Structure-activity study of chicken calcitonin gene-related peptide (CGRP) on vasorelaxation in rat mesenteric resistance vessels.
Structure-activity relationship of the chicken calcitonin gene-related peptide (cCGRP) was investigated and compared with human-alpha-CGRP (hCGRP) and rat CGRP (rCGRP) in the perfused mesenteric vascular beds of rats. In precontracted mesenteric vascular beds, cCGRP, hCGRP and rCGRP produced a concentration-dependent vasodilation. The vasodilator activities of cCGRP and rCGRP were equipotent and more potent than that of hCGRP. (Ala2,7)cCGRP and (Des-1-Ala)-alpha-deamino cCGRP were 100- and 10-fold less potent than cCGRP, respectively. However, cCGRP[1-36] reduced vasodilator activity. The cCGRP[8-37] produced a vasoconstriction. Both cCGRP[8-37] and hCGRP[8-37] caused parallel shifts of the concentration-response curves of rCGRP to the right, but both peptides did not affect the maximum response and vasodilator responses to isoproterenol, these peptides being equipotent antagonists (pA2 values: 7.6 and 7.4). In rat brain membrane preparations, cCGRP and its fragments and analogues, except for cCGRP[1-36], competed for specific binding sites with [125I]-hCGRP. These results suggest that cCGRP has a potent vasodilator activity for which the disulfide bridge at position 2 and 7 of cCGRP is an important site and that position 37 is necessary for the binding of the peptide to the receptor. Also, cCGRP[8-37] is a competitive CGRP-receptor antagonist.
Department of Pharmacology, Miyazaki Medical College, Japan.
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Nuki
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Kawasaki
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Takasaki
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Wada
D000595:Amino Acid Sequence; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D002645:Chickens; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008969:Molecular Sequence Data; D051381:Rats; D013152:Splanchnic Circulation / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects*
D015740:Calcitonin Gene-Related Peptide; D007545:Isoproterenol