Pieper G M, Siebeneich W
Department of Transplant Surgery, Medical College of Wisconsin, Milwaukee 53226, USA.
J Pharmacol Exp Ther. 1997 Oct;283(1):138-47.
Nitronyl nitroxides react with nitric oxide radical (.NO) to form imino nitroxides. We used a nitronyl nitroxide, [2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3 oxide] (CPTIO) to evaluate the contribution of .NO to basal tone and acetylcholine-induced endothelium-dependent relaxation in control vs. diabetic rat aortic rings. In rings precontracted with phenylephrine, CPTIO produced an additional increment in tension that was greater in control vs. diabetic rings. Tension after CPTIO was similar to that observed in rings pretreated with the NO synthase inhibitor, L-nitroarginine or in rings without endothelium. This increment was insensitive to indomethacin, cysteine, tetraethylammonium or catalase, but was sensitive to inhibition by the soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxaline-1-one. L-Nitroarginine blocked relaxation to ACH by 100 and 90% in control and diabetic rings, respectively. In contrast, CPTIO produced a concentration-dependent inhibition of ACH-induced relaxation that was greater in control rings. The residual CPTIO-resistant component of relaxation was equivalent to 26 and 43% of initial precontraction in control vs. diabetic rings, respectively, and was not altered by indomethacin, catalase, cysteine or tetraethylammonium but was significantly inhibited by 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxaline-1-one. These data suggest the release of additional unknown factor(s) that cannot be discerned using NO synthase inhibitors only. This CPTIO-resistant dilator is likely not a cyclooxygenase product or a hyperpolarizing factor but a factor that acts, in part, by activation of guanylate cyclase. This substance is possibly .NO that is not available for reaction with CPTIO either by its diffusibility and sequestration or molecular rearrangement to a redox active form (i.e., not free .NO) or is a completely different vasodilator. The use of a more lipid soluble nitronyl nitroxide derivative suggests a portion of the CPTIO-resistant relaxation in diabetic (but not control) rings could be explained by .NO sequestered in the lipid phase.
硝酮氮氧化物与一氧化氮自由基（·NO）反应形成亚氨基氮氧化物。我们使用了一种硝酮氮氧化物，[2-(4-羧基苯基)-4,4,5,5-四甲基咪唑啉-1-氧基 3-氧化物]（CPTIO）来评估在对照与糖尿病大鼠主动脉环中，·NO对基础张力以及乙酰胆碱诱导的内皮依赖性舒张的贡献。在用去氧肾上腺素预收缩的血管环中，CPTIO使张力进一步增加，对照血管环比糖尿病血管环增加得更多。CPTIO处理后的张力与用一氧化氮合酶抑制剂L-硝基精氨酸预处理的血管环或无内皮的血管环中观察到的张力相似。这种增加对吲哚美辛、半胱氨酸、四乙铵或过氧化氢酶不敏感，但对可溶性鸟苷酸环化酶抑制剂1H-[1,2,4]恶二唑并[4,3,-a]喹喔啉-1-酮的抑制敏感。L-硝基精氨酸在对照和糖尿病血管环中分别使对乙酰胆碱的舒张作用阻断100%和90%。相反，CPTIO对乙酰胆碱诱导的舒张产生浓度依赖性抑制，对照血管环中抑制作用更强。对照和糖尿病血管环中，CPTIO抗性的残余舒张成分分别相当于初始预收缩的26%和43%，且不受吲哚美辛、过氧化氢酶、半胱氨酸或四乙铵影响，但1H-[1,2,4]恶二唑并[4,3,-a]喹喔啉-1-酮可显著抑制。这些数据表明释放了额外的未知因子，仅使用一氧化氮合酶抑制剂无法识别。这种CPTIO抗性的扩张剂可能不是环氧化酶产物或超极化因子，而是一种部分通过激活鸟苷酸环化酶起作用的因子。该物质可能是由于其扩散和螯合作用或分子重排为氧化还原活性形式（即非游离·NO）而无法与CPTIO反应的·NO，或者是一种完全不同的血管扩张剂。使用更具脂溶性的硝酮氮氧化物衍生物表明，糖尿病（而非对照）血管环中部分CPTIO抗性舒张可能由脂质相中螯合的·NO解释。
