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Role of Kappa Opioid Receptors in Vasculopathy of Diabetic Rats and the Related Mechanisms

Author: ZhouZuo
Tutor: WangHaiChang
School: Fourth Military Medical University
Course: Internal Medicine
Keywords: κ opioid receptor Diabetes Mesenteric artery Vasomotor function Aortic structure
CLC: R587.1
Type: Master's thesis
Year: 2010
Downloads: 30
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Abstract

Diabetes mellitus (DM) has been confirmed by the World Health Organization (WHO) as one of the major killer of human health in the 21st century, its complications, and great harm. DM vascular lesions in macrovascular and microvascular can occur, can lead to clinical limb ischemia disease and end-organ failure, a serious impact on the quality of life of patients, diabetes patients to death, leading causes of disability. Mainly endothelial dysfunction vasomotor dysfunction, the DM early signs of vascular lesions and cardiovascular risk factors. Endogenous opioid peptides (EOPs), including the enkephalins, endorphins, and dynorphin three families, its corresponding receptor δ receptor, μ and κ opiate receptor. The study has confirmed the EOPs and its receptors in the cardiovascular system abound synthesis and release of opioid peptides and heart can prompt EOPs and opioid receptors in the regulation of cardiovascular function plays a very important role. κ opioid receptor (KOR) is the major subtypes of opioid receptors in the cardiovascular system, the change may be one of the factors that cause cardiovascular disease. KOR decreased expression of various causes of heart failure had significantly decreased opioid-dependent regulatory function and cardiovascular protection function. Excited KOR have beneficial role in the prevention and treatment of diseases such as ischemic heart disease, hypertension, and pulmonary hypertension. However, few studies KOR DM vasculopathy. The purpose of this study was to observe the KOR selective agonists U50, 488H and selective blocking agent nor-BNI streptozotocin-induced DM rat mesenteric artery vasomotor function and aortic structure detection KOR expression, and to explore its mechanism of action, and to provide a theoretical basis and potential therapeutic strategy for the prevention and treatment of DM vascular lesions. Objective: 1. KOR expression changes observed DM rat arterial tissue. 2. Observed the KOR selective agonists U50, the 488H and selective blocker nor-BNI expression. Observation excitement or inhibition of KOR DM rat mesenteric artery vasomotor function. 4. Observe the excitement or inhibition of KOR the DM rat aortic structure. 5. Observation of excitement or inhibition of KOR expression of the DM rats vasoactive factor. 6. Observed excited or inhibition of KOR inflammatory factor expression in DM rats. Method: 1. Diabetic rat model by intraperitoneal injection of STZ (50 mg / kg) methods. 2 the immunohistochemical methods detect aortic tissue KOR expression changes. 3. Western blot method to detect the changes of the mesenteric artery tissue KOR expression. The observed changes in mesenteric artery vasomotor function. Away from the body arteries ring technology. 5 HE staining and electron microscopy technique to observe the changes of the aortic structure. 6. ELISA was used to detect changes in the serum Ang Ⅱ and sICAM-1 content. 7. Western blot was used to detect the change of eNOS and NF-κB expression in mesenteric artery tissue. Results: 1 rat aortic KOR expression, KOR mainly distributed in the aortic intima. 2 compared with normal rats, the expression of the DM rat aorta and small mesenteric artery tissue KOR increase intraperitoneal injection KOR selective agonist U50, 488H (1.0 mg / kg / day for 10 consecutive days) can be further raised the the KOR's expression in the aorta and mesenteric small arteries organization; intraperitoneal injection KOR selective blocker nor-BNI (0.5 mg / kg / day for 10 consecutive days) will be cut by the aorta and the superior mesenteric small artery tissue KOR expression. 3. Compared with normal rats, the DM rat mesenteric artery systolic and diastolic function disorders, vascular ring contractile response to KCl and NE caused a significant increase (p lt; 0.05), endothelium-dependent relaxation of ACh caused significantly decreased (p-lt; 0.05), and no significant change in the SNP cause of endothelium-dependent relaxation response; mesenteric small arteries organization eNOS expression reduce rather NF-κB expression increased (p-lt; 0.01); serum Ang Ⅱ level and serum sICAM -1 were elevated (p lt; 0.01); The HE staining observed by light microscopy aortic visible: in mesangial proliferative smooth muscle cells arranged in disorder, local uneven thickness of the collagen fibers, the internal elastic laminae, disorganized, are broken separation phenomenon; electron microscopy observation aortic ultrastructure visible: endothelial cell swelling, necrosis, or even fall off, smooth muscle cell proliferation, hypertrophy, migration to the intima lower irregular hyperplasia, extracellular collagen fibers, elastic fiber layer irregular thickening. 4. U50, 488H the DM rat mesenteric artery systolic and diastolic function can be significantly improved (p lt; 0.05) decrease in the expression of NF-κB (p lt; 0.01), the serum level of Ang Ⅱ increased expression of eNOS in mesenteric small arteries organization and serum sICAM-1 water mean reduction (p lt; 0.01), improved structural disorder of the aorta. 5. Nor-BNI treatment of the DM rat small mesenteric artery systolic and diastolic function further deterioration (p lt; 0.05), small mesenteric artery tissue eNOS expression further reduced NF-κB expression further increased (p lt; 0.01), serum Ang Ⅱ levels and serum sICAM-1 levels further elevated (p lt; 0.01), further aggravating the structural disorder of the aorta. Conclusion: rat aortic KOR expression, KOR mainly distributed in the aortic intima. KOR expression in the DM rat aorta and mesenteric small arteries organization than in normal rats significantly increased KOR selective agonist U50, 488H can be further raised KOR expression KOR selective blocker nor-BNI is down the expression of KOR. Excited KOR improve DM rat small mesenteric artery vasomotor function and aortic structure; mechanisms may include: (1) increased eNOS expression, lowered the level of Ang Ⅱ, thereby improving endothelial function; ② inhibition of NF-κB in lower sICAM- 1 levels, thereby reducing the level of inflammation. The results of this study KOR mediated DM vascular lesion treatment provides a potential therapeutic strategies and theoretical basis for further research.

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CLC: > Medicine, health > Internal Medicine > Endocrine diseases and metabolic diseases > Islet disease > Diabetes
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