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Adrenomedullin Enhances Cell Proliferation and Deoxyribonucleic Acid Synthesis in Rat Adrenal Zona Glomerulosa: Receptor Subtype Involved and Signaling Mechanism

Department of Human Anatomy and Physiology, Section of Anatomy, University of Padua (P.G.A., G.M., G.G.N.), I-35–121 Padua, Italy; Department of Histology and Embryology, Poznan School of Medicine (A.M., L.K.M.), PL-60781, Poznan, Poland; and Department of Pharmacology, Tulane University Medical Center (H.C.C.), New Orleans, Louisiana 70112-2699

Address all correspondence and requests for reprints to: Prof. G. G. Nussdorfer, Department of Human Anatomy and Physiology, Section of Anatomy, Via Gabelli 65, I-35121 Padova, Italy. E-mail: ggnanat{at}ipdunidx.unipd.it

The effect of adrenomedullin (ADM) on the proliferative activity of the rat adrenal cortex has been investigated in vivo, using an in situ perfusion technique of the intact left gland. ADM and other chemicals were dissolved in the perfusion medium, and the perfusion was continued for 180 min. ADM infusion concentration dependently increased the mitotic index and [³H]thymidine incorporation into DNA in the zona glomerulosa (ZG; the maximal effective concentration was 10^-8 M), but not in inner adrenocortical layers, where basal proliferative activity was negligible. The effect of 10^-8 M ADM was equipotently counteracted by both the calcitonin gene-related peptide (CGRP) type 1 receptor antagonist CGRP-(8–37) and ADM-(22–52). The adenylate cyclase inhibitor SQ-22536 (10^-4 M), the cAMP blocker Rp-cAMP-S (10^-3 M), and the protein kinase A inhibitor H-89 (10^-5 M), although counteracting the ZG proliferogenic action of 10^-9 M ACTH, did not affect the 10^-8 M ADM-elicited increase in ZG DNA synthesis. Similar results were obtained using the phospholipase C inhibitor U-73122 (10^-5 M), the inositol-1,4,5-trisphosphate antagonist D,L-myo-inositol-1,4,5-trisphosphothiate (10^-4 M), and the protein kinase C inhibitor calphostin C (10^-5 M), which, however, significantly inhibited the ZG proliferogenic effect of 10^-9 M angiotensin II. The growth-promoting action of 10^-8 M ADM was not affected by the phospholipase A2 inhibitor AACOCF3 (10^-5 M), the cyclooxygenase (COX) inhibitor indomethacin (10^-5 M), or the mixed COX/lipoxygenase inhibitor phenidone (10^-5 M). In contrast, the ZG proliferogenic effect of 10^-8 M ADM was abolished by either the tyrosine kinase (TK) inhibitor tyrphostin-23 (10^-5 M) or the mitogen-activated protein kinase (MAPK) antagonists PD-98059 and U0216 (10^-4 M). ADM (10^-8 M) stimulated TK and p42/p44 MAPK activity in dispersed ZG, but not ZF, cells, and the effect was reversed by either 10^-6 M CGRP-(8–37) and ADM-(22–52) or preincubation with 10^-5 M tyrphostin-23. Collectively, our findings indicate that 1) ADM stimulates cell proliferation in the rat ZG, through CGRP-(8–37)- and ADM-(22–52)-sensitive receptors, probably of the CGRP1 subtype; and 2) the mitogenic effect of ADM is mediated by activation of the TK-MAPK cascade, without any involvement of the adenylate cyclase/protein kinase A-, phospholipase C/protein kinase C-, and COX- or lipoxygenase-dependent signaling pathways.

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