We advanced our studies on the protective role of Angiotensin II AT1 antagonists in brain ischemia. Protection is dependent in arterial remodeling and facilitated dilation of cerebral arteries, resulting in increased cerebral blood flow, decreased reduction in blood flow during stroke and decreased neuronal injury. AT1 antagonists are superior to other anti-hypertensive drugs. In a related study, we demonstrated upregulation of AT1 receptors in AT2 gene-deficient mice. This explains their phenotype, increased response to Angiotensin II, sodium retention and blood pressure and supports the hypothesis of cross talk between AT1 and AT2 receptors. AT1 receptor expression is increased in some, but not all, organs expressing AT1 receptors, and in cells that do not express AT2 receptors in wild-type mice. Thus, mechanisms of cross talk between AT1 and AT2 receptors are organ-specific and indirect. The relative predominance of AT2 receptors when AT1 receptors are blocked is responsible for at least part of the therapeutic effects of AT1 antagonists. AT2 gene-deficient mice express also express increased numbers of receptors for the vasoconstrictor endothelin and the vasodilator, sodium excreting atrial natriuretic peptide. Thus, lack of expression of one receptor (AT2) results in a cascade of multiple feedback and adaptive mechanisms in related systems. We further demonstrate that AT1 and AT2 receptors play a role during stress. Angiotensin receptors in pituitary and adrenal glands are more important during the acute phase of the stress response, whereas the response of brain AT1 receptors is long lasting and regulatory not only of the acute but of the adaptive response to repeated stress. All these results indicate that pharmacological modulation of AT1 receptors could have therapeutic implications for the prevention and treatment of brain ischemia and stress related disorders. Finally, our studies on the molecular requirements for antagonist binding of the AT1 receptor have come to a conclusion. With the use of site-directed mutagenesis of the human and gerbil AT1 receptors, we have established that selected amino acids are responsible for the affinity of the receptor for non-peptidic antagonists. These studies are essential for the future development of selective and potent AT1 antagonists of therapeutic importance.
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