Nitric oxide (NO) is a newly discovered lipophilic gas synthesized by NO synthase (NOS) in the central nervous system that can alter short- and long-term synaptic function. There is now good evidence that NO is synthesized in neural structures essential for the regulation of salt- water balance. Specifically, this network includes magnocellular neurons in the supraoptic and paraventricular nuclei, where oxytocin (OT) and vasopressin (VP) are synthesized, and the subfornical organ (SFO), involved in drinking behavior. NO could, therefore, modulate water balance by influencing activity of neurons at these sites. Our preliminary studies demonstrated that blockade of NOS with NG-monomethyl- L arginine (NMMA) administered intracerebroventricularly (icv) enhances secretion of OT, but not VP, and attenuates water intake in 24h dehydrated rats. These results indicate that NO promotes rehydration by regulating neural mechanisms controlling drinking behavior and the preferential release of VP over OT during dehydration. We propose to examine further the role of NO in the modulation of neurosecretory function and drinking behavior in response to osmotic stimulation, hemorrhage and angiotensin II stimulation. NMMA will be injected icv to conscious rats under these conditions of reduced intracellular or extracellular volume to determine if NO influences release of OT drinking behavior. We will then investigate if the modulatory role of NO on OT release involves participation of endogenous opioid peptide (EOP) since both NMMA and blockade of opiate receptors with naloxone enhance the rise in plasma OT without changing glucose utilization in the hypothalamo- neurohypophysial system during dehydration. Two possibilities will be tested: a) If the attenuation of OT release during dehydration is mediated by NO facilitating secretion of an EOP (NO EOP OT), then icv injection of L-arginine, the substrate for NOS, should decrease or prevent the effect of norbinaltorphimine, a kappa opiate receptor antagonist. b) If this attenuation of OT secretion is mediated by an EOP faciliting formation of NO (EOP NO OT), then icv injection of dynorphin-A (1-8), a kappa receptor agonist, should decrease or prevent the effect of NMMA. Because regulation of salt-water balance is closely linked t mechanisms affecting arterial blood pressure, this study may provide important clinical information regarding preventive medicine applied to hypertension.
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