The vasorelaxant effect of adrenomedullin, proadrenomedullin N-terminal 20 peptide and amylin in human skin.
In this study we aimed to assess in vivo, the vasodilator effects of adrenomedullin, proadrenomedullin N-terminal 20 peptide (PAMP) and amylin in human skin vasculature and compare the responses to the effects mediated by the endogenous neuropeptides calcitonin gene-related peptide (CGRP) and substance P and to examine the mRNA expression of calcitonin receptor-like receptor (CL-R) and receptor-activity modifying proteins, RAMP1, RAMP 2 and RAMP3 in human subcutaneous arteries. Changes in skin blood flow of the forearm were measured using a Laser Doppler Imager after intradermal injection of the peptides. The mRNA expression was assessed by real-time reverse transcriptase-polymerase chain reaction (real-time PCR). CGRP, adrenomedullin and amylin induced concentration-dependent, long-lasting increases in skin blood flow. The response to PAMP was shorter in duration appearing similar to the transient response induced by substance P. PAMP (10(-6)-10(-5) M) caused distinct itch sensation and local erythema. This effect could be abolished when combining the histamine H1-receptor antagonist mepyramin and PAMP. Real-time PCR data showed a higher level of mRNA for RAMP2 than CL-R, RAMP1 and RAMP3 in the tissue. Though the PCR data demonstrated the presence of mRNA for both CGRP1 and adrenomedullin receptors the rank order of potency (CGRP>adrenomedullin>amylin) for the blood flow increase indicated vasodilatation for these peptides was induced by activation of CGRP1 receptors. Intradermal injection of CGRP, adrenomedullin and amylin induces long lasting dilatation of human skin vasculature by activation of CGRP1 receptors. PAMP induces transient vasodilatation. PAMP but not CGRP, adrenomedullin and amylin causes itch sensation and local erythema. The transient effect on vasodilatation as response to PAMP is discussed.
Hasbak
Philip
P
Department of Clinical Experimental Research, University Hospital of Glostrup, Glostrup, Denmark. philip@hasbak.dk
Eskesen
Karen
K
Lind
Henrik
H
Holst
Jan
J
Edvinsson
Lars
L
D053607:Adrenomedullin; D000328:Adult; D000682:Amyloid / Q000008:administration & dosage / Q000494:pharmacology*; D015740:Calcitonin Gene-Related Peptide / Q000008:administration & dosage / Q000494:pharmacology; D058286:Calcitonin Receptor-Like Protein; D004305:Dose-Response Relationship, Drug; D005542:Forearm; D006801:Humans; D007271:Injections, Intradermal; D058228:Islet Amyloid Polypeptide; D017078:Laser-Doppler Flowmetry; D008297:Male; D010455:Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D058265:Receptors, Adrenomedullin; D018003:Receptors, Calcitonin / Q000235:genetics; D018000:Receptors, Peptide / Q000235:genetics; D012039:Regional Blood Flow / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D040521:Subcutaneous Tissue / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D013373:Substance P / Q000008:administration & dosage / Q000494:pharmacology; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects*
D000682:Amyloid; C545578:CALCRL protein, human; D058286:Calcitonin Receptor-Like Protein; D058228:Islet Amyloid Polypeptide; D010455:Peptides; D012333:RNA, Messenger; D058265:Receptors, Adrenomedullin; D018003:Receptors, Calcitonin; D018000:Receptors, Peptide; D053607:Adrenomedullin; D013373:Substance P; D015740:Calcitonin Gene-Related Peptide