Key result
Transgenic rats with low brain angiotensinogen exhibited an increased corticosterone response to CRH, ACTH, and forced swim tests compared to controls, suggesting an adrenal mechanism.
In a transgenic rat model with low brain angiotensinogen, stress responses were increased rather than attenuated, suggesting an adrenal mechanism involving upregulation of MC2 and AT2 receptors.
Hypothesis-generating for adrenal stress responses in transgenic models; leaves open human HPA axis relevance pending translational studies.
AT(1) 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 AT(1) 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 AT(2) receptors (Agtr2) in the adrenals of TGR(ASrAOGEN), whereas mRNA levels of Crh, Pomc, and AT(1) 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 AT(1) 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 AT(2) receptors seems to be involved in the stimulated facilitation of adrenal corticosterone release for effectuating the stimulated stress responses.
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Müller‐Fielitz et al. (2009) studied Low brain angiotensinogen. Transgenic rat TGR(ASrAOGEN) (low brain angiotensinogen) vs. Appropriate controls was evaluated on HPA reactivity (corticosterone response to CRH/ACTH challenge and forced swim test). Transgenic rats with low brain angiotensinogen exhibited an increased corticosterone response to CRH, ACTH, and forced swim tests compared to controls, suggesting an adrenal mechanism.
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