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Angiotensin II AT₁ and AT₂ Receptors Contribute to Maintain Basal Adrenomedullary Norepinephrine Synthesis and Tyrosine Hydroxylase Transcription

Section on Pharmacology (M.J., I.A., C.B., J.M.S.), Division of Intramural Research Programs, National Institute of Mental Health, and Pathology Section (Z.-X.Y., S.Q., V.J.F.), National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892; and Institute of Cell Biology (H.I.), University of Bern, CH-3012 Bern, Switzerland

Address all correspondence and requests for reprints to: Miroslava Jezova, Section on Pharmacology, Division of Intramural Research Programs, National Institute of Mental Health, 10 Center Drive, Building 10, Room 2D-57, Bethesda, Maryland 20892. E-mail: armandoi{at}intra.nimh.nih.gov.

Angiotensin II (Ang II) AT₁ receptors have been proposed to mediate the Ang II-dependent and the stress-stimulated adrenomedullary catecholamine synthesis and release. However, in this tissue, most of the Ang II receptors are of the AT₂ type. We asked the question whether AT₁ and AT₂ receptors regulate basal catecholamine synthesis. Long-term AT₁ receptor blockade decreased adrenomedullary AT₁ receptor binding, AT₂ receptor binding and AT₂ receptor protein, rat tyrosine hydroxylase (TH) mRNA, norepinephrine (NE) content, Fos-related antigen 2 (Fra-2) protein, phosphorylated cAMP response element binding protein (pCREB), and ERK2. Long-term AT₂ receptor blockade decreased AT₂ receptor binding, TH mRNA, NE content and Fra-2 protein, although not affecting AT₁ receptor binding or receptor protein, pCREB or ERK2. Angiotensin II colocalized with AT₁ and AT₂ receptors in ganglion cell bodies. AT₂ receptors were clearly localized to many, but not all, chromaffin cells. Our data support the hypothesis of an AT₁/AT₂ receptor cross-talk in the adrenomedullary ganglion cells, and a role for both receptor types on the selective regulation of basal NE, but not epinephrine formation, and in the regulation of basal TH transcription. Whereas AT₁ and AT₂ receptors involve the Fos-related antigen Fra-2, AT₁ receptor transcriptional effects include pCREB and ERK2, indicating common as well as different regulatory mechanisms for each receptor type.

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