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 (CRH), adrenocorticotropic hormone (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 SHR.

SHR were either treated with candesartan (2 mg/kg), ramipril (1 mg/kg) or mibefradil (12 mg/kg) for 5 weeks. In addition to baseline levels, CORT and ACTH responses to injection of CRH (100 µg/kg) were monitored over 4 h. Messenger RNA of CRH, proopiomelanocortin (POMC), 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 AT₁-receptors or ACE 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 downregulation of hypothalamic CRH expression have the potential to reduce HPA-axis activity during chronic AT₁-blockade or ACE inhibition.