Our goal was to identify the role of poly(ADP-ribose) polymerase (PARP) in cerebrovascular dysfunction in Type 1 diabetes mellitus (T1D). In a first series of studies, rats were assigned to nondiabetic and diabetic (streptozotocin; 50 mg/kg IP) groups. Two to three months after injection of streptozotocin, we examine in vivo responses of pial arterioles to nitric oxide synthase (NOS)-dependent (adenosine diphosphate (ADP), acetylcholine and histamine) and -independent (nitroglycerin) agonists. After the initial examination of reactivity to the agonists, we treated pial arterioles acutely with an inhibitor of PARP (PJ-34; 1 microM), and then we again examined responses to the agonists. In a second series of studies, we examine superoxide production (lucigenin chemiluminescence) by parietal cortex tissue in nondiabetic and diabetic rats. We found that dilation of pial arterioles in response to ADP, acetylcholine and histamine, but not to nitroglycerin, was impaired in diabetic compared to nondiabetic rats. In addition, although PJ-34 did not alter responses in nondiabetic rats, PJ-34 alleviated T1D-induced impairment of NOS-dependent vasodilation. We also found that basal production of superoxide was increased in diabetic compared to nondiabetic rats and that PJ-34 decreased this basal production of superoxide. Our findings suggest that T1D impairs NOS-dependent reactivity of cerebral arterioles by a mechanism that appears to be related to the formation of superoxide via activation of PARP.

译文

:我们的目标是确定聚(ADP-核糖)聚合酶(PARP)在1型糖尿病(T1D)的脑血管功能障碍中的作用。在第一个系列研究中,将大鼠分为非糖尿病和糖尿病(链脲佐菌素; 50 mg / kg IP)组。注射链脲佐菌素后两到三个月,我们检查了小动脉对一氧化氮合酶(NOS)依赖性(二磷酸腺苷(ADP),乙酰胆碱和组胺)和非依赖性(硝酸甘油)激动剂的体内反应。初步检查与激动剂的反应性后,我们用PARP抑制剂(PJ-34; 1 microM)急性治疗了小动脉,然后再次检查了对激动剂的反应。在第二系列研究中,我们检查了非糖尿病和糖尿病大鼠顶叶皮质组织的超氧化物生成(荧光素化学发光)。我们发现,与非糖尿病大鼠相比,糖尿病患者对ADP,乙酰胆碱和组胺(而非对硝酸甘油)响应的小动脉小动脉扩张受到损害。此外,尽管PJ-34不会改变非糖尿病大鼠的反应,但PJ-34减轻了T1D诱导的NOS依赖性血管舒张功能受损。我们还发现,与非糖尿病大鼠相比,糖尿病患者的基础过氧化物含量增加,而PJ-34降低了基础过氧化物含量。我们的发现表明,T1D通过一种机制似乎削弱了NOS依赖性的脑小动脉反应性,该机制似乎与通过激活PARP形成超氧化物有关。

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