Exercise training improves erectile dysfunction in diabetes: role of central mech

运动训练可改善糖尿病患者的勃起功能障碍：中枢机械的作用

• 批准号: 8039089
• 负责人: KAUSHIK P PATEL
• 金额: $ 31.66万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8039089
• 关键词: Address; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Biochemical; Biochemical Genetics; Brain; Cell Nucleus; Cells; Chronic; Complications of Diabetes Mellitus; Conscious; Data; Diabetes Mellitus; Elements; Enzyme Inhibition; Erectile dysfunction; Exercise; Functional disorder; Gene Transfer; Genes; Genetic; Health; Hyperglycemia; Hypothalamic structure; Immunohistochemistry; Infusion procedures; Insulin-Dependent Diabetes Mellitus; Laboratories; Measurement; Measures; Mediating; Messenger RNA; Methodology; Methods; Microinjections; Molecular; Molecular Biology Techniques; Muscle relaxation phase; N-Methylaspartate; Nerve; Neural Pathways; Neurons; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Oxidases; Oxytocin; Patients; Penile Erection; Peptidyl-Dipeptidase A; Peripheral; Physiological; Plasma; Proteins; Rattus; Reactive Oxygen Species; Receptor, Angiotensin, Type 1; Regulation; Role; Sexual Dysfunction; Signal Pathway; Signal Transduction; Smooth Muscle; Spinal Cord; Stimulus; Streptozocin; Superoxide Dismutase; Superoxides; System; Testing; Therapeutic; Time; Training; Transfection; Very Light Exercise; Viagra; Western Blotting; Work; adenoviral-mediated; autonomic neuropathy; base; diabetic; diabetic patient; erection; human NOS3 protein; improved; inhibitor/antagonist; insight; male; mimetics; neuroregulation; paraventricular nucleus; penis; phosphoric diester hydrolase; receptor; receptor expression; relating to nervous system; response; sildenafil

DESCRIPTION (provided by applicant): Erectile dysfunction is a serious and common complication of diabetes mellitus. Apart from peripheral actions of corporal smooth muscle relaxation, the activation of sympathetic and parasympathetic nerves involved central mechanisms are also responsible for penile erection. We have shown that 1) in rats with streptozotocin (STZ)-induced type I diabetes (T1D) the erectile response to central administrated N-methyl-D-aspartic acid (NMDA) in the PVN is blunted, 2) NMDA-induced erection is nitric oxide (NO)-mediated, 3) neuronal NO synthase (nNOS) in the PVN of T1D rats is reduced, 4) replacing nNOS specifically in the PVN (via adenoviral-mediated gene transfer) restores the NMDA- induced erection in T1D rats, 5) plasma levels of angiotensin II (Ang II) are increased and Ang II type 1 (AT1) receptors in the PVN are up-regulated in T1D rats, 6) Ang II modulates autonomic outflow via a reactive oxygen species (ROS), particularly superoxide (O2-) mechanism, 7) Ang II down-regulates nNOS in cultured neuronal cells. Exciting preliminary results obtained in our laboratory suggest that exercise training (ExT) dramatically improves central NMDA-induced erectile response in T1D. Based on these intriguing preliminary data and previous work, the present project will attempt to address the hypothesis that ExT improves central NMDA- induced erectile dysfunction in T1D rats by regulating NO and Ang II-O2- signaling pathways in the PVN. In Aim 1 we will determine the impact of ExT on central NMDA-NO-induced erectile dysfunction in T1D rats. In Aim 2 we will determine the contribution of Ang II to central NMDA-NO- induced erectile dysfunction in T1D rats. In Aim 3 we will determine if the enhanced Ang II contributes to central NMDA-NO-induced erectile dysfunction in T1D rats via stimulation of O2-. In Aim 4 we will determine if ExT has beneficial effects on central NMDA-NO-induced erectile dysfunction through the actions on Ang II-O2- signaling in the PVN of T1D rats. These aims will be addressed in T1D rats using complementary methodologies in the whole animal to the cellular level; physiological measurement of erectile function, microinjection of the PVN in conscious and anesthetized animals, adenoviral gene transfection, O2- and NO metabolite measurements, immunohistochemistry, molecular biology techniques to measure mRNA message using real time PCR and Western blot to measure the protein within specific brain nuclei. The successful completion of the proposed studies should provide significant new information regarding the central mechanisms, specifically within the PVN of the hypothalamus, involved in altered neural regulation of erectile function and the therapeutic benefits of ExT on erectile dysfunction in T1D. Understanding the role of central mechanisms, (not much studied to date), in the altered neural drive would enhance our ability to treat the diabetic sexual dysfunction. PUBLIC HEALTH RELEVANCE: Erectile dysfunction is a serious and common complication of diabetes mellitus. The proposed mechanisms for erectile dysfunction in diabetes include both peripheral and central abnormalities However, in diabetic male patients sildenafil (Viagra) appears to be therapeutic only in 50% of the patients at the level of the penis. The proposed studies should provide significant new information regarding the central mechanisms involved in altered neural regulation of erectile function and the therapeutic benefits of exercise training on erectile dysfunction in diabetes. Understanding the role of central mechanisms, (not much studied to date), in the altered neural drive would enhance our ability to treat the diabetic sexual dysfunction.

描述（由申请人提供）：勃起功能障碍是糖尿病的严重且常见的并发症。除了体光肌肉放松的外围作用外，涉及中心机制的交感神经和副交感神经的激活也导致阴茎勃起。 We have shown that 1) in rats with streptozotocin (STZ)-induced type I diabetes (T1D) the erectile response to central administrated N-methyl-D-aspartic acid (NMDA) in the PVN is blunted, 2) NMDA-induced erection is nitric oxide (NO)-mediated, 3) neuronal NO synthase (nNOS) in the PVN of T1D减少大鼠，4）在PVN（通过腺病毒介导的基因转移）中特别替换NNO，恢复了T1D大鼠中NMDA诱导的勃起，5）血管素II（ANG II）的血浆水平增加，ANG II类型1（ANG II）通过PVN中的ANG II型受体增加了ANG的ANG ANG中的1（AT AT型）。氧（ROS），尤其是超氧化物（O2-）机制，7）ANG II下调了培养的神经元细胞中的NNO。在我们的实验室中获得的令人兴奋的初步结果表明，运动训练（EXT）急剧改善了NMDA诱导的中央T1D勃起反应。基于这些有趣的初步数据和先前的工作，本项目将尝试通过调节PVN中的NO和ANG II-O2-信号通路来提高T1D大鼠中NMDA诱导的中央NMDA诱导的勃起功能障碍的假设。在AIM 1中，我们将确定EXT对T1D大鼠中中央NMDA-NO诱导的勃起功能障碍的影响。在AIM 2中，我们将确定ANG II对T1D大鼠中中央NMDA-NMDA-NOD诱导的勃起功能障碍的贡献。在AIM 3中，我们将通过刺激O2-确定增强的ANG II是否有助于T1D大鼠中央NMDA-NMDA-NOS-NO诱导的勃起功能障碍。在AIM 4中，我们将通过对T1D大鼠PVN中的ANG II-O2信号传导的作用来确定EXT是否对中央NMDA-NMDA-NO诱导的勃起功能障碍具有有益作用。这些目标将在T1D大鼠中使用整个动物中的互补方法来解决细胞水平。勃起功能的生理测量，在有意识和麻醉动物中PVN的显微注射，腺病毒基因转染，O2-和无代谢物测量，免疫组织化学，分子生物学技术，用于使用实时PCR和Western Blot测量MRNA消息以测量特定脑核中的蛋白质，以测量mRNA信息。拟议的研究的成功完成应提供有关中心机制的重要新信息，特别是在下丘脑的PVN中，涉及勃起功能的神经调节的改变以及EXT在T1D中勃起功能障碍的治疗益处。了解中心机制的作用（迄今为止研究还不多）在改变的神经驱动器中会增强我们治疗糖尿病性功能障碍的能力。公共卫生相关性：勃起功能障碍是糖尿病的严重且常见的并发症。糖尿病中勃起功能障碍的拟议机制包括外周和中枢异常，但是，在糖尿病男性患者西地那非（伟哥）中，在阴茎水平的50％的患者中，似乎仅在50％的患者中具有治疗性。拟议的研究应提供有关勃起功能改变神经调节的中心机制的重要新信息，以及糖尿病中勃起功能障碍运动训练的治疗益处。了解中心机制的作用（迄今为止研究还不多）在改变的神经驱动器中会增强我们治疗糖尿病性功能障碍的能力。