ALTERED NITRIC OXIDE MECHANISMS IN PVN DURING DIABETES

胰岛素依赖型糖尿病（IDDM）患者和所有IDDM动物模型都表现出自主调节的改变。这种异常增加了糖尿病患者死亡的风险。这些异常背后的主要机制尚不清楚。我们最近获得的数据表明，室旁核（PVN），一个已知接收来自各种内脏传入信息并改变交感神经流出的中心部位，可能有助于改变糖尿病状态下的自主神经流出。此外，PVN内一氧化氮（NO）和γ -氨基丁酸（GABA）机制的改变可能参与了这种自主流出。这一提议验证了PVN内NO和GABA机制的破坏导致IDDM期间交感神经流出改变的假设。我们建议：首先，确定IDDM大鼠的NO机制是否改变；第二，确定PVN内NO机制是否导致IDDM大鼠交感神经活动的改变；第三，确定PVN内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NO和GABA机制的相互作用是否发生改变。预计PVN内的NO和GABA机制有助于IDDM期间常见的自主神经流出改变。这些结果应该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PVN内NO和GABA系统的参与，以及糖尿病状态下交感神经激活的改变。了解交感神经驱动改变中尚未研究的中枢机制的作用，将提高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.