雄性和雌性Sprague Dawley大鼠壁内冠状动脉中降钙素基因相关肽（CGRP）受体的特征

Characterization of calcitonin gene-related peptide (CGRP) receptors in intramural coronary arteries from male and female Sprague Dawley rats.

作者信息

Sheykhzade M, Nyborg N C

机构信息

Department of Pharmacology, The Royal Danish School of Pharmacy, Copenhagen O.

出版信息

Br J Pharmacol. 1998 Apr;123(7):1464-70. doi: 10.1038/sj.bjp.0701760.

DOI:10.1038/sj.bjp.0701760

PMID:9579744

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1565309/

Abstract

In this study we characterized the CGRP-receptor subtype by Schild-plot analysis using the C-terminal fragment, human-alphaCGRP(8-37), a putative competitive CGRP1-receptor selective antagonist. In addition, the effect of rat-alphaCGRP was compared with that of homologous peptides rat-betaCGRP, rat-amylin, rat-adrenomedullin and [Cys(Acm)2,7]-human-alphaCGRP, a putative selective CGRP2-receptor agonist, in the left coronary arteries of 3 months old male and female Sprague Dawley rats. 2. 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(-5) M prostaglandin F2alpha (PGF2alpha), after which agonists were added to the organ bath in a cumulative manner. 3. Rat-alphaCGRP induced endothelium-independent relaxations in male and female Sprague-Dawley rats. Rat-betaCGRP concentration-response relations (10[-11]-10[-7] M) were similar to those of rat-alphaCGRP in either sex. The maximal relaxations induced by rat-amylin and rat-adrenomedullin, both at 10(-6) M, were significantly (P<0.05) lower than those induced by rat-alpha- and rat-betaCGRP. In contrast, the selective CGRP2-receptor agonist [Cys(Acm)2,7]-human-alphaCGRP failed to induce significant relaxations at the highest concentration used (10[-7] M) in the coronary arteries of male and female rats. 4. The C-terminal fragment, human-alphaCGRP(8-37) blocked concentration-dependently (10[-7]-10[-6] M) the rat-alphaCGRP-induced relaxation in 10(-5) M PGF2alpha-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-alphaCGRP(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-alphaCGRP(8-37) between male (6.99+/-0.10, n=13) and female (6.95+/-0.08, n=13) rats. 5. The concentration-response relationships for rat-alpha- and rat-betaCGRP 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.

摘要

在本研究中，我们使用C端片段人α降钙素基因相关肽（hαCGRP(8 - 37)）（一种假定的竞争性CGRP1受体选择性拮抗剂），通过Schild图分析对CGRP受体亚型进行了表征。此外，在3月龄雄性和雌性Sprague Dawley大鼠的左冠状动脉中，比较了大鼠αCGRP与同源肽大鼠βCGRP、大鼠胰淀素、大鼠肾上腺髓质素以及[Cys(Acm)2,7]-人αCGRP（一种假定的选择性CGRP2受体激动剂）的作用。2. 两组大鼠左前降支（LAD）冠状动脉壁内远端的分离血管环被安装在双丝肌动描记器上。然后将动脉拉伸至其最佳管腔直径以产生主动张力，并先用10⁻⁵ M前列腺素F2α（PGF2α）进行预收缩，之后以累积方式向器官浴中添加激动剂。3. 大鼠αCGRP在雄性和雌性Sprague - Dawley大鼠中诱导非内皮依赖性舒张。大鼠βCGRP浓度 - 反应关系（10⁻¹¹ - 10⁻⁷ M）在两性中与大鼠αCGRP相似。大鼠胰淀素和大鼠肾上腺髓质素在10⁻⁶ M时诱导的最大舒张明显（P < 0.05）低于大鼠α - 和大鼠βCGRP诱导的舒张。相反，选择性CGRP2受体激动剂[Cys(Acm)2,7]-人αCGRP在雄性和雌性大鼠冠状动脉中使用的最高浓度（10⁻⁷ M）下未能诱导明显舒张。4. C端片段人αCGRP(8 - 37)以浓度依赖性方式（10⁻⁷ - 10⁻⁶ M）阻断10⁻⁵ M PGF2α预收缩冠状动脉中大鼠αCGRP诱导的舒张。雄性和雌性大鼠Schild图回归线的斜率与1无显著（P > 0.05）差异，人αCGRP(8 - 37)在雄性和雌性大鼠动脉中的pA2值分别为6.93和6.98。雄性（6.99 ± 0.10，n = 13）和雌性（6.95 ± 0.08，n = 13）大鼠中，人αCGRP(8 - 37)的估计pKB值无显著（P > 0.05）差异。5. 大鼠α - 和大鼠βCGRP的浓度 - 反应关系在雄性和雌性Sprague Dawley大鼠中相似。壁内小冠状动脉中的主要CGRP受体亚型在两性中似乎都属于CGRP1受体亚型。