ROLE OF NEUROPEPTIDES AND BIOGENIC AMINES IN STRESS AND BRAIN ISCHEMIA

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We have cloned and characterized an atypical gerbil Angiotensin II AT-1 receptors but three orders of magnitude lower affinity for AT-1 antagonists than other AT-1 mammalian receptors (gAT- 1a). The gAT-1a receptor is formed and expressed in large numbers in hypoxia-sensitive neurons of the gerbil hippocampus. These findings suggest a role of Angiontensin II in hippocampal function, and provide an opportunity to determine, with site- directed mutagenesis, the specific aminoacids responsible for the affinity of the receptor for non-peptide antagonists of clinical use. We set up a culture system for gerbil hippocampal neurons, to study the receptor regulation and signal transduction mechanisms. We found an additional AT-1 and one AT- 2 receptor genes, and we cloned these two receptors. Studies are in progress to determine their pharmacological profiles. By comparison of rodent species such as the gerbil, rat and mouse, we have determined that in selected brain nucleus, the expression of Angiotensin II receptor subtypes is species- dependent. We have continued our studies on the development of the expression of Angiotensin II receptor subtypes, from postnatal day 1 to adulthood, to determine their role in the development of motor, sensory and hippocampal systems. We continue our experiments to clarify the regulation of rat brain Angiotensin II receptor subtypes during stress. We found that chronic treatment of rats with AT-1 receptor antagonists reverses the alterations in cerebral blood flow autoregulation which occur in genetic hypertension, and results in a blockade of Angiotnesin binding to brain AT-1 receptors. This supports the hypothesis of a possible benefit of AT-1 antagonists in the treatment of hypertension-related cerebrovascular disease.