title: Increased angiotensin II AT(1) receptor expression in paraventricular nucleus and hypothalamic-pituitary-adrenal axis stimulation in AT(2) receptor gene disrupted mice.
abstract: Angiotensin II AT(2) receptor gene-disrupted mice have increased blood pressure and response to angiotensin II, behavioral alterations, greater response to stress, and increased adrenal AT(1) receptors. We studied hypothalamic AT(1) 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 AT(2) receptor-gene disrupted mice and wild-type controls. To confirm the role of adrenal AT(1) receptors, we treated wild-type C57 BL/6J mice with the AT(1) antagonist candesartan for 2 weeks, and measured adrenal hormones, catecholamines and tyrosine hydroxylase mRNA. In the absence of AT(2) receptor transcription, we found increased AT(1) 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 AT(2) 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, AT(1) 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 AT(2) receptor gene-disrupted mice to exogenous angiotensin II, support the hypothesis of cross-talk between AT(1) and AT(2) receptors, indicate that the activity of the hypothalamic-pituitary-adrenal axis parallels the AT(1) receptor expression, and suggest that expression of AT(1) receptors can be dependent on AT(2) receptor expression. Our results provide an explanation for the increased sensitivity to stress in this model.
authors.affiliation: Section on Pharmacology, National Institute of Mental Health, Bethesda, Md 20892, USA. Armandoi@intra.nimh.nih.gov
authors.forename: Inés
authors.initials: I
authors.lastname: Armando
authors.forename: José A
authors.initials: JA
authors.lastname: Terrón
authors.forename: Alicia
authors.initials: A
authors.lastname: Falcón-Neri
authors.forename: Ito
authors.initials: I
authors.lastname: Takeshi
authors.forename: Walter
authors.initials: W
authors.lastname: Häuser
authors.forename: Tadashi
authors.initials: T
authors.lastname: Inagami
authors.forename: Juan M
authors.initials: JM
authors.lastname: Saavedra
mesh_terms: D000305:Adrenal Cortex Hormones / Q000097:blood; D000311:Adrenal Glands / Q000201:enzymology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D002395:Catecholamines / Q000378:metabolism; D005260:Female; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology*; D007031:Hypothalamus / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism*; D010913:Pituitary-Adrenal System / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics
chemical_list: D000305:Adrenal Cortex Hormones; D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D002395:Catecholamines; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D014446:Tyrosine 3-Monooxygenase; C081643:candesartan