Angiotensin II inhibition reduces stress sensitivity of hypothalamo-pituitary-adrenal axis in spontaneously hypertensive rats

Angiotensin II type 1 (AT₁) receptors are expressed within organs of the hypothalamo-pituitary-adrenal (HPA) axis and seem to be important for its stress responsiveness. Secretion of CRH, ACTH, and corticosterone (CORT) is increased by stimulation of AT₁ receptors. In the present study, we tested whether a blockade of the angiotensin II system attenuates the HPA axis reactivity in spontaneously hypertensive rats. Spontaneously hypertensive rats were treated with candesartan (2 mg/kg), ramipril (1 mg/kg), or mibefradil (12 mg/kg) for 5 wk. In addition to baseline levels, CORT and ACTH responses to injection of CRH (100 μg/kg) were monitored over 4 h. mRNA of CRH, proopiomelanocortin, AT_1A, AT_1B, and AT₂ receptors was quantified by real-time PCR. All treatments induced equivalent reductions of blood pressure and had no effect on baseline levels of CORT and ACTH. However, both candesartan and ramipril significantly reduced CRH-stimulated plasma levels of ACTH (-26 and -15%) and CORT (-36 and -18%) and lowered hypothalamic CRH mRNA (-25 and -29%). Mibefradil did not affect any of these parameters. Gene expression of AT_1A, AT_1B, and AT₂ receptors within the HPA axis was not altered by any drug. We show for the first time that antihypertensive treatment by inhibition of AT ₁ receptors or angiotensin-converting enzyme attenuates HPA axis reactivity independently of blood pressure reduction. This action is solely evident after CRH stimulation but not under baseline conditions. Both a reduced pituitary sensitivity to CRH and a down-regulation of hypothalamic CRH expression have the potential to reduce HPA axis activity during chronic AT ₁ blockade or angiotensin-converting enzyme inhibition.