Adrenomedullin(16–31) Has Pressor Activity in the Rat But Not the Cat

Champion, Hunter C.; Friedman, D.E; Lambert, David G.; Murphy, William A.; Coy, David H.; Kadowitz, Philip J.

doi:10.1016/s0196-9781(96)00251-3

Cited by 16 publications

(10 citation statements)

References 12 publications

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“…The AM receptor antagonist AM 22-52 did not completely block this response, even at 10 K6 M concentration. This antagonist has been shown previously to be inefficient at blocking the AM receptor, therefore, the result observed in our study is not surprising (Champion et al 1997, Nishikimi et al 1998. It is clear that HMECs express at least one fully functional AM receptor sub-type, which when activated leads to an increased level of cAMP.…”

Section: Am (10supporting

confidence: 70%

Adrenomedullin increases the expression of calcitonin-like receptor and receptor activity modifying protein 2 mRNA in human microvascular endothelial cells

Schwarz¹,

Renshaw²,

Kapas³

et al. 2006

Journal of Endocrinology

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Adrenomedullin (AM) is a multifunctional peptide hormone, which plays a significant role in vasodilation and angiogenesis, implicating it in hypertension as well as in carcinogenesis. AM exerts its effects via the calcitonin receptor-like receptor (CRLR, now known as CL) complexed with either receptor activity modifying protein (RAMP) 2 or 3. We have investigated the effect of AM on immortalized human microvascular endothelial cells 1, since endothelial cells are a major source as well as a target of AM actions in vivo. Cells treated with AM showed elevated cAMP in a time (5-45 min)-dependent and dose (10 K6 -10 K14 M)-dependent manner. Pre-treatment with the AM receptor antagonist AM 22-52 partially suppressed the AM-induced increase in cAMP levels. An increase in extracellular signal-regulated kinase 1/2 phosphorylation was observed after 5 min of treatment with 10 K8 M AM. This phosphorylation was specific, since we were able to block the AM-induced effect with 1 mM U0126, a specific mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor. Using realtime PCR, we were able to show for the first time that AM upregulates peptide and mRNA expression of vascular endothelial growth factor (VEGF). However, AM treatment of cells did not result in increased cell proliferation. Instead, we observed that AM and VEGF induced cell migration, which could be inhibited by the AM 22-52 and anti-VEGF antibody respectively. AM also significantly elevated mRNA levels of CL (after 2 and 24 h treatment) and RAMP2 (after 1 and 24 h treatment). The upregulation of the AM receptor at two time points reflects possibly different cellular responses to short-and long-term exposure to AM.

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Section: Am (10supporting

confidence: 70%

Adrenomedullin increases the expression of calcitonin-like receptor and receptor activity modifying protein 2 mRNA in human microvascular endothelial cells

Schwarz¹,

Renshaw²,

Kapas³

et al. 2006

Journal of Endocrinology

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“…(1997a) found that, in the perfused hindlimb vascular bed of the cat, ADM (22–52) did not influence vasodilator responses to ADM, but inhibited the responses to the structurally similar peptide, calcitonin gene‐related peptide (CGRP). However, there is evidence to suggest that the mechanisms underlying the cardiovascular effects of ADM fragments may differ between rats and cats ( Nossaman et al ., 1996 ; Champion et al ., 1997a , 1997b ) and, in a more recent study ( Dogan et al ., 1997 ), it was shown that co‐infusion of ADM (22–52) with ADM inhibited the regional cerebral vasodilator effects of ADM in rats. Therefore, our first objective was to determine an effective antagonistic dose of ADM (22–52) against the regional systemic vasodilator effects of exogenous ADM in vivo ( Gardiner et al ., 1995a ), before assessing the influence of that dose of ADM (22–52) on the vasodilator responses to LPS infusion under different conditions.…”

Section: Introductionmentioning

confidence: 99%

Influence of CGRP (8–37), but not adrenomedullin (22–52), on the haemodynamic responses to lipopolysaccharide in conscious rats

Gardiner

March

Kemp

et al. 1999

British J Pharmacology

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1 The functional involvement of the vasodilator peptides, adrenomedullin (ADM) and calcitonin gene-related peptide (CGRP), in the haemodynamic sequelae of continuous infusion of lipopolysaccharide (LPS) was assessed in conscious, male, Long Evans rats, by the use of peptide antagonists. 2 It was demonstrated that ADM (22-52) at a dose of 500 nmol kg 71 h 71 caused signi®cant inhibition of the eects of ADM (1 nmol kg 71 ), without aecting responses to CGRP (0.1 or 1 nmol kg 71 ). 3 Even when the regional vasodilator responses to LPS infusion were enhanced (by pre-treatment with dexamethasone and the endothelin antagonist, SB 209670, or by pretreatment with SB 209670 and the AT 1 -receptor antagonist, losartan), ADM (22-52) had no signi®cant cardiovascular eects. In contrast, the CGRP 1 -receptor antagonist, CGRP (8-37), caused small, but signi®cant, inhibitions of the hypotensive and renal and mesenteric vasodilator eects of LPS, but only 6 h after onset of infusion in the presence of dexamethasone and SB 209670. 4 The results indicate that, in this model of endotoxaemia, the marked regional vasodilatations seen in the presence of dexamethasone and SB 209670 do not involve ADM, but do involve CGRP, albeit only to a small extent.

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“…Interestingly, C-terminally shortened fragments, which contained the bioactive ring structure, like ADM 1-25 , ADM [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] , ADM [15][16][17][18][19][20][21][22] , ADM [16][17][18][19][20][21] and ADM [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] , were shown to possess vasopressor activity. This adverse effect to full-length ADM 1-52 is not mediated by the interaction with CLR/RAMP complexes but probably involves the release of catecholamines and the activation of α-adrenergic receptors [102][103]…”

Section: Additional Targets For Adrenomedullinmentioning

confidence: 99%

Adrenomedullin – new perspectives of a potent peptide hormone

Schönauer

Els‐Heindl

Beck‐Sickinger

2017

Journal of Peptide Science

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Adrenomedullin (ADM) is a 52-amino acid multifunctional peptide, which belongs to the calcitonin gene-related peptide (CGRP) superfamily of vasoactive peptide hormones. ADM exhibits a significant vasodilatory potential and plays a key role in various regulatory mechanisms, predominantly in the cardiovascular and lymphatic system. It exerts its effects by activation of the calcitonin receptor-like receptor associated with one of the receptor activity-modifying proteins 2 or 3. ADM was first isolated from human phaeochromocytoma in 1993. Numerous studies revealed a widespread distribution in various tissues and organs, which is reflected by its multiple physiological roles in health and disease. Because of its anti-inflammatory, anti-apoptotic and proliferative properties, ADM exhibits potent protective functions under diverse pathological conditions, but it is also critically involved in tumor progression. ADM has therefore raised great interest in therapeutic applications and several clinical trials already revealed promising results. However, because the receptor activation mode has not yet been fully elucidated, a rational design of potent and selective ligands is still challenging. Detailed information on the binding mode of ADM from a recently reported crystal structure as well as efforts to improve its plasma stability and bioavailability may help to overcome these limitations in the future. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

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Adrenomedullin(16–31) Has Pressor Activity in the Rat But Not the Cat

Cited by 16 publications

References 12 publications

Adrenomedullin increases the expression of calcitonin-like receptor and receptor activity modifying protein 2 mRNA in human microvascular endothelial cells

Adrenomedullin increases the expression of calcitonin-like receptor and receptor activity modifying protein 2 mRNA in human microvascular endothelial cells

Influence of CGRP (8–37), but not adrenomedullin (22–52), on the haemodynamic responses to lipopolysaccharide in conscious rats

Adrenomedullin – new perspectives of a potent peptide hormone

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