Immunohistochemical detection of the calcitonin receptor-like receptor protein in the microvasculature of rat endothelium

Hagner, Stephanie A; Haberberger, Rainer Viktor; Hay, Debbie L.; Facer, P.; Reiners, Katja; Voigt, Karlheinz; McGregor, G.P.

doi:10.1016/j.ejphar.2003.09.030

Cited by 16 publications

(17 citation statements)

References 16 publications

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“…Northern-blot analysis revealed previously that RAMP2, which confers AM selectivity to the receptor, is highly expressed in rat lung tissues compared with RAMP1 and RAMP3 [20]. Using selective CRLR antibodies and immunohistochemistry, Hagner et al [21,22] demonstrated intense staining in the alveolar capillaries of both humans and rats. These previous findings, together with the present study, suggest that lung AM clearance is mediated by specific AM receptors, possibly at the level of the pulmonary vascular endothelium.…”

Section: Discussionmentioning

confidence: 95%

Biodistribution, plasma kinetics and quantification of single-pass pulmonary clearance of adrenomedullin

2005

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The biodistribution, pharmacokinetics and multi-organ clearance of the vasodilator peptide AM (adrenomedullin) were evaluated in rats and its single-pass pulmonary clearance was measured in dogs by the indicator-dilution technique. Intravenously administered 125I-rAM(1-50) [rat AM(1-50)] was rapidly cleared following a two-compartment model with a very rapid distribution half-life of 2.0 min [95% CI (confidence interval), 1.98-2.01] and an elimination half-life of 15.9 min (95% CI, 15.0-16.9). The lungs retained most of the injected activity with evidence of single-pass clearance, since retention was lower after intra-arterial (13.5+/-0.6%) compared with intravenous (30.4+/-1.5%; P < 0.001) injection. Lung tissue levels of total endogenous AM were 20-fold higher than in other organs with no difference in plasma levels across the pulmonary circulation. In dogs, there was 36.4+/-2.1% first-pass unidirectional extraction of 125I-rAM(1-50) by the lungs that was reduced to 21.9+/-2.4% after the administration of unlabelled rAM(1-50) (P < 0.01). Extraction was not affected by calcitonin-gene-related peptide administration (40.6+/-2.9%), but was slightly reduced by the C-terminal fragment of human AM(22-52) (31.4+/-3.3%; P < 0.01). These data demonstrate that the lungs are a primary site for AM clearance in vivo with approx. 36% first-pass extraction through specific receptors. This suggests that the lungs not only modulate circulating levels of this peptide, but also represent its primary target.

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Section: Discussionmentioning

confidence: 95%

Biodistribution, plasma kinetics and quantification of single-pass pulmonary clearance of adrenomedullin

2005

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“…A study evaluating the distribution of the calcitonin receptorlike receptor, the other heterodimeric component of the specific AM receptor (CRLR/RAMP2), demonstrated intense staining in the lung capillaries (30). Another study demonstrated colocalization of the endothelial cell marker and the calcitonin receptorlike receptor in pulmonary capillaries and lung endothelial cell expression of the calcitonin receptorlike receptor and RAMP2 (31).…”

Section: Discussionmentioning

confidence: 99%

PulmoBind, an Adrenomedullin-Based Molecular Lung Imaging Tool

et al. 2013

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Previous studies showed that adrenomedullin (AM) could be a promising agent for molecular imaging of the pulmonary circulation, with abundant specific binding sites at the pulmonary vascular endothelium. The purpose of this work was to design an AM-based compound that encompasses the desired imaging properties without posing safety issues for clinical applications. Methods: AM analogs were synthesized through solid-phase peptide synthesis. They were evaluated for 99m Tc labeling efficiency and in vivo lung uptake. Biodistribution and hemodynamic characteristics of the lead compound were determined in anesthetized dogs as well as by a dosimetric analysis. Lung perfusion was evaluated in the monocrotaline model of pulmonary arterial hypertension in rats. Results: A cyclic AM (residues 22-52) analog encompassing a polyethylene glycol spacer and a tetrapeptide chelating moiety was found to possess the desired characteristics, with 90.7% 6 0.3% (mean 6 SD) labeling efficiency, 40% lung uptake at 10 min after injection, and a favorable safety profile. Lung uptake of the 99m Tc-labeled compound was markedly reduced in rats with pulmonary arterial hypertension. Conclusion: This lead compound could be a suitable clinical imaging agent for the molecular diagnosis of disorders of the pulmonary circulation.

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“…The AM receptor is a heterodimer composed of the calcitonin receptor-like receptor and receptor activity-modifying protein 2, both of which are highly expressed in the lungs (1,5). The AM receptor is abundantly expressed in human alveolar capillaries and in rat pulmonary microvascular endothelial cells (10,11). Thus, human and rat lungs contain specific AM-binding sites (12,13) at a density higher than that in any other organ studied (13).…”

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confidence: 99%

Use of Adrenomedullin Derivatives for Molecular Imaging of Pulmonary Circulation

Harel

Fu²,

Nguyen³

et al. 2008

J Nucl Med

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Currently, there is no low-molecular-weight agent for imaging of the pulmonary circulation. Adrenomedullin (AM) is a peptide predominantly cleared by the pulmonary circulation through specific endothelial receptors. We developed human AM derivatives radiolabeled with 99m Tc and evaluated their biodistribution, plasma kinetics, and utility as pulmonary vascular imaging agents. Methods: Two derivatives radiolabeled with 99m Tc were evaluated: the natural cyclic form of the peptide, to which the chelator diethylenetriaminepentaacetic acid was added (C-DTPA-AM), and the linear form, which allows direct labeling (L-AM). The compounds were injected into dogs, and the activities of the tracers in blood and in organs were determined with a nuclear medicine camera. Single-pass pulmonary clearance was measured by the indicator dilution technique. The capacity to image perfusion defects was evaluated after surgical pulmonary artery ligation. Results: Both derivatives were rapidly cleared from plasma, with elimination half-lives of 42 and 32 min for C-DTPA-AM and L-AM, respectively. The lungs retained most of the activity after 30 min; this activity was higher (P 5 0.02) for L-AM (42% 6 5% [mean 6 SEM]) than for C-DTPA-AM (27% 6 1%). Lung activity slowly declined over time but was maintained after 2 h at approximately 20% for both tracers. The single-pass pulmonary clearance of plasma L-AM was 414 6 85 mL/min. There was a higher level of urinary excretion of L-AM than of C-DTPA-AM. After pulmonary artery ligation, perfusion defects were easily detectable by external imaging. Conclusion: AM derivatives are promising compounds for molecular imaging of the pulmonary circulation. L-AM displayed higher levels of initial lung retention and of kidney excretion.

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Immunohistochemical detection of the calcitonin receptor-like receptor protein in the microvasculature of rat endothelium

Cited by 16 publications

References 16 publications

Biodistribution, plasma kinetics and quantification of single-pass pulmonary clearance of adrenomedullin

Biodistribution, plasma kinetics and quantification of single-pass pulmonary clearance of adrenomedullin

PulmoBind, an Adrenomedullin-Based Molecular Lung Imaging Tool

Use of Adrenomedullin Derivatives for Molecular Imaging of Pulmonary Circulation

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