Increased angiotensin II AT1 receptor expression in paraventricular nucleus and hypothalamic-pituitary-adrenal axis stimulation in AT2 receptor gene disrupted mice

Document Type

Journal Article

Publication Date

12-1-2002

Journal

Neuroendocrinology

Volume

76

Issue

3

DOI

10.1159/000064525

Keywords

Adrenal gland; Adrenal steroids; Angiotensin receptors; Catecholamines; Corticotropin; Paraventricular nucleus; Renin-angiotensin system; Stress

Abstract

Angiotensin II AT2 receptor gene-disrupted mice have increased blood pressure and response to angiotensin II, behavioral alterations, greater response to stress, and increased adrenal AT1 receptors. We studied hypothalamic AT1 receptor binding and mRNA by receptor autoradiography and in situ hybridization, adrenal catecholamines by HPLC, adrenal tyrosine hydroxylase mRNA by in situ hybridization and pituitary and adrenal hormones by RIA in AT2 receptor-gene disrupted mice and wild-type controls. To confirm the role of adrenal AT1 receptors, we treated wild-type C57 BL/6J mice with the AT1 antagonist candesartan for 2 weeks, and measured adrenal hormones, catecholamines and tyrosine hydroxylase mRNA. In the absence of AT2 receptor transcription, we found increased AT1 receptor binding in brain areas involved in the regulation of the hypothalamic-pituitary-adrenal axis, the hypothalamic paraventricular nucleus and the median eminence, and increased adrenal catecholamine synthesis as shown by higher adrenomedullary tyrosine hydroxylase mRNA and higher adrenal dopamine, norepinephrine and epinephrine levels when compared to wild-type mice. In addition, in AT2 receptor gene-disrupted mice there were higher plasma adrenocorticotropin (ACTH) and corticosterone levels and lower adrenal aldosterone content when compared to wild-type controls. Conversely, AT1 receptor inhibition in CB57 BL/6J mice reduced adrenal tyrosine hydroxylase mRNA and catecholamine content and increased adrenal aldosterone content. These results can help to explain the enhanced response of AT2 receptor gene-disrupted mice to exogenous angiotensin II, support the hypothesis of cross-talk between AT1 and AT2 receptors, indicate that the activity of the hypothalamic-pituitary-adrenal axis parallels the AT1 receptor expression, and suggest that expression of AT1 receptors can be dependent on AT2 receptor expression. Our results provide an explanation for the increased sensitivity to stress in this model. Copyright © 2002 S. Karger AG, Basel.

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