ALTERED NITRIC OXIDE MECHANISMS IN PVN DURING DIABETES

胰岛素依赖型糖尿病（IDDM）患者和所有的IDDM动物模型都表现出自主神经调节的改变。这种异常增加了糖尿病期间死亡的风险。这些异常背后的中枢机制知之甚少。 我们最近获得的数据表明，室旁核（PVN），一个中央站点已知接收来自各种内脏传入的传入信息，并改变交感神经流出，可能有助于改变自主神经流出在糖尿病状态。 此外，室旁核内一氧化氮（NO）和γ-氨基丁酸（GABA）机制的改变可能参与了这种自主神经流出。 这项建议测试的假设，破坏一氧化氮和GABA机制PVN内有助于改变交感神经流出在IDDM。 我们建议：第一，确定在患有IDDM的大鼠中NO机制是否改变;第二，确定在患有IDDM的大鼠中PVN内的NO机制是否有助于改变交感神经活性;第三，确定在患有IDDM的大鼠中PVN内的GABA机制是否有助于改变交感神经活性;和第四，确定在患有IDDM的大鼠中PVN内的NO和GABA机制是否存在改变的相互作用。 预计室旁核内的NO和GABA机制有助于在IDDM期间通常观察到的自主神经流出的改变。 结果应提供重要的新信息，改变交感神经兴奋的中枢机制，特别是参与PVN内的NO和GABA系统，在糖尿病状态下的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.