DIABETIC VASCULAR ENDOTHELIUM & ADRENERGIC NERVES

糖尿病血管内皮

• 批准号: 3355075
• 负责人: RICHARD A COHEN
• 金额: $ 18.49万
• 依托单位: BOSTON UNIVERSITY MEDICAL CENTER HOSP
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-01 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3355075
• 关键词: adenosinetriphosphatase; aldehyde reductase; alpha adrenergic receptor; atherosclerosis; diabetic neuropathy; hypertension; isolation perfusion; laboratory rabbit; medical complication; membrane transport proteins; muscle contraction; newborn animals; potassium; prostaglandins; protein kinase C; sodium; thromboxanes; vascular endothelium; vascular smooth muscle; vasoconstriction

The goal is to determine mechanisms for abnormal vascular reactivity in diabetes mellitus. The hypothesis is that the hyperglycemic milieu leads to dysfunction of endothelial cells and sympathetic nerves within blood vessels, which then abnormally regulate vascular smooth muscle contraction. Studies demonstrated that the endothelium-dependent relaxation to acetylcholine of diabetic aorta is impaired. The normal relaxation by endothelium-derived relaxing factor is counteracted by the production by diabetic endothelial cells of vasoconstrictor prostanoids including thromboxane Az. The abnormal endothelial cell function is likely due to hyperglycemia, because the endothelium of normal aorta exposed to high glucose concentrations also responds abnormally by producing vasoconstrictor prostanoids. Preliminary studies indicate that cultured aortic endothelial cells exposed to elevated glucose will provide a useful mode in which to identify bioassayable endothelium-derived vasoconstrictor prostanoids. Prostanoids including 6-keto-PGF1a, thromboxane B2, PGF2a, PGE2, and 15-HETE will be measured by radioimmunoassay, and radiochromatography will be used to analyze metabolic products of 14C- arachidonic acid to identify the vasoconstrictors involved. Neuropathic changes were also found in diabetic rabbit arteries with reduced quantities and abnormal release of norepinephrine with reduced prejunctional inhibition by the endothelium. The modulation of endogenous norepinephrine release from adrenergic nerves and metabolism by diabetic endothelium will be investigated. The proposed studies will pursue the physiological mechanisms of the altered endothelial cell and adrenergic nerve function in arteries from diabetic rabbits and normal arteries exposed to high glucose. Evidence will be sought for abnormal aldose reductase activity, myo- inositol levels, g-proteins, protein kinase C, and Na/K ATPase. Because of the importance of microvascular disease in diabetes, new studies are proposed to study reactivity of isolated coronary and mesenteric microvessels, and resistance vessels in perfused hearts.

目的是确定异常血管反应性的机制 糖尿病。 假设是高血糖环境导致 血液中内皮细胞和交感神经的功能障碍 血管，然后异常调节血管平滑肌收缩。 研究表明，内皮依赖性放松 糖尿病主动脉的乙酰胆碱受损。 正常放松 内皮衍生的放松因子由生产来抵消 血管收缩前列腺素的糖尿病内皮细胞包括 动脉盒AZ。 异常内皮细胞功能可能是由于 高血糖，因为正常主动脉的内皮暴露于高 葡萄糖浓度也通过产生异常反应 血管收缩前列腺素。 初步研究表明培养 暴露于升高葡萄糖的主动脉内皮细胞将提供有用的 在其中识别可生物弥补的内皮衍生的血管收缩剂的模式 前列腺素。 前列腺素，包括6-酮PGF1A，Thromboxane B2，PGF2A， PGE2和15-HETE将通过放射免疫测定法进行测量，并且 放射色谱法将用于分析14C-的代谢产物 花生四烯酸鉴定涉及的血管收缩剂。 神经疗法 在糖尿病兔动脉中也发现了变化 并异常释放去甲肾上腺素，持续性降低 内皮抑制。 内源性去甲肾上腺素的调节 从糖尿病内皮中释放出肾上腺素能神经和代谢，将 被调查。 拟议的研究将追求生理 改变内皮细胞和肾上腺神经功能功能的机制 糖尿病兔和正常动脉暴露于高葡萄糖的动脉。 将寻求证据以促使异常的醛糖还原酶活性，myo- 肌醇水平，G蛋白，蛋白激酶C和Na/K ATPase。 由于 微血管疾病在糖尿病中的重要性，新研究是 提议研究分离的冠状动脉和肠系膜的反应性 微血管和灌注心脏中的阻力容器。