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Endothelins Stimulate Deoxyribonucleic Acid Synthesis and Cell Proliferation in Rat Adrenal Zona Glomerulosa, Acting through an Endothelin A Receptor Coupled with Protein Kinase C- and Tyrosine Kinase-Dependent Signaling Pathways

Departments of Anatomy (G.M., P.R., G.G.N.) and Clinical and Experimental Medicine (G.P.R.), University of Padua, I-35121 Padua, Italy; and the Department of Histology, Poznan School of Medicine (L.K.M., A.M.), PL-60781 Poznan, Poland

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

The effects of endothelins (ET) on the proliferative activity of the rat adrenal cortex have been investigated in vivo, using an in situ perfusion technique of the intact left gland. The chemicals were dissolved in the perfusion medium, and the perfusion continued for 120 min. ET-1 concentration dependently increased the mitotic index and [³H]thymidine incorporation into DNA in the zona glomerulosa (ZG; 6- and 3-fold increases, respectively, at a 10^-8 M concentration), but not in the inner adrenocortical layers, where the basal proliferative activity was negligible. The effect of 10^-8 M ET-1 was blocked by the ETA receptor antagonist BQ-123, whereas the ETB receptor antagonist BQ-788 was ineffective. ET-2 and ET-3 (10^-8 M) enhanced DNA synthesis in the ZG, but their effects were less intense than that of 10^-8 M ET-1 and were directly related to their binding potency for the ETA receptor subtype (ET-1 > ET-2 >> ET-3). The selective ETB receptor agonists BQ-3020, IRL-1620, and sarafotoxin-6B were ineffective. The ZG proliferogenic action of 10^-8 M ET-1 was reversed by both the protein kinase C inhibitor Ro31–8220 and the tyrosine kinase inhibitor tyrphostin-23; a complete blockade was obtained at a 10^-6-M concentration of each inhibitor. In contrast, neither the protein kinase A inhibitor H-89 (10^-5 M) nor the cyclooxygenase and lipoxygenase inhibitors indomethacin and phenidone (10^-5 M) affected ET-1 action. Collectively, our findings indicate that ETs stimulate the proliferation of rat adrenal ZG cells, acting through ETA receptors coupled with protein kinase C- and tyrosine kinase-dependent signaling pathways. The results of the present study are in keeping with the view that in mammals, ZG is the proliferative layer involved in the maintenance of growth of the entire adrenal cortex and with the previous autoradiographic demonstration that ZG is the only adrenocortical layer provided with ETA receptors.

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