Effects of a novel corticotropin-releasing-hormone receptor type I antagonist on human adrenal function

Corticotropin-releasing hormone (CRH) is the principal regulator of the hyp othalamic-pituitary-adrenal (HPA) axis and an activator of the sympathoadre nal (SA) and systemic sympathetic (SS) systems. Mental disorders, including major depression and, more recently, Alzheimer's disease have been associa ted with dysregulation of the HPA axis and the SA/SS systems. Treatment of rats or monkeys with the novel CRH receptor type 1 (CRH-R1) antagonist anta larmin inhibits the HPA and/or the SA/SS axes. This is the first study to e xamine the potential direct effect of antalarmin on human adrenal function. Adrenocortical and adrenomedullary cells were characterized by double-immu nohistochemistry with anti-17 alpha hydroxylase (cortical cells) and anti-c hromogranin A (chromaffin cells). Expression of CRH, ACTH, CRH type I and t ype II receptor mRNA were analyzed by reverse-transcription (RT) PCR, Human adrenal cortical and/or chromaffin cells in co-culture were incubated with CRH, antalarmin, and both CRH and antalarmin in vitro. Exposure of these c ells to corticotropin or vehicle medium served as positive and negative con trols, respectively. Cortical and chromaffin tissues were interwoven in the human adrenals, and both in site and in the co-culture system the endocrin e cell types were in close cellular contact. ACTH, CRH, and CRH-R1 and CRH- R2 mRNAs were expressed in the human adrenal as determined by RT-PCR. CRH ( 10(-8) M) led to a moderate increase of cortisol release (145.7+/-20.0%) fr om cortical and chromaffin adrenal cells in co-culture. This effect corresp onded to 41.8% of the maximal increase induced by ACTH (10(-8) M). The acti on of CRH was completely inhibited by antalarmin. CRH, ACTH, and both CRH-R 1 and CRH-R2 mRNAs are expressed in the adult human adrenal gland, CRH stim ulates cortisol production in cortical and chromaffin cell co-cultures. Thi s effect is blocked by antalarmin, a selective CRH-R1 receptor antagonist, suggesting that CRH-R1 receptors are involved in an intraadrenal CRH/ACTH c ontrol system in humans.