Stress sensitivity is increased in transgenic rats with low brain angiotensinogen

Abstract

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(ASrAO-GEN), 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.

Double blockade of angiotensin II (AT1)‐receptors and ACE does not improve weight gain and glucose homeostasis better than single‐drug treatments in obese rats

“…However, the early ACTH response was diminished by all drug regimens. In agreement with the literature (Müller et al ., 2007; 2010), we demonstrated in controls that corticosterone remained elevated for 90 min, although ACTH had already returned to baseline levels. In contrast to controls, the corticosterone response was diminished by TEL or RAM or even normalized by TEL + RAM after 90 min.…”

“…Before stress testing, blood samples were taken from a tail nick in order to establish the baseline conditions of the stress hormones. Then, 30 and 90 min after swimming (7 min) in a basin (diameter 35 cm, water depth 20 cm, water temperature 15°C), tail blood was taken again to determine ACTH, corticosterone and glucose levels (Müller et al ., 2010).…”

Locus Coeruleus Dysfunction in Transgenic Rats with Low Brain Angiotensinogen

“…TGR rats display behavioral deficits, that is, increased sensitivity to stress and anxiety, as well as indices of depression [17][18][19]50]. Furthermore, we report, here, that TGR rats exhibit sleep disorders associated with increased daily PS duration and blunted adaptation to sleep deprivation.…”

Corticosterone oscillations during mania induction in the lateral hypothalamic kindled rat—Experimental observations and mathematical modeling

“…injection, yielding a CRH concentration of 3×10 −9 M < [CRH] < 3×10 −8 M in the peripheral blood circulation (calculated for 5.25 l of blood in an average male of 70 kg; or for 70 ml/kg for rats). This level of change in CRH concentration is typically well tolerated, with the most common side effects being transient facial flushing and rare dyspnea or hypotension [103]; and was shown to induce a 3-fold increase in corticosterone concentration [104]. In comparison with these values, an increase in CRH levels of 5×10 −8 M in an LHK-induced manic-like episode, as was predicted by the model, seems not to be entirely unrealistic, but calls for testing in future studies.…”