Vascular responses to 8-nitro-cyclic GMP in non-diabetic and diabetic mice
Vascular responses to 8-nitro-cyclic GMP in non-diabetic and diabetic mice
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非糖尿病和糖尿病小鼠对 8-硝基环 GMP 的血管反应
DOI：
10.1111/j.1476-5381.2011.01201.x
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发表时间：
2011
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et al
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作者：
Tokutomi Y.;et al
背景与提示8-硝基鸟苷3′，5 ′-环磷酸（8-Nitroguanosine 3′，5 ′-cyclicmonophosphate，8-nitro-cGMP）是一氧化氮（nitric oxide，NO）依赖性的第二信使，但其在血管疾病病理生理学中的作用尚不清楚。为了研究8-硝基-cGMP在糖尿病小鼠中的药理活性，我们比较了其对非糖尿病和糖尿病小鼠胸主动脉血管反应性的影响。实验方法在野生型（C57 BL/6）、非糖尿病db/+和肥胖/糖尿病db/db小鼠的胸主动脉环中进行血管张力记录。分别通过Western blot和二氢乙锭荧光检测内皮一氧化氮合酶（eNOS）解偶联和超氧化物。浓度高达10 µM的KEY CYP 18 TS 8-硝基-cGMP可增强苯肾上腺素诱导的C57 BL/6和db/+小鼠子宫内膜收缩，但对db/db小鼠子宫内膜收缩无影响。 使用8-溴-cGMP未观察到这种增强。用l-NAME（100 µM）、超氧化物歧化酶（100 U·mL−1）或tiron（1 mM）预处理C57 BL/6和db/+小鼠的睾丸，可消除8-硝基-cGMP-诱导的苯肾上腺素收缩增强作用。 在8-硝基（10 µM）处理的C57 BL/6血管中，eNOS二聚体/单体比率显著降低，血管超氧化物产生增加，表明8-硝基通过eNOS解偶联诱导的超氧化物产生可能介导苯肾上腺素收缩的增强。 在较高浓度（>10 µM）下，8-硝基可使C57 BL/6、db/+和db/db小鼠的苯丙氨酸收缩性平滑肌松弛。 8-硝基-induced relaxation in db/db mouse arthritas was found to be resistant to a phosphodiesterase 5 inhibitor，zaprinast（1 µM）.CONCLUSIONS AND IMPLICATIONsThe vasodilator effect of 8-硝基-induced relaxation in db/db mouse arthritas may prove to improvement of the vascular endothelial dysfunction in diabetic mice，represent a novel pharmacological approach to prevent complications with diabetes.
BACKGROUND AND PURPOSE8‐Nitroguanosine 3′,5′‐cyclic monophosphate (8‐nitro‐cGMP), formed nitric oxide (NO)‐dependently, is a physiological second messenger, yet little is known about its role in the pathophysiology of vascular diseases. To study the pharmacological activity of 8‐nitro‐cGMP in diabetic mice, we compared its effects on vascular reactivity of aortas from non‐diabetic and diabetic mice.EXPERIMENTAL APPROACHVascular tension recording was performed in thoracic aortic rings from wild‐type (C57BL/6), non‐diabetic db/+ and obese/diabetic db/db mice. Endothelial NO synthase (eNOS) uncoupling and superoxide were tested by Western blot and dihydroethidium fluorescence respectively.KEY RESULTS8‐Nitro‐cGMP, at concentrations up to 10 µM, enhanced phenylephrine‐induced contractions in aortas from C57BL/6 and db/+ mice, but not from db/db mice. This enhancement was not observed with 8‐bromo‐cGMP. Pretreatment of aortas from C57BL/6 and db/+ mice withl‐NAME (100 µM), superoxide dismutase (100 U·mL−1) or tiron (1 mM), abolished 8‐nitro‐cGMP‐induced enhancement of the phenylephrine contraction. In 8‐nitro‐cGMP (10 µM)‐treated C57BL/6 aortas, eNOS dimer/monomer ratio was significantly decreased and vascular superoxide production increased, suggesting that 8‐nitro‐cGMP‐induced superoxide production via eNOS uncoupling may mediate the enhancement of the phenylephrine contraction. At higher concentrations (>10 µM), 8‐nitro‐cGMP produced relaxation of the phenylephrine‐contracted aortas from C57BL/6, db/+ and db/db mice. The 8‐nitro‐cGMP‐induced relaxation in db/db mouse aortas was found to be resistant to a phosphodiesterase 5 inhibitor, zaprinast (1 µM).CONCLUSIONS AND IMPLICATIONSThe vasodilator effect of 8‐nitro‐cGMP may contribute to amelioration of the vascular endothelial dysfunction in diabetic mice, representing a novel pharmacological approach to prevent the complications associated with diabetes.