Mazzocchi G, Albertin G, Andreis P G, Neri G, Malendowicz L K, Champion H C, Bahçelioglu M, Kadowitz P J, Nussdorfer G G
Department of Human Anatomy and Physiology, University of Padua, Italy.
Peptides. 1999 Dec;20(12):1479-87. doi: 10.1016/s0196-9781(99)00159-x.
Adrenomedullin (ADM) is a hypotensive peptide, highly expressed in the mammalian adrenal medulla, which belongs to a peptide superfamily including calcitonin gene-related peptide (CGRP) and amylin. Quantitative autoradiography demonstrated the presence of abundant [125I]ADM binding sites in both zona glomerulosa (ZG) and adrenal medulla. ADM binding was selectively displaced by ADM(22-52), a putative ADM-receptor antagonist, and CGRP(8-37), a ligand that preferentially antagonizes the CGRP1-receptor subtype. ADM concentration-dependently inhibited K+-induced aldosterone secretion of dispersed rat ZG cells, without affecting basal hormone production. Both ADM(22-52) and CGRP(8-37) reversed the ADM effect in a concentration-dependent manner. ADM counteracted the aldosterone secretagogue action of the voltage-gated Ca2+-channel activator BAYK-8644, and blocked K+- and BAYK-8644-evoked rise in the intracellular Ca2+ concentration of dispersed ZG cells. ADM concentration-dependently raised basal catecholamine (epinephrine and norepinephrine) release by rat adrenomedullary fragments, and again the response was blocked by both ADM(22-52) and CGRP(8-37). ADM increased cyclic-AMP release by adrenal-medulla fragments, but not capsule-ZG preparations, and the catecholamine response to ADM was abolished by the PKA inhibitor H-89. Collectively, the present findings allow us to draw the following conclusions: (1) ADM modulates rat adrenal secretion, acting through ADM(22-52)-sensitive CGRP1 receptors, which are coupled with different signaling mechanisms in the cortex and medulla; (2) ADM selectively inhibits agonist-stimulated aldosterone secretion, through a mechanism probably involving the blockade of the Ca2+ channel-mediated Ca2+ influx; (3) ADM raises catecholamine secretion, through the activation of the adenylate cyclase/PKA signaling pathway.
肾上腺髓质素（ADM）是一种降压肽，在哺乳动物肾上腺髓质中高度表达，它属于一个肽超家族，包括降钙素基因相关肽（CGRP）和胰淀素。定量放射自显影显示，在肾小球带（ZG）和肾上腺髓质中均存在丰富的[125I]ADM结合位点。ADM结合被ADM（22 - 52）（一种假定的ADM受体拮抗剂）和CGRP（8 - 37）（一种优先拮抗CGRP1受体亚型的配体）选择性取代。ADM浓度依赖性地抑制分散的大鼠ZG细胞中钾离子诱导的醛固酮分泌，而不影响基础激素产生。ADM（22 - 52）和CGRP（8 - 37）均以浓度依赖性方式逆转ADM的作用。ADM抵消了电压门控钙通道激活剂BAYK - 8644的醛固酮促分泌作用，并阻断了钾离子和BAYK - 8644引起的分散ZG细胞内钙浓度升高。ADM浓度依赖性地增加大鼠肾上腺髓质碎片的基础儿茶酚胺（肾上腺素和去甲肾上腺素）释放，并且该反应再次被ADM（22 - 52）和CGRP（8 - 37）阻断。ADM增加肾上腺髓质碎片的环磷酸腺苷释放，但不增加被膜 - ZG制剂的环磷酸腺苷释放，并且PKA抑制剂H - 89消除了对ADM的儿茶酚胺反应。总的来说，目前的研究结果使我们能够得出以下结论：（1）ADM通过对ADM（22 - 52）敏感的CGRP1受体调节大鼠肾上腺分泌，这些受体在皮质和髓质中与不同的信号传导机制偶联；（2）ADM通过可能涉及阻断钙通道介导的钙内流的机制选择性抑制激动剂刺激的醛固酮分泌；（3）ADM通过激活腺苷酸环化酶/PKA信号通路增加儿茶酚胺分泌。
