性嘌呤受体激动剂ADP的血栓素A2介导的血管收缩作用，抑制一氧化氮合酶的药物可能通过与脂多糖诱导的内皮一氧化氮合酶抑制协同作用，加重脓毒症诱导的血管收缩和缺血。
