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: 8242632
• 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 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8242632
• 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(申请人提供)：勃起功能障碍是糖尿病的一种严重和常见的并发症。除了躯体肌肉松弛的外周作用外，涉及中枢机制的交感神经和副交感神经的激活也是阴茎勃起的原因。在链脲佐菌素(STZ)诱导的I型糖尿病(T1D)大鼠中，PVN对中枢注射N-甲基-D-天冬氨酸(NMDA)的勃起反应迟钝，2)NMDA诱导的勃起是由一氧化氮(NO)介导的，3)T1D大鼠PVN中的神经元型一氧化氮合酶(NNOS)减少，4)替换PVN中的nNOS(经腺病毒介导的基因转移)可恢复NMDA诱导的T1D大鼠的勃起。5)T1D大鼠血浆血管紧张素Ⅱ(Ang II)水平升高，PVN血管紧张素II 1型受体(AT1)表达上调；6)Ang II通过活性氧(ROS)，特别是超氧阴离子(O2-)机制调节自主神经流出；7)Ang II下调培养神经细胞nNOS。我们实验室获得的令人兴奋的初步结果表明，运动训练(EXT)显著改善了中枢NMDA诱导的T1D勃起反应。基于这些有趣的初步数据和以前的工作，本项目将试图解决这样的假设，即Ext通过调节PVN中的NO和Ang II-O2-信号通路来改善NMDA诱导的T1D大鼠中枢性勃起功能障碍。在目标1中，我们将确定Ext对中枢NMDA-NO诱导的T1D大鼠勃起功能障碍的影响。在目标2中，我们将确定Ang II在中枢NMDA-NO诱导的T1D大鼠勃起功能障碍中的作用。在目标3中，我们将确定增强的Ang II是否通过刺激O2-参与中枢NMDA-NO诱导的T1D大鼠勃起功能障碍。在目标4中，我们将通过对T1D大鼠室旁核Ang II-O2-信号的作用，确定Ext是否对NMDA-NO诱导的中枢性勃起功能障碍有有益的作用。这些目标将在T1D大鼠身上实现，方法包括：整个动物的细胞水平的互补方法；勃起功能的生理学测量；清醒和麻醉动物的PVN显微注射；腺病毒基因导入；O2-和NO代谢物测量；免疫组织化学；分子生物学技术测量mRNAs信息；使用实时定量聚合酶链式反应和蛋白质印迹技术测量特定脑核中的蛋白质。这些研究的成功完成将为T1D勃起功能的中枢机制提供重要的新信息，特别是在下丘脑室旁核内，涉及勃起功能的神经调节改变和EXT对勃起功能障碍的治疗益处。了解中枢机制在改变的神经驱动中的作用(迄今研究不多)将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严重而常见的并发症。已提出的糖尿病勃起功能障碍的机制包括外周和中枢异常，然而，在糖尿病男性患者中，西地那非(伟哥)似乎只在阴茎水平对50%的患者有疗效。这项拟议的研究将提供重要的新信息，涉及勃起功能神经调节改变的中枢机制，以及运动训练对糖尿病勃起功能障碍的治疗益处。了解中枢机制在改变的神经驱动中的作用(迄今研究不多)将增强我们治疗糖尿病性功能障碍的能力。

项目成果

Exercise training improves the defective centrally mediated erectile responses in rats with type I diabetes.

运动训练可改善 I 型糖尿病大鼠中枢介导的勃起反应缺陷。

• DOI: 10.1111/j.1743-6109.2011.02442.x
• 发表时间: 2011
• 期刊: The journal of sexual medicine
• 作者: Zheng,Hong;Mayhan,WilliamG;Patel,KaushikP
• 通讯作者: Patel,KaushikP

Attenuated dopaminergic tone in the paraventricular nucleus contributing to sympathoexcitation in rats with Type 2 diabetes.

室旁核多巴胺能减弱导致 2 型糖尿病大鼠交感神经兴奋。

• DOI: 10.1152/ajpregu.00323.2013
• 发表时间: 2014
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: Zheng,Hong;Liu,Xuefei;Li,Yulong;Mishra,ParasK;Patel,KaushikP
• 通讯作者: Patel,KaushikP