gms | German Medical Science

It was shown, that AT1A-receptors were stress-dependently upregulated in hypothalami and adrenals and that AT1-stimulation increased CRH, corticosterone (CORT) and ACTH. Compared to normotensive rats, SHR are more stress sensitive, which was related to an increased AT1A-expression in pituitary glands. The question arose, whether chronic antihypertensive treatment reduces HPA reactivity.

SHR were treated (5 weeks) with candesartan (2mg/kg), ramipril (1) or mibefradil (12). In addition to baseline levels, CORT and ACTH were monitored after CRH-injections (100µg/kg i.v.) over 4h. mRNA of CRH, POMC, AT1A- AT1B- and AT2-receptors was quantified by real time rt-PCR.

Efficacy of treatment was ascertained by equieffective reduction of MAP. Baseline levels of CORT and ACTH were similar in all groups. The CRH-induced ACTH-release (Cmax=641pg/ml) was reduced by candesatan (26%) and ramipril (15%), but not by mibefradil The CORT release of controls (Cmax=327Dng/ml) was consequently diminished only by candesartan (36%) and ramipril (18%). Compared to controls (2.77x106 copies mRNA/100ng cDNA), hypothalamic CRH mRNA was decreased by candesartan (39%) and ramipril (42%). The gene expression of AT1A-, AT1B- and AT2-receptors was not altered by any drug within the HPA-axis.

We conclude, that attenuation of HPA reactivity in SHR is less dependent on normalization of MAP but rather on a sufficient blockade of AT1-receptors, since mibefradil lowers blood pressure but failed to influence CORT or ACTH. The necessity of stress for an effective attenuation of the HPA axis by AT1-blockade is suggested, because only CRH-stimulated but not baseline levels of stress hormones were reduced. Thus, chronic antihypertensive AT1-blockade mainly lessens HPA axis by reduction of pituitary ACTH release. In addition, the participation of a central mechanism is likely due to CRH mRNA downregulation, but needs further investigations. A shift in AT-receptor expression is not participated.