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¹ Institute of Experimental and Clinical Pharmacology and Toxicology
² Institute of Medical Biometry and Statistics, University of Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
³ Max-Delbrück-Center for Molecular Medicine (MDC), Berlin-Buch, 13125 Berlin, Germany

(Correspondence should be addressed to W Raasch; Email: raasch{at}medinf.mu-luebeck.de)

AT₁ blockers attenuate hypothalamo-pituitary–adrenal (HPA) axis reactivity in hypertension independently of their potency to lower blood pressure. A reduced pituitary sensitivity to CRH and a downregulation of hypothalamic CRH expression have been suggested to influence HPA axis activity during chronic AT₁ blockade. This study was aimed at confirming the role of central angiotensin II in regulating HPA reactivity by using the transgenic rat TGR(ASrAOGEN), a model featuring low levels of brain angiotensinogen. Different stress tests were performed to determine HPA reactivity in TGR(ASrAOGEN) and appropriate controls. In TGR(ASrAOGEN), blood pressure was diminished compared to controls. The corticosterone response to a CRH or ACTH challenge and a forced swim test was more distinct in TGR(ASrAOGEN) than it was in controls and occurred independently of a concurrent enhancement in ACTH. Using quantitative real-time PCR, we found increased mRNA levels of melanocortin 2 (Mc2r) and AT₂ receptors (Agtr2) in the adrenals of TGR(ASrAOGEN), whereas mRNA levels of Crh, Pomc, and AT₁ receptors (Agtr1) remained unchanged in hypothalami and pituitary glands. Since stress responses were increased rather than attenuated in TGR(ASrAOGEN), we conclude that the reduced HPA reactivity during AT₁ blockade could not be mimicked in a specific transgenic rat model featuring a centrally inactivated renin–angiotensin–aldosterone system. The ACTH independency of the enhanced corticosterone release during CRH test and the enhanced corticosterone response to ACTH rather indicates an adrenal mechanism. The upregulation of adrenal MC2 and AT₂ receptors seems to be involved in the stimulated facilitation of adrenal corticosterone release for effectuating the stimulated stress responses.