Plasma Adrenomedullin Concentrations in Patients with Adrenal Pheochromocytoma

Background: The hypotensive peptide adrenomedullin was first isolated in extracts of human pheochromocytoma. There is, however, no information available on the behaviour of circulating adrenomedullin or on the correlation with catecholamines in patients with pheochromocytoma. Objectives: 1) to investigate whether plasma adrenomedullin levels were changed in 10 patients with pheochromocytoma when compared to 21 healthy subjects and 16 patients with essential hypertension; 2) to determine whether or not adrenomedullin has a counter-regulatory role in catecholamine excess in pheochromocytoma or is responsible for hemodynamic modifications before and after tumour resection; 3) to determine tissue distribution of ir-adrenomedullin in the pheochromocytoma. Methods: Plasma adrenomedullin and catecholamine levels were measured in all patients with pheochromocytoma before and four weeks after tumour removal. In the four patients undergoing resection of tumours, plasma levels of adrenomedullin were measured at different time-points during surgery. Results: The mean plasma adrenomedullin concentrations (± SD) in patients with pheochromocytoma (37.9 ± 6 pg/ml) were significantly higher (p < 0.0001) than those in normal subjects (13.7 ± 6.1 pg/ml) and patients with essential hypertension (22.5 ± 9.1pg/ml). Adrenomedullin levels correlated with plasma noradrenaline (r = 0.516, p = 0.0124). In all patients with pheochromocytoma, plasma adrenomedullin concentrations decreased after removal of tumours (from 37.9 ± 6 to 10.9 ± 4.6 pg/ml; p < 0.0001). In the four patients studied during surgery, baseline plasma adrenomedullin and noradrenaline levels were markedly elevated, and increased significantly with tumour manipulation, decreasing 24 hours after operation. Adrenal medulla cells surrounding the pheochromocytoma site stained for ir-adrenomedullin, whereas only isolated cells of pheochromocytoma stained for the peptide. Conclusions: This study demonstrates that circulating adrenomedullin is increased in pheochromocytoma, and is also correlated with plasma noradrenaline levels. Adrenomedullin may represent an additional biochemical parameter for clinical monitoring of patients with pheochromocytoma.

Key words:

Adrenal gland - Adrenomedullin - Catecholamine - Hypertension - Pheochromocytoma

References

• 1 Crout J R, Sjoersma A. Turnover and metabolism of catecholamines in patients with pheochromocytoma.  J Clin Invest. 1964;  43 94-102
• 2 Sano T, Saito H, Inaba F L, Hizawa K, Saito S, Yamanoi A, Mizunuma Y, Matsumura M, Juasa M, Hiraishi K. Immunoreactive somatostatin and vasoactive intestinal polipeptide in adrenal pheochromocytoma: An immunochemical and ultrastructural study.  Cancer. 1983;  52 282-289
• 3 Baldi E, De Feo M L, Geppetti P, Carla V, Maggi M, Pupilli C, Spillantini M G, Brocchi A, Mannelli M. Measurement of catecholamines, met-enkephaline, somatostatin and substance P-like immunoreactivities in 12 human pheochromocytomas.  J Endocrinol Invest. 1988;  11 133-138
• 4 Januszewicz W, Wocial B, Ignatowsa-Switalska H, Dutkiewicz-Raczkowska M, Feltynowski T, Januszewicz A, Tapinski M, Zukowska-Grojec Z, Szostek M. Alterations in plasma neuropeptide Y immunoreactivity and catecholamine levels during surgical removal of pheochromocytoma.  J Hypertens. 1998;  16 543-547
• 5 Herrera M F, Stone E, Deitel M, Asa S L. Pheochromocytoma producing multiple vasoactive peptides.  Arch Surg. 1992;  127 105-108
• 6 Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, Eto T. Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma.  Biochem Biophys Res Commun. 1993;  192 553-560
• 7 Ichiki Y, Kitamura K, Kangawa K Kawamoto M, Matsuo  H, Eto T. Distribution and characterization of immunoreactive adrenomedullin in human tissue and plasma.  Febs Lett. 1994;  338 6-10
• 8 Sato K, Hirata Y, Irai T, Iwashina M, Marumo F. Characterization of immunoreactive adrenomedullin in human plasma and urine.  Life Sci. 1995;  57 189-194
• 9 Di lorio R, Marinoni E, Scavo D, Letizia C, Cosmi E V. Adrenomedullin in pregnancy (letter).  Lancet. 1997;  349 328
• 10 Ishiyama Y, Kitamura K, Ichiki Y, Nakamura S, Kida O, Kangawa K, Eto T. Haemodynamic effects of a novel hypotensive peptide, human adrenomedullin in rats.  Eur J Pharmacol. 1993;  241 271-273
• 11 Hishimitsu T, Nishikimi T, Saito Y, Kitamura K, Eto T, Kangawa K, Matsuo H, Omae T, Matshoka K. Plasma level of adrenomedullin, a newly identified hypotensive peptide in patients with hypertension and renal failure.  J Clin Invest. 1994;  94 2158-2161
• 12 Kohno N, Hanemira T, Kano H, Horio T, Yokokawa K, Ikeda M, Minami M, Yasumari K, Yoshikawa J. Plasma adrenomedullin correlations in essential hypertension.  Hypertension. 1996;  27 102-107
• 13 Letizia C, De Toma G, Cerci S, Massa R, Coassin S, Subioli S, Scuro L, De Ciocchis A. Adrenomedullin levels are high in primary aldosteronism due to adenoma and declive after surgical cure.  Blood Press. 1998;  7 19-23
• 14 Di lorio R, Marinoni E, Letizia C, Alò P, Villaccio B, Cosmi E V. Adrenomedullin, a new vasoactive peptide in preeclampsia.  Hypertension. 1998;  32 758-763
• 15 Letizia C, Cerci S, Centanni M, De Toma G, Subioli S, Scuro L, Scavo D. Circulating levels of adrenomedullin in patients with Addison’s disease before and after corticoisteroid treatment.  Clin Endocrinol. 1998;  48 145-148
• 16 Marinoni E, Picca A, Scucchi L, Cosmi E V, Di lorio R. Immunohistochemical localization of endothelin-1 in placenta and fetal membranes in term and preterm human pregnancy.  Am J Reprod Immunol. 1995;  34 213-218
• 17 Nishikimi T, Kitamura K, Yoshihiko S, Shimada K, Ishimitsu T, Takamiya M, Kangawa K, Matsuo H, Eto T, Omae T, Mattsuoka H. Clinical studies on the sites of production and clearance of circulating adrenomedullin in human subjects.  Hypertension. 1994;  24 600-604
• 18 Katoh F, Kitamura K, Yamamoto Y, Eto T, Kangawa K, Niimura H, Wada A. Cosecretion of adrenomedullin with catecholamines from bovine adrenal medullary cells.  J Hypertens. 1994;  12 (Suppl 3) S238
• 19 Katoh F, Kitamura K, Niina H, Yamamoto R, Washimine H, Kangawa K, Yamamoto Y, Kobayashi H, Eto T, Wada A. Proadrenomedullin N-terminal 20 peptide (PAMP) and endogenous anticholinergic peptide: its exocytic secretion and inibition of catecholamine secretion in adrenal medulla.  J Neurochem. 1995;  64 459-461
• 20 Nakanishi N, Onozawa S, Matsumoto R, Hasegawa H, Yamada S. Cyclic AMP-dependent modulation of vesicular monoamine transport in pheochromocytoma cells.  J Neurochem. 1995;  64 600-607
• 21 Kapas S, Martinez A, Cutitta F, Hinson J P. Local production and action of adrenomedullin in the rat adrenal zona glomerulosa.  J Endocrinol. 1998;  156 477-484
• 22 Andreis P G, Neri G, Prayer-Galletti T, Rossi G P, Gottardo G, Malendowicz L K, Nussdorfer G G. Effects of adrenomedullin on the human adrenal glands: An in vitro study.  J Clin Endocrinol Metab. 1997;  82 1167-1170
• 23 Hinson J P, Kapas S. The role of endothelial cell products in regulation of adrenocortical function: actions of endothelin, nitric oxide, adrenomedullin and PAMP.  Horm Metab Res. 1998;  30 334-340
• 24 Champion H C, Fry R C, Murphy W A, Coy D H, Radowitz P J. Catecholamine release mediates pressor effects of adrenomedullin (15 - 22) in the rats.  Hypertension. 1996;  28 1041-1046
• 25 Satoh F, Takahashi K, Murakami O, Totsume K, Sone M, Ohneda M, Abe K, Miura Y, Hayashi Y, Sassano H, Mouri T. Adrenomedullin in human brain, adrenal glands and tumour tissues of pheochromocytoma, ganglioneuroblastoma and neuroblastoma.  J Clin Endocrinol Metab. 1995;  80 1750-1752
• 26 Liu J, Kahri A I, Heikkila P, Voutilanen R. Adrenomedullin gene expression and its different regulation in human adrenocortical and medullary tumours.  J Endocrinol. 1997;  155 483-490
• 27 Newell K A, Prinz R A, Brooks M H, Glisson S N, Barbato A L, Freeark R J. Plasma catecholamine changes during excision of pheochromocytoma.  Surgery. 1988;  104 1064-1073