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Inhibitory effect of adrenomedullin (ADM) on the aldosterone response of human adrenocortical cells to angiotensin-II: Role of ADM(22–52)-sensitive receptors

1998; Elsevier BV; Volume: 63; Issue: 26 Linguagem: Inglês

10.1016/s0024-3205(98)00520-7

1879-0631

Anna S. Belloni, Paola G. Andreis, Gian Paolo Rossi, Alessandra Mingrino, Hunter C. Champion, Philip J Kadowitz, William A. Murphy, D.H. Coy, Gastone G. Nussdorfer,

Pharmacological Effects and Assays

Human adrenomedullin (ADM) is a 52-amino acid hypotensive peptide, which possesses a disulfide bridge-formed six-membered ring in 16–21 position. The ring structure, and both the N- and C-terminal amino-acid sequences 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 effect of this peptide on the aldosterone response of zona glomerulosa (ZG) cells to angiotensin-II (ANG-II). Autoradiography showed the presence of abundant [125I]ADM(1–52) binding sites in the ZG of human adrenals, which were displaced not only by cold ADM(1–52), but also by both 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, concentration-dependently inhibited ANG-II-stimulated aldosterone secretion of dispersed human adrenocortical cells. The aldosterone antisecretagogue actions of ADM(1–52) and ADM(13–52) were counteracted by ADM(22–52) in a concentration-dependent manner, while other ADM fragments were ineffective. In light of these findings the following conclusions could be drawn: (i) human ZG cells are provided with ADM(22–52)-sensitive receptors; (ii) the six-membered ring structure and the C-terminal, but 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, while the ring structure is required for the receptor activation.