ALTERED NITRIC OXIDE MECHANISMS IN PVN DURING DIABETES

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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.