Shah Dhvanit I, Singh Manjeet
Department of Pharmaceutical Sciences and Drug Research, Faculty of Medicine, Punjabi University, Punjab, India.
Endothelium. 2006 Jul-Aug;13(4):267-77. doi: 10.1080/10623320600904047.
The study has been designed to investigate the effect of 8-Br-cAMP, an activator of protein kinase A (PKA), in diabetes mellitus- and hyperhomocysteinemia-induced vascular endothelial dysfunction. Streptozotocin (55 mg kg-1, i.v.) and methionine (1.7% w/w, p.o., 4 weeks) were administered to rats to produce diabetes mellitus (serum glucose >200 mg dL-1) and hyperhomocysteinemia (serum homocysteine >10 microM), respectively. Vascular endothelial dysfunction was assessed using isolated aortic ring preparation, electron microscopy of thoracic aorta, and serum concentration of nitrite/nitrate. The expression of mRNA for p22phox and endothelial nitric oxide synthase (eNOS) was assessed by using reverse transcriptase-polymerase chain reaction (TBARS) (RT-PCR). Serum thiobarbituric acid-reactive substances (TBARS) concentration and aortic superoxide anion concentration were estimated to assess oxidative stress. 8-Br-cAMP (5 mg kg-1, i.p.) or atorvastatin (30 mg kg-1, p.o.) prevented diabetes mellitus- and hyperhomocysteinemia-induced attenuation of acetylcholine-induced endothelium-dependent relaxation, impairment of vascular endothelial lining, decrease in expression of mRNA for eNOS, serum nitrite/nitrate concentration, and increase in expression of mRNA for p22phox, superoxide anion, and serum TBARS. The ameliorative effect of 8-Br-cAMP was prevented by N omega-nitro-L-arginine methyl ester (L-NAME) (25 mg kg-1, i.p.) and glibenclamide (5 mg kg-1, i.p.). Therefore, it may be concluded that 8-Br-cAMP-induced activation of PKA may improve vascular endothelial dysfunction.
本研究旨在探讨蛋白激酶A（PKA）激活剂8-溴环磷酸腺苷（8-Br-cAMP）对糖尿病和高同型半胱氨酸血症诱导的血管内皮功能障碍的影响。分别给大鼠注射链脲佐菌素（55 mg kg-1，静脉注射）和蛋氨酸（1.7% w/w，口服，4周），以分别诱导糖尿病（血清葡萄糖>200 mg dL-1）和高同型半胱氨酸血症（血清同型半胱氨酸>10 microM）。使用离体主动脉环标本、胸主动脉电子显微镜检查以及血清亚硝酸盐/硝酸盐浓度来评估血管内皮功能障碍。通过逆转录聚合酶链反应（RT-PCR）评估p22phox和内皮型一氧化氮合酶（eNOS）的mRNA表达。通过测定血清硫代巴比妥酸反应性物质（TBARS）浓度和主动脉超氧阴离子浓度来评估氧化应激。8-溴环磷酸腺苷（5 mg kg-1，腹腔注射）或阿托伐他汀（30 mg kg-1，口服）可预防糖尿病和高同型半胱氨酸血症诱导的乙酰胆碱诱导的内皮依赖性舒张减弱、血管内皮内衬损伤、eNOS的mRNA表达降低、血清亚硝酸盐/硝酸盐浓度降低以及p22phox、超氧阴离子和血清TBARS的mRNA表达增加。Nω-硝基-L-精氨酸甲酯（L-NAME）（25 mg kg-1，腹腔注射）和格列本脲（5 mg kg-1，腹腔注射）可阻止8-溴环磷酸腺苷的改善作用。因此，可以得出结论，PKA的激活可能改善血管内皮功能障碍。
