Interaction of human adrenomedullin 13-52 with calcitonin gene-related peptide receptors in the microvasculature of the rat and hamster.
1. Adrenomedullin (ADM), a recently discovered circulating hypotensive peptide, shares limited sequence homology with the sensory nerve-derived vasodilator, calcitonin gene-related peptide (CGRP). This study compared the vasodilator effect of sequence 13-52 of human adrenomedullin (ADM13-52) with that of human alpha CGRP (CGRP), in the microvasculature of the hamster cheek pouch and rat skin in vivo. 2. Single arterioles (20-40 microns diameter) in the hamster cheek pouch were visualised by intravital microscopy and video recording, and measured by image analysis. Both ADM13-52 (1 pmol-0.4 nmol) and CGRP (0.1 pmol-1 nmol) evoked dose-related increases in the diameter of preconstricted arterioles (n = 6). ADM13-52 (ED50 14 pmol) was 20 fold less active than CGRP (ED50 0.71 pmol). The kinetics of onset and decline of vasodilator responses to both peptides were similar, with vasodilator responses to both peptides reaching a maximum at ca. 2 min, and reversing after 10-15 min (n = 5-7). The submaximal increase in blood flow evoked by ADM13-52 was significantly inhibited (P < 0.05; n = 6) by the CGRP1 receptor antagonist, CGRP8-37, at a dose (300 nmol kg-1, i.v.) that we have previously shown to inhibit significantly equivalent vasodilator responses to CGRP in this preparation. 3. In experiments measuring changes in local blood flow in rat skin by a 133xenon clearance technique, intradermal injection of both ADM13-52 (3-300 pmol) and CGRP (0.1-30 pmol) evoked dose-related increases in local blood flow. ADM13-52 (ED50 27 pmol) was 17 fold less potent than CGRP (ED501.6 pmol) (n = 6). The submaximal increase in blood flow evoked by both peptides was significantly inhibited (P<0.02; n = 5) by CGRP837 (100 nmol kg-1, i.v.).4. We conclude that ADM13-52 is a potent vasodilator in the microvasculature of the hamster and rat invivo. It mediates its vasodilator effect by arteriolar dilatation and this effect is due, at least in part, to the stimulation of CGRPI receptors.
Hall
J M
JM
Biomedical Sciences Division, King's College London, U.K.
Siney
L
L
Lippton
H
H
Hyman
A
A
Kang-Chang
J
J
Brain
S D
SD
D053607:Adrenomedullin; D000595:Amino Acid Sequence; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D015740:Calcitonin Gene-Related Peptide / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D002610:Cheek; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008647:Mesocricetus; D008833:Microcirculation / Q000187:drug effects; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000187:drug effects* / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D017386:Sequence Homology, Amino Acid; D012867:Skin / Q000098:blood supply / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D000959:Antihypertensive Agents; D010446:Peptide Fragments; D010455:Peptides; D018015:Receptors, Calcitonin Gene-Related Peptide; D053607:Adrenomedullin; D015740:Calcitonin Gene-Related Peptide