Characterization of CGRP(1) receptors in the guinea pig basilar artery.
The purpose of the present study was to characterise receptors mediating calcitonin gene-related peptide (CGRP)-induced relaxation of guinea pig basilar artery. This was done by investigating vasomotor responses in vitro and performing autoradiographic binding studies. We also intended to study the importance of an intact endothelium. Agonist studies showed that peptides of the CGRP family induced relaxation of the guinea pig basilar artery with the following order of potency: human beta-CGRP=human alpha-CGRP>>adrenomedullin=[acetamidomethyl-Cys(2,7)]alpha-human CGRP ([Cys(ACM)(2,7)]CGRP)=amylin. These data are in concord with those of the autoradiographic binding studies that showed displacement of [125I] human alpha-CGRP binding with the following order of potency: human alpha-CGRP=human beta-CGRP>>adrenomedullin=human alpha-CGRP-(8-37)>>Cys(ACM)(2,7)]CGRP. In blockade experiments, the relaxant responses to human alpha- and human beta-CGRP were competitively blocked by the CGRP(1) receptor antagonist human alpha-CGRP-(8-37), while those of adrenomedullin and amylin were blocked non-competitively. In order to examine whether amylin induced relaxation via amylin or CGRP receptors, we studied the antagonistic effect of amylin-(8-37) on the weak relaxant response to amylin and found that it was not blocked by amylin-(8-37). These findings, together with the finding that the CGRP(2) receptor agonist [Cys(ACM)(2,7)]CGRP only induced a weak relaxation in the highest concentrations examined, suggest that the CGRP family of peptides mediate relaxation by CGRP(1)-type receptors. Removal of the endothelium, the addition of N(G)-nitro-L-arginine methyl ester (L-NAME), methylene blue or indomethacin did not affect the concentration-response curves of the CGRP analogues, neither in the presence nor in the absence of human CGRP-(8-37). The study shows the presence of a relaxant CGRP(1) receptor on the smooth muscle cells of guinea pig basilar artery. Various endothelial factors did not influence relaxant responses.
Jansen-Olesen
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Department of Pharmacology, The Royal Danish School of Pharmacy, Universitetsparken 2, 2100 Copenhagen, Denmark. io@dfh.dk
Kaarill
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Edvinsson
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D053607:Adrenomedullin; D000682:Amyloid / Q000494:pharmacology; D000818:Animals; D000897:Anti-Ulcer Agents / Q000494:pharmacology; D001488:Basilar Artery / Q000187:drug effects* / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006168:Guinea Pigs; D006801:Humans; D058228:Islet Amyloid Polypeptide; D008297:Male; D010455:Peptides / Q000494:pharmacology; D058265:Receptors, Adrenomedullin; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000187:drug effects* / Q000502:physiology; D058287:Receptors, Islet Amyloid Polypeptide; D018000:Receptors, Peptide / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D000682:Amyloid; D000897:Anti-Ulcer Agents; D058228:Islet Amyloid Polypeptide; D010455:Peptides; D058265:Receptors, Adrenomedullin; D018015:Receptors, Calcitonin Gene-Related Peptide; D058287:Receptors, Islet Amyloid Polypeptide; D018000:Receptors, Peptide; D014665:Vasodilator Agents; D053607:Adrenomedullin; D015740:Calcitonin Gene-Related Peptide