Angiotensin II AT1 and AT2 Receptor Types Regulate Basal and Stress-Induced Adrenomedullary Catecholamine Production through Transcriptional Regulation of Tyrosine Hydroxylase

Authors

  • I ARMANDO,

    Corresponding author
    1. Section on Pharmacology, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA
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  • M JEZOVA,

    1. Section on Pharmacology, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA
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  • C BREGONZIO,

    1. Section on Pharmacology, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA
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  • G BAIARDI,

    1. Section on Pharmacology, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA
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  • J M. SAAVEDRA

    1. Section on Pharmacology, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA
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Address for correspondence: Ines Armando, Ph.D., Section on Pharmacology, DIRP, NIMH, NIH, DHHS, 10 Center Drive, MSC 1514, Bldg. 10, Room 2D-57, Bethesda, MD 20892, USA. Voice: 301-402-6860; fax: 301-402-0337. e-mail: ArmandoI@intra.nimh.nih.gov

Abstract

Abstract: The sympathoadrenal response to stress includes a profound increase in adrenomedullary catecholamine synthesis driven by stimulation of tyrosine hydroxylase (TH) transcription. We studied the role of Angiotensin II type 1 and 2 (AT1 and AT2) receptors during isolation stress, and under basal conditions. Pretreatment of rats with the AT1 receptor antagonist candesartan for 14 days prior to isolation completely prevented the stress-induced stimulation of catecholamine synthesis, decreasing tyrosine hydroxylase transcription by preventing the expression of the transcriptional factor, Fos-related antigen 2 (Fra-2). In addition, AT1 receptor antagonism prevented the stress-induced increase in adrenomedullary AT2 receptor binding and protein. Treatment of non-stressed, grouped animals under basal conditions with the AT1 receptor or with PD 123319, an AT2 receptor antagonist, decreased the adrenomedullary norepinephrine (NE) content and TH transcription. While AT1 receptor antagonism decreased the levels of Fra-2 and the phosphorylated forms of cAMP responsive element binding protein (pCREB) and EKR2 (p-ERK2, phosphor-p42 MAP kinase), the AT2 antagonist decreased Fra-2 with no change in the phosphorylation of CREB or EKR2. Our results demonstrate that both adrenomedullary AT1 and AT2 receptor types maintain and promote the adrenomedullary catecholamine synthesis and the transcriptional regulation of TH. Instead of opposing effects, however, our results indicate a complex synergistic regulation between the AT1 and AT2 receptor types.

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