The adrenomedullin receptor acts as clearance receptor in pulmonary circulation.
Adrenomedullin (AM) is a powerful pulmonary vasodilator with antimitogenic properties. We investigated the role of the AM receptor (AMR) and the calcitonin gene-related peptide type-1 receptor (CGRP1R) in regulating pulmonary vascular AM levels. The AMR antagonist hAM(22-52) (120 nmol/L) significantly elevated AM release compared with controls to 250% after 2 h in isolated rat lungs and to 830% after 4 h in pulmonary artery endothelial cells (PAEC). CGRP1R blockade had no effect. AMR blockade did not influence prepro-AM mRNA levels nor did inhibition of protein synthesis by cycloheximide (0.01 mg/mL) abolish the effect of the AMR antagonist. Radioligand-binding studies with PAEC membranes revealed a decrease by 44% of the AMR density in response to AMR antagonism. Altogether, the pulmonary vascular AMR represents not only a functionally active, but also a clearance receptor; its expression is constitutively stimulated by basal AM. This identifies a novel mechanism for controlling pulmonary AM levels.
Dschietzig
Thomas
T
Medizinische Klinik m. S. Kardiologie, Angiologie und Pulmologie, Charité (Campus Mitte), Schumannstrasse 20/21, 10117 Berlin, Germany.
Azad
Hamid Adib
HA
Asswad
Louay
L
Böhme
Claudia
C
Bartsch
Cornelia
C
Baumann
Gert
G
Stangl
Karl
K
D053607:Adrenomedullin; D000818:Animals; D001667:Binding, Competitive; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D008024:Ligands; D008168:Lung / Q000098:blood supply / Q000502:physiology*; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011651:Pulmonary Artery / Q000166:cytology / Q000502:physiology; D011652:Pulmonary Circulation / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D058265:Receptors, Adrenomedullin; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D018000:Receptors, Peptide / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D008024:Ligands; D010446:Peptide Fragments; D010455:Peptides; D011498:Protein Precursors; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D058265:Receptors, Adrenomedullin; D018015:Receptors, Calcitonin Gene-Related Peptide; D018000:Receptors, Peptide; C104782:adrenomedullin (22-52); C112034:preproadrenomedullin; C058636:calcitonin gene-related peptide (8-37); D053607:Adrenomedullin; D003513:Cycloheximide; D015740:Calcitonin Gene-Related Peptide