ALTERED NITRIC OXIDE MECHANISMS IN PVN DURING DIABETES

胰岛素依赖型糖尿病(IDDM)患者和所有IDDM动物模型均表现出自主神经调节改变。这种异常增加了糖尿病期间死亡的风险。人们对这些异常的核心机制知之甚少。我们最近获得的数据表明，室旁核(PVN)是已知的从各种内脏传入接受传入信息并改变交感神经流出的中心部位，可能在糖尿病状态下参与改变自主神经流出。此外，PVN内改变的一氧化氮(NO)和γ-氨基丁酸(GABA)机制可能参与了这种自主神经流出。这一建议验证了这样一种假说，即破坏PVN内的NO和GABA机制有助于在IDDM期间改变交感神经流出。我们建议：第一，确定IDDM大鼠是否没有机制改变；第二，确定PVN内是否没有任何机制导致IDDM大鼠交感神经活动改变；第三，确定PVN内的GABA机制是否有助于IDDM大鼠交感神经活动的改变；第四，确定IDDM大鼠PVN内是否存在NO和GABA机制的改变相互作用。预计室旁核内的NO和GABA机制有助于在IDDM期间观察到的改变的自主神经流出。这些结果将为交感神经兴奋改变的中枢机制提供重要的新信息，特别是在糖尿病状态下，室旁核内的NO和GABA系统参与交感神经激活的改变。了解中枢机制在交感神经驱动改变中的作用，将增强我们治疗糖尿病及其心血管并发症的能力。

Patients with insulin dependent diabetes mellitus (IDDM) and all animals models of IDDM exhibit altered autonomic regulation. This abnormality increases the risk of mortality during diabetes. The central mechanisms which underlie these abnormalities are poorly understood. We have recently obtained data which suggest that the paraventricular nucleus (PVN), a central site known to receive afferent information from various visceral afferents and to alter sympathetic outflow, may contribute to altered autonomic outflow during the diabetic state. Furthermore, altered nitric oxide (NO) and gamma-amino butyric acid (GABA) mechanisms within the PVN may be involved in this autonomic outflow. This proposal tests the hypothesis that disrupted NO and GABA mechanisms within the PVN contribute to the altered sympathetic outflow during IDDM. We propose to: first, determine if NO mechanisms are altered in rats with IDDM; second, determine if NO mechanisms within the PVN contributes to the altered sympathetic nerve activity in rats with IDDM; third determine if GABA mechanisms within the PVN contributes to the altered sympathetic nerve activity in rats with IDDM; and fourth, determine if there is altered interaction of NO and GABA mechanisms within the PVN in rats with IDDM. It is anticipated that NO and GABA mechanisms within the PVN contribute to the altered autonomic outflow commonly observed during IDDM. The results should provide significant new information regarding central mechanisms of altered sympatho-excitations specifically involvement of the NO and GABA systems within the PVN, in the altered sympathetic neural activation in the diabetic state. Understanding the role of the central mechanisms, not studied to date, in the altered sympathetic neural drive would enhance our ability to treat the diabetic condition and its cardiovascular complications.