Ang-(1-7) activates the vasodilator systems which oppose the hypertensive At1-mediated actions of Ang II. We propose three aims to investigate the potential mechanisms for the actions of Ang-(1-7).
Aim 1 : A novel non-At1, non-AT2 receptor [AT(1-7)] is responsible for the hemodynamic and vascular actions of Ang-(1-7). 125I-[Sar/1-Thr/8]Ang II binding, in the presence of blocking concentrations of AT1 and AT2 receptor antagonists, demonstrated a novel Ang-(1-7) receptive site sit mesenteric artery and aorta of SHR treated with a combination of lisinopril/losartan. The binding site displayed a pharmacological profile with agonists and antagonists that previously characterized in endothelial cells. We will now determine whether this receptor is unique to the vasculature or exhibits a more widespread distribution (kidney, heart and brain) using receptor binding techniques.
Aim 2 : Ang-(1-7) actions blocked by At1 or AT2 receptor antagonists are not attributable to classical AT1 or AT2 receptors. In addition to the actions of Ang-(1- 7) at the novel non-AT1 non-AT2 AT(1-7) receptor, several actions of Ang-(1-7) are similar to Ang II or are blocked by AT1 or AT2 receptor antagonists. Ang-(1-7) generally displays low affinity for typical AT1 or AT2 receptors and is not associated with vasoconstrictor, pressor or drinking responses. Thus, we propose that isoforms of AT1 or AT2 receptors are responsible for the actions of Ang-(1-7) that are blocked by AT1 or AT2 receptor antagonists. We will use receptor knockout mice to show that the Ang-(1-7) actions or binding sites inhibited by AT1 or AT2 receptor antagonists do not persist in these receptor knockout animals. We will also characterize the protein forms of At1 and AT2 receptors known to exist in various tissues for differences in pharmacology toward Ang-(1-7) and [D-Ala/7]-Ang-(1-7).
Aim 3 : Ang-(1-7) counteracts the actions of Ang II at the AT1 receptor by desensitization and/or down-regulation of the AT1 receptor via homologous (through prostaglandins or nitric oxide) mechanisms. Acute and chronic exposure to elevated Ang-(1-7) decreases AT1 receptors and AT1 receptor-mediated responses in brain, kidney and cells in cultured. Prostaglandins causes heterologous down-regulation of other receptors and decrease in AT1 receptor mRNA with nitric oxide are reported. Alternatively, Ang-(1-7) acts as a weak agonist at the AT1 receptor, in a process similar to homologous receptor regulation. Preliminary studies in CHO-AT/1A cells indicated a direct effect of Ang-(1-7) on the AT/1A receptor, consistent with agonist-induced homologous down-regulation. We will use in vivo and in vitro models to determine the effects of acute and long-term treatments with Ang-(1-7) on AT1 receptor affinity and density and AT1 receptor mRNA by RT-PCR in the presence or absence of cyclooxygenase or nitric oxide synthase blockade.
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