INHIBITORY EFFECT OF ADRENOMEDULLIN (ADM) ON THE ALDOSTERONE RESPONSEOF HUMAN ADRENOCORTICAL-CELLS TO ANGIOTENSIN-II - ROLE OF ADM(22-52)-SENSITIVE RECEPTORS

Human adrenomedullin (ADM) is a 52-amino acid hypotensive peptide, whi ch possesses a disulfide bridge-formed six-membered ring in 16-21 posi tion. The ring structure, and both the N- and C-terminal amino-acid se quences seem to play a key role in the vascular effects of ADM(1-52), and we have investigated whether the same is true for the inhibitory e ffect of this peptide on the aldosterone response of zona glomerulosa (ZG) cells to angiotensin-II (ANG-II). Autoradiography showed the pres ence of abundant [I-125]ADM(1-52) binding sites in the ZG of human adr enals, which were displaced not only by cold ADM(1-52), but also by ba th ADM(13-52) and ADM(22-52); ADM fragments 1-12, 15-22 and 16-31 were ineffective. ADM(1-52) and ADM(13-52), but not other fragments, conce ntration-dependently inhibited ANG-II-stimulated aldosterone secretion of dispersed human adrenocortical cells. The aldosterone antisecretag ogue actions of ADM(1-52) and ADM(13-52) were counteracted by ADM(22-5 2) in a concentration-dependent manner, while other ADM fragments were ineffective. In light of these findings the following conclusions cou ld be drawn: (i) human ZG cells are provided with ADM(22-52)-sensitive receptors; (ii) the six-membered ring structure and the C-terminal, b ut not N-terminal, amino-acid sequence are both essential for,ADM(1-52 ) to exert its antimineralocorticoid action; and probably (iii) the C- terminal sequence is needed for ADM(1-52) to bind its ZG receptors, wh ile the ring structure is required for the receptor activation.