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H Müller, Institute of experimental and clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany
J Kröger, Institute of experimental and clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany
O Jöhren, Institute of experimental and clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany
S Szymczak, Institute of Medical Biometry and Statistics, University of Lübeck, Lübeck, Germany
M Bader, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
P Dominiak, Institute of experimental and clinical Pharmacology and Toxicology, University of Lübeck, Lübeck, Germany
W Raasch, Institute of experimental and clinical Pharmacology and Toxicology, Universitiy of Lübeck, Lübeck, 23528, Germany

Correspondence: Walter Raasch, Email: raasch{at}medinf.mu-luebeck.de

Objective. AT1-blockers attenuate hypothalamo-pituitary-adrenal (HPA)-axis reactivity in hypertension independently of their potency to lower blood pressure. A reduced pituitary sensitivity to corticotropin-releasing hormone (CRH) and a down-regulation of hypothalamic CRH expression have been suggested to influence HPA-axis activity during chronic AT1-blockade.

Design. 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.

Results. In TGR(ASrAOGEN) blood pressure was diminished compared to controls. The corticosterone response to a CRH or adrenocorticotropic hormone (ACTH) challenge and a forced swim test (FST) 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 MC2- and AT2-receptor in the adrenals of TGR(ASrAOGEN), whereas mRNA-levels of CRH, pro-opiomelanocortin (POMC) and AT1-receptors remained unchanged in hypothalami and pituitary glands.

Conclusions. 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 RAAS. 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.