Csanyi Gabor, Lepran Istvan, Flesch Timea, Telegdy Gyula, Szabo Gyula, Mezei Zsofia
Department of Pathophysiology, Albert Szent-Gyorgyi Medical and Pharmaceutical Center, University of Szeged, Semmelweis 1, 6725 Szeged, Hungary.
Pharmacol Rep. 2007 Jul-Aug;59(4):447-55.
It is not known whether the impairment of nitric oxide (NO)-dependent vasodilation of the aorta of diabetic rats is associated with any changes in the endothelial production of vasoactive prostanoids and endothelium-derived hyperpolarizing factor (EDHF). Therefore, we analyzed the contribution of NO, vasoactive prostanoids and EDHF to the decreased endothelium-dependent vasorelaxation in Sprague-Dawley rats at 4 and 8 weeks after diabetes mellitus induced by streptozotocin (STZ). The acetylcholine-induced (Ach) endothelium-dependent relaxation was significantly decreased in the thoracic aorta 8 weeks after the STZ-injection (Ach 10(-6) M: 73.1 +/- 7.4% and 56.7 +/- 7.9% for control and diabetic rats, respectively). The sodium nitroprusside-induced (NaNP) endothelium-independent vasodilation was also impaired in the diabetic rats (8 weeks after STZ) (NaNP 10(-8) M: 74.2 +/- 11.4% and 35.9 +/- 9.4% for control and diabetic rats, respectively). In contrast, the basal NO production, as assessed by the N omega-nitro-L-arginine methyl ester (L-NAME)-induced vasoconstriction was not modified in diabetes. Moreover, the amount of 6-keto-PGF(1 alpha) (stable metabolite of prostacyclin / prostaglandin I2 / PGI2 ), 12-L-hydroxy-5,8,10-heptadecatrienoic acid (12-HHT) and thromboxane B2 (TxB2 ) (stable metabolite of thromboxane A2 - TxA2) were significantly increased in the 8 weeks diabetic rat aorta. The EDHF-pathway did not change in the aortic endothelium during the development of STZ-induced diabetes. Our results indicate that STZ-induced diabetes mellitus did not modify the basal NO production, but induced the impairment of acetylcholine- and sodium nitroprusside-induced vasodilation in the thoracic aorta. In parallel with the impairment of NO-dependent vasodilation, the basal PGI2, 12-HHT and TxA2 synthesis were increased. The EDHF-pathway did not contribute to the endothelium-dependent relaxation either in control or diabetic aorta. The above alterations in the endothelial function may play an important role in the development of endothelial dysfunction and vascular complications of diabetes.
糖尿病大鼠主动脉中一氧化氮（NO）依赖性血管舒张功能的损害是否与血管活性前列腺素和内皮衍生超极化因子（EDHF）的内皮生成变化有关尚不清楚。因此，我们分析了NO、血管活性前列腺素和EDHF对链脲佐菌素（STZ）诱导糖尿病后4周和8周的Sprague-Dawley大鼠内皮依赖性血管舒张功能降低的作用。STZ注射8周后，胸主动脉中乙酰胆碱（Ach）诱导的内皮依赖性舒张功能显著降低（Ach 10(-6) M：对照组和糖尿病大鼠分别为73.1±7.4%和56.7±7.9%）。糖尿病大鼠（STZ注射8周后）硝普钠（NaNP）诱导的非内皮依赖性血管舒张功能也受损（NaNP 10(-8) M：对照组和糖尿病大鼠分别为74.2±11.4%和35.9±9.4%）。相比之下，通过Nω-硝基-L-精氨酸甲酯（L-NAME）诱导的血管收缩评估的基础NO生成在糖尿病中未发生改变。此外，8周糖尿病大鼠主动脉中6-酮-PGF(1α)（前列环素/前列腺素I2/PGI2的稳定代谢产物）、12-L-羟基-5,8,10-十七碳三烯酸（12-HHT）和血栓素B2（TxB2）（血栓素A2-TxA2的稳定代谢产物）的量显著增加。在STZ诱导的糖尿病发展过程中，主动脉内皮中的EDHF途径未发生变化。我们的结果表明，STZ诱导的糖尿病并未改变基础NO生成，但诱导了胸主动脉中乙酰胆碱和硝普钠诱导的血管舒张功能受损。与NO依赖性血管舒张功能受损同时，基础PGI2、12-HHT和TxA2合成增加。EDHF途径在对照组或糖尿病主动脉的内皮依赖性舒张中均未起作用。内皮功能的上述改变可能在糖尿病内皮功能障碍和血管并发症的发展中起重要作用。
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