title: Characterisation of CGRP receptors in human and porcine isolated coronary arteries: evidence for CGRP receptor heterogeneity.
abstract: This study sets out to characterise calcitonin gene-related peptide (CGRP) receptors in human and porcine isolated proximal and distal coronary arteries using BIBN4096BS. Human (h)-alphaCGRP induced relaxations that were blocked by BIBN4096BS in all arteries studied. In contrast to the other vessels, the Schild plot slope in the human distal coronary artery segments (0.68 +/- 0.07) was significantly less than unity and BIBN4096BS potently blocked these responses (pK(b) (10 nM): 9.29 +/- 0.34, n = 5). In the same preparation, h-alphaCGRP(8-37) behaved as a weak antagonist of h-alphaCGRP-induced relaxations (pK(b) (3 microM): 6.28 +/- 0.17, n = 4), with also a Schild plot slope smaller than unity. The linear agonists, [ethylamide-Cys(2,7)]-h-alphaCGRP ([Cys(Et)(2,7)]-h-alphaCGRP) and [acetimidomethyl-Cys(2,7)]-h-alphaCGRP ([Cys(Acm)(2,7)]-h-alphaCGRP), had a high potency (pEC(50): 8.21 +/- 0.25 and 7.25 +/- 0.14, respectively), suggesting the presence of CGRP(2) receptors, while the potent blockade by BIBN4096BS (pK(b) (10 nM): 10.13 +/- 0.29 and 9.95 +/- 0.11, respectively) points to the presence of CGRP(1) receptors. Using RT-PCR, mRNAs encoding for the essential components for functional CGRP(1) receptors were demonstrated in both human proximal and distal coronary artery. Further, h-alphaCGRP (100 nM) increased cAMP levels, and this was attenuated by BIBN4096BS (1 microM). The above results demonstrate the presence of CGRP(1) receptors in all coronary artery segments investigated, but the human distal coronary artery segments seem to have an additional population of CGRP receptors not complying with the currently classified CGRP(1) or CGRP(2) receptors.
authors.affiliation: Department of Pharmacology, University Medical Center Rotterdam, The Netherlands.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Gupta
authors.forename: Suneet
authors.initials: S
authors.lastname: Mehrotra
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Villalón
authors.forename: Ingrid M
authors.initials: IM
authors.lastname: Garrelds
authors.forename: René
authors.initials: R
authors.lastname: de Vries
authors.forename: Jorge P
authors.initials: JP
authors.lastname: van Kats
authors.forename: Hari S
authors.initials: HS
authors.lastname: Sharma
authors.forename: Pramod R
authors.initials: PR
authors.lastname: Saxena
authors.forename: Antoinette
authors.initials: A
authors.lastname: Maassenvandenbrink
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000031:analogs & derivatives / Q000494:pharmacology; D058286:Calcitonin Receptor-Like Protein; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005576:Colforsin / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D011799:Quinazolines / Q000494:pharmacology; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin / Q000235:genetics / Q000378:metabolism; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013373:Substance P / Q000494:pharmacology; D013552:Swine; D013997:Time Factors; D050819:Transcription Factor Brn-3A / Q000235:genetics / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C545578:CALCRL protein, human; D058286:Calcitonin Receptor-Like Protein; D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C494188:POU4F1 protein, human; D010879:Piperazines; D020033:Protein Isoforms; D011799:Quinazolines; C488966:RAB11FIP1 protein, human; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin; D018015:Receptors, Calcitonin Gene-Related Peptide; D050819:Transcription Factor Brn-3A; D014662:Vasoconstrictor Agents; D005576:Colforsin; D013373:Substance P; D011189:Potassium Chloride; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000242:Cyclic AMP; D015740:Calcitonin Gene-Related Peptide; C406305:olcegepant