Inhibitory effect of BIBN4096BS, CGRP(8-37), a CGRP antibody and an RNA-Spiegelmer on CGRP induced vasodilatation in the perfused and non-perfused rat middle cerebral artery.
OBJECTIVE
A new concept for the inhibition of CGRP signalling has been developed by interaction with the CGRP molecule per se by using a CGRP antibody or a CGRP binding RNA-Spiegelmer (NOX-C89). We have compared these CGRP scavengers with two known receptor antagonists (CGRP8-37 and BIBN4096BS) on CGRP-induced relaxations in the rat middle cerebral artery (MCA). Furthermore, the role of the endothelial barrier has been studied.


METHODS
We used the luminally perfused MCA in an arteriograph, pressurized to 85 mm Hg and myograph studies of isolated ring segments of the MCA.


RESULTS
In myograph studies and in the perfusion system during abluminal application, alphaCGRP and betaCGRP induced concentration-dependent dilatation of the MCA. Given luminally neither peptide was significantly vasodilator. Adrenomedullin and amylin induced weak dilatations. In myograph experiments, relaxation induced by alphaCGRP was prevented by the four CGRP blockers (CGRP8-37, BIBN4096BS, the CGRP antibody and NOX-C89.). In abluminal perfusion experiments, the relaxant response to alphaCGRP was prevented by these agents to a varying degree. Dilatation induced by abluminal application of alphaCGRP was inhibited by luminal CGRP8-37 but not by luminal BIBN4096BS, CGRP antibody or NOX-C89.


CONCLUSIONS
alpha or betaCGRP acted on smooth muscle cell CGRP receptors in rat MCA and were effectively prevented from reaching these receptors by the endothelial barrier. The CGRP blockers significantly inhibited alphaCGRP induced relaxation but were also prevented from reaching the CGRP receptors by the arterial endothelium.
Edvinsson
L
L
Department of Medicine, Institute of Clinical Sciences, University Hospital, Lund, Sweden. lars.edvinsson@med.lu.se
Nilsson
E
E
Jansen-Olesen
I
I
D053607:Adrenomedullin / Q000494:pharmacology; D000682:Amyloid / Q000494:pharmacology; D000818:Animals; D000906:Antibodies / Q000378:metabolism / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism; D066298:In Vitro Techniques; D058228:Islet Amyloid Polypeptide; D008297:Male; D020768:Middle Cerebral Artery / Q000187:drug effects* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009213:Myography; D009841:Oligonucleotides / Q000378:metabolism / Q000494:pharmacology*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D010477:Perfusion; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology*; D011799:Quinazolines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000378:metabolism / Q000494:pharmacology*
D000682:Amyloid; D000906:Antibodies; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D058228:Islet Amyloid Polypeptide; D009841:Oligonucleotides; D010446:Peptide Fragments; D010879:Piperazines; D011799:Quinazolines; D018015:Receptors, Calcitonin Gene-Related Peptide; D014665:Vasodilator Agents; C058636:calcitonin gene-related peptide (8-37); D053607:Adrenomedullin; D015740:Calcitonin Gene-Related Peptide; C406305:olcegepant