Tissue hypoxygenation activates the adrenomedullin system in vivo

Abstract

Our study aimed to investigate the influence of tissue hypo-oxygenation on the adrenomedullin (ADM) system in vivo. For this purpose, male Sprague-Dawley rats were exposed to normobaric hypoxia (8% oxygen) or to functional anemia [0.1% carbon monoxide (CO)] or to cobalt chloride (60 mg/kg) for 6 h. Messenger RNA levels for ADM and its receptor (ADM-R) were assessed in diverse organs by RNase protection assay. Additionally, ADM protein concentrations in these organs, as in plasma, were determined by a RIA. We found that ADM mRNA abundance increased in response to hypoxia and to CO inhalation up to 15-fold in all organs examined. Similarly, ADM-R mRNA abundance increased during hypoxia and CO inhalation in all organs examined with exception of the liver. The effects of hypoxia and of CO inhalation on ADM and ADM-R mRNAs were mimicked by injection of cobaltous chloride. Hypoxia also significantly increased ADM protein content in all organs, and plasma levels of ADM rose twofold in response to hypoxia and CO inhalation. These findings indicate that tissue hypoxia leads to a widespread activation of the ADM system, which comprises a parallel stimulation of ADM and ADM receptor mRNA as enhanced ADM protein synthesis and secretion. The ADM system may, therefore, play a significant role in the physiological response to tissue hypoxia. It appears that ADM and ADM-R belong to the family of classic oxygen-regulated genes, which are activated by a decrease of the pericellular oxygen tension through the same intracellular signaling cascade.

Adrenomedullin inhibits hypoxic cell death by upregulation of Bcl-2 in endometrial cancer cells: a possible promotion mechanism for tumour growth

“…In addition, ADM upregulation was mimicked by CoCl 2 which is known to change the redox state of the central iron atom of heme proteins similarly to the e ect of hypoxia (Gleadle et al, 1995). These results con®rm the observations in several animal and cell systems that ADM seems to be a ubiquitously hypoxiaregulated gene (Garayoa et al, 2000;Hofbauer et al, 2000).…”

Responses to human CGRP, ADM, and PAMP in human thymic arteries

“…1). PAMP (12)(13)(14)(15)(16)(17)(18)(19)(20) was a partial agonist, and the maximal response to PAMP (12)(13)(14)(15)(16)(17)(18)(19)(20) was significantly smaller than the maximal vasodilator response observed with CGRP, ADM, or PAMP ( Fig. 1).…”

“…In terms of relative potency, CGRP and ADM were similar with an approximate ED 50 of 10 Ϫ8 M and were 10-fold more potent than PAMP. The truncated PAMP analog PAMP (12)(13)(14)(15)(16)(17)(18)(19)(20) was a partial agonist that elicited ϳ50% of the maximal vasodilator response to the full-sequence peptide, suggesting that activity was retained when the first 11 amino acids were deleted, but that these residues may be necessary for the full expression of vasodilator activity. Although PAMP (12-20) is a partial agonist in human thymic arteries, this truncated peptide does not inhibit Ca 2ϩ -dependent agoniststimulated aldosterone secretion (2).…”

“…Human PAMP, PAMP (12)(13)(14)(15)(16)(17)(18)(19)(20), human synthetic ADM, CGRP(8-37) (Peptide Research Labs, Tulane Medical School), and human CGRP (Peptides International) were dissolved in 0.9% NaCl. Acetylcholine bromide, sodium nitroprusside, and ET-1 (Sigma) were dissolved in 0.9% NaCl.…”

Adrenomedullin Can Protect Against Pulmonary Vascular Remodeling Induced by Hypoxia

“…11 In addition, AM and its receptor expression were enhanced in the lung of chronic hypoxic animal models. 12 Also, in the clinical setting, plasma AM concentration was increased in patients with pulmonary hypertension associated with mitral stenosis. 13 AM could have a potential organ-protective action, probably by reducing oxidative stress.…”