Angiotensin II AT1 receptor blockade prevents the hypothalamic corticotropin-releasing factor response to isolation stress

Abstract

Sustained pretreatment with angiotensin II AT(1) receptor antagonists prevents the sympathoadrenal and hormonal responses to 24 h isolation stress. To elucidate the mechanism of the anti-stress effects of AT(1) receptor antagonism, we examined the effect of subcutaneous infusion of candesartan, a non-competitive AT(1) receptor antagonist, 0.5 mg/kg/day for 14 days, to Wistar rats on the hypothalamic pituitary adrenal (HPA) axis after 24 h isolation stress. In the morning of day 15, we measured AT(1) receptors corticotropin-releasing factor (CRF) mRNA and immunoreactive CRF in the paraventricular nucleus (PVN), the pituitary adrenocorticotropin hormone (ACTH) and adrenal corticosterone content, and the urinary corticosterone excretion. In rats not treated with candesartan, 24 h isolation stress increased pituitary ACTH, adrenal corticosterone content and AT(1) receptor binding in the PVN but decreased CRF mRNA and CRF content in the PVN. This indicates enhanced CRF utilization not compensated by CRF gene transcription and effective glucocorticoid feedback inhibition in spite of the increase in AT(1) receptor expression. The effects of stress on HPA axis activation and CRF mRNA and content in the PVN were prevented by candesartan pretreatment, suggesting that activation of AT(1) receptors is required for the HPA axis response to isolation. Our results support the hypothesis that the activity of PVN AT(1) receptors is part of the mechanism necessary for development of a full stress-induced HPA axis activation. Inhibition of central AT(1) receptors limits the CRF response to stress and should be considered as a therapeutic tool to preserve homeostasis under chronic stress conditions.

Figure 1

Representative autoradiograms of AT₁ receptor binding (upper row) and CRF mRNA (lower row) in the paraventricular nucleus of grouped or isolated animals treated with vehicle or the AT₁ blocker. AT₁ receptor binding is localized to the parvocellular and periventricular regions of the PVN. CRF mRNA is expressed in the parvocellular PVN and can be superimposed to the parvocellular AT₁ receptor binding. Arrows point to the 3^rd ventricle. Scale bar = 1 mm.

Figure 2

Quantitative autoradiography of AT₁ receptor binding (A) and expression of CRF mRNA (B) in the paraventricular nucleus of grouped or isolated animals treated with vehicle or the AT₁ blocker. Bars represent means ± S.E.M. of groups of six rats measured individually. * P<0.05 vs. grouped treated with vehicle; ** P<0.01 vs. grouped or isolated rats treated with vehicle; # p<0.05 vs. all others.

Figure 3

Content of CRF in the paraventricular nucleus of grouped or isolated animals treated with vehicle or the AT₁ blocker. Results are expressed as the mean ± S.E.M. of groups of six rats measured individually. * P<0.05 vs. all others.

Figure 4

Content of ACTH in the pituitary gland of grouped or isolated animals treated with vehicle or the AT₁ blocker. Results are expressed as the mean ± S.E.M. of groups of six rats measured individually. * P<0.05 vs. all others.

Figure 5

Content of corticosterone in the adrenal gland of grouped or isolated animals treated with vehicle or the AT₁ blocker. Results are expressed as the mean ± S.E.M. of groups of six rats measured individually. * P<0.05 vs. all others ** P<0.01 vs. grouped treated with vehicle.

Figure 6

Urinary excretion of corticosterone in isolated rats treated with vehicle or the AT₁ blocker. Results are expressed as the mean ± S.E.M. of groups of six rats measured individually. * P<0.05.