Article date: April 1998
By: Majid Sheykhzade, Niels C. Berg Nyborg, in Volume 123, Issue 7, pages 1464-1470
In this study we characterized the CGRP‐receptor subtype by Schild‐plot analysis using the C‐terminal fragment, human‐αCGRP(8–37), a putative competitive CGRP1‐receptor selective antagonist. In addition, the effect of rat‐αCGRP was compared with that of homologous peptides rat‐βCGRP, rat‐amylin, rat‐adrenomedullin and [Cys(Acm)2,7]‐human‐αCGRP, a putative selective CGRP2‐receptor agonist, in the left coronary arteries of 3 months old male and female Sprague Dawley rats.
Isolated rings from the distal, intramural part of the left anterior descending (LAD) coronary artery in both groups of rats were mounted on a double wire‐myograph. The arteries were then stretched to their optimal lumen diameter for active tension development and precontracted with 10−5m prostaglandin F2α (PGF2α), after which agonists were added to the organ bath in a cumulative manner.
Rat‐αCGRP induced endothelium‐independent relaxations in male and female Sprague‐Dawley rats. Rat‐βCGRP concentration‐response relations (10−11–10−7m) were similar to those of rat‐αCGRP in either sex. The maximal relaxations induced by rat‐amylin and rat‐adrenomedullin, both at 10−6m, were significantly (P<0.05) lower than those induced by rat‐α‐ and rat‐βCGRP. In contrast, the selective CGRP2‐receptor agonist [Cys(Acm)2,7]‐human‐αCGRP failed to induce significant relaxations at the highest concentration used (10−7m) in the coronary arteries of male and female rats.
The C‐terminal fragment, human‐αCGRP(8–37) blocked concentration‐dependently (10−7–10−6m) the rat‐αCGRP‐induced relaxation in 10−5m PGF2α‐precontracted coronary arteries. The slopes of the regression lines of the Schild‐plots for both male and female rats were not significantly (P>0.05) different from unity and the pA2 values for human‐αCGRP(8–37) were 6.93 and 6.98 in arteries from male and female rats, respectively. There was no significant (P>0.05) difference in estimated pKB values for human‐αCGRP(8–37) between male (6.99±0.10, n=13) and female (6.95±0.08, n=13) rats.
The concentration‐response relationships for rat‐α‐ and rat‐βCGRP were similar in male and female Sprague Dawley rats. The predominant CGRP receptor subtype in small intramural coronary arteries appeared to belong to the CGRP1‐receptor subtype in both sexes.
In this study we characterized the CGRP‐receptor subtype by Schild‐plot analysis using the C‐terminal fragment, human‐αCGRP(8–37), a putative competitive CGRP1‐receptor selective antagonist. In addition, the effect of rat‐αCGRP was compared with that of homologous peptides rat‐βCGRP, rat‐amylin, rat‐adrenomedullin and [Cys(Acm)2,7]‐human‐αCGRP, a putative selective CGRP2‐receptor agonist, in the left coronary arteries of 3 months old male and female Sprague Dawley rats.
Isolated rings from the distal, intramural part of the left anterior descending (LAD) coronary artery in both groups of rats were mounted on a double wire‐myograph. The arteries were then stretched to their optimal lumen diameter for active tension development and precontracted with 10−5m prostaglandin F2α (PGF2α), after which agonists were added to the organ bath in a cumulative manner.
Rat‐αCGRP induced endothelium‐independent relaxations in male and female Sprague‐Dawley rats. Rat‐βCGRP concentration‐response relations (10−11–10−7m) were similar to those of rat‐αCGRP in either sex. The maximal relaxations induced by rat‐amylin and rat‐adrenomedullin, both at 10−6m, were significantly (P<0.05) lower than those induced by rat‐α‐ and rat‐βCGRP. In contrast, the selective CGRP2‐receptor agonist [Cys(Acm)2,7]‐human‐αCGRP failed to induce significant relaxations at the highest concentration used (10−7m) in the coronary arteries of male and female rats.
The C‐terminal fragment, human‐αCGRP(8–37) blocked concentration‐dependently (10−7–10−6m) the rat‐αCGRP‐induced relaxation in 10−5m PGF2α‐precontracted coronary arteries. The slopes of the regression lines of the Schild‐plots for both male and female rats were not significantly (P>0.05) different from unity and the pA2 values for human‐αCGRP(8–37) were 6.93 and 6.98 in arteries from male and female rats, respectively. There was no significant (P>0.05) difference in estimated pKB values for human‐αCGRP(8–37) between male (6.99±0.10, n=13) and female (6.95±0.08, n=13) rats.
The concentration‐response relationships for rat‐α‐ and rat‐βCGRP were similar in male and female Sprague Dawley rats. The predominant CGRP receptor subtype in small intramural coronary arteries appeared to belong to the CGRP1‐receptor subtype in both sexes.
British Journal of Pharmacology (1998) 123, 1464–1470; doi:10.1038/sj.bjp.0701760
DOI: 10.1038/sj.bjp.0701760
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