Hypoosmolality and hyponatremia caused by the syndrome of inappropriate antidiuresis (SIAD) is a significant cause of morbidity and mortality in hospitalized patients. However, despite recognition of this clinical disorder for almost 30 years, many aspects of the pathogenesis of hypoosmolality with inappropriate antidiuresis remain unclear. In part this is due to the lack of a good animal model allowing sustained hypoosmolality without escape from antidiuresis. This proposal describes the development of such a model using continuous infusions of vasopressin or 1-deamino-(8-D-arginine) vasopressin in rats eating a balanced liquid diet of sufficient caloric density to maintain stable body weights. The experiments proposed will utilize this animal model to characterize the pathogenesis of hypoosmolality with inappropriate antidiuresis and to study the physiological adaptations which occur in response to states of chronic severe hypoosmolality, specifically: 1) the mechanisms of cellular adaptation to sustained extracellular hypoosmolality, 2) the patterns of neurohypophyseal secretion of vasopressin and oxytocin after adaptation to sustained extracellular hypoosmolality, and 3) the mechanisms of brain adaptation to sustained extracellular hypoosmolality and the consequences of such compensatory changes for brain hydration following subsequent correction to normotonicty. A better understanding of the pathophysiology during sustained hypoosmolality in the rat should also be of direct relevance to several related aspects of human SIAD, specifically: 1) the relative importance of cellular inactivation of solute versuys cellular loss of solute in the pathogenesis of hyponatremia, 2) the mechanisms responsible for the reset osmostat pattern of vasopressin secretion in SIAD, and 3) the potential relation between hypoosmolality and demyelinating disorders such as pontine and extrapontine myelinolysis as well as the pathophysiological mechanisms leading to such demyelinative changes. Applying existing methods and procedures in this laboratory to an established animals model of sustained severe hypoosmolality will allow completion of studies which should therefore lead to significant advances in our understanding of how organisms, including humans, adapt to derangements in extracellular osmolality. Such knowledge should in turn permit a more enlightened approach to the clinical management of disorders of water and elecrolyte metabolism.
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