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降钙素基因相关肽(CGRP)受体介导猪冠状动脉中CGRP、肾上腺髓质素和胰淀素诱导的舒张。用非肽拮抗剂“化合物1”(WO98/11128)进行表征。

CGRP receptors mediating CGRP-, adrenomedullin- and amylin-induced relaxation in porcine coronary arteries. Characterization with 'Compound 1' (WO98/11128), a non-peptide antagonist.

作者信息

Hasbak P, Sams A, Schifter S, Longmore J, Edvinsson L

机构信息

Department of Clinical Experimental Research, University Hospital of Glostrup, Glostrup, Denmark.

出版信息

Br J Pharmacol. 2001 Aug;133(8):1405-13. doi: 10.1038/sj.bjp.0704210.

Abstract
  1. Calcitonin gene-related peptide (CGRP), amylin and adrenomedullin (AM) belong to the same family of peptides. Accumulating evidence indicate that the calcitonin (CT) receptor, the CT receptor-like receptor (CRLR) and receptor-activity-modifying proteins (RAMPs) form the basis of all the receptors in this family of peptides. 2. Using reverse transcriptase - polymerase chain reaction the presence of mRNA sequences encoding the CRLR, RAMP1 and RAMP2 were demonstrated in porcine left anterior descending (LAD) coronary arteries, whereas porcine calcitonin (CT) receptor mRNA was not present. The partial porcine mRNA sequences shared 82 - 92% nucleotide identity with human sequences. 3. The human peptides alphaCGRP, betaCGRP, AM and amylin induced relaxation with pEC(50) values of 8.1, 8.1, 6.7 and 6.1 M respectively. 4. The antagonistic properties of a novel non-peptide CGRP antagonist 'Compound 1' (WO98/11128), betaCGRP(8 - 37) and the proposed AM receptor antagonist AM(22 - 52) were compared to the well-known CGRP(1) receptor antagonist alphaCGRP(8 - 37). 5. The alphaCGRP(8 - 37) and betaCGRP(8 - 37) induced concentration-dependent (10(-7) - 10(-5) M) rightward shift of both the alphaCGRP and betaCGRP concentration-response curves. betaCGRP(8 - 37) (10(-6) M) had the same effect as alphaCGRP(8 - 37) (10(-6) M), but with less potent rightward shift of the concentration-response curves for alphaCGRP, AM and amylin. 6. Preincubation with 'Compound 1' (10(-7) - 10(-5) M) and AM(22 - 52) (10(-6) M) had no significant antagonistic effect. 7. In conclusion, the building blocks forming CGRP and AM receptors were present in the porcine LAD, whereas those of the amylin receptor were not. alphaCGRP, betaCGRP, AM and amylin mediated vasorelaxation via the CGRP receptors. No functional response was detected to adrenomedullin via the adrenomedullin receptor.
摘要
  1. 降钙素基因相关肽(CGRP)、胰淀素和肾上腺髓质素(AM)属于同一肽家族。越来越多的证据表明,降钙素(CT)受体、CT受体样受体(CRLR)和受体活性修饰蛋白(RAMP)构成了该肽家族所有受体的基础。2. 利用逆转录-聚合酶链反应在猪左前降支(LAD)冠状动脉中证实了编码CRLR、RAMP1和RAMP2的mRNA序列的存在,而猪降钙素(CT)受体mRNA不存在。猪mRNA部分序列与人类序列的核苷酸同一性为82%-92%。3. 人肽αCGRP、βCGRP、AM和胰淀素分别以8.1、8.1、6.7和6.1 M的pEC(50)值诱导血管舒张。4. 将新型非肽CGRP拮抗剂“化合物1”(WO98/11128)、βCGRP(8 - 37)和拟用的AM受体拮抗剂AM(22 - 52)的拮抗特性与著名的CGRP(1)受体拮抗剂αCGRP(8 - 37)进行了比较。5. αCGRP(8 - 37)和βCGRP(8 - 37)诱导αCGRP和βCGRP浓度-反应曲线浓度依赖性(10(-7)-10(-5) M)右移。βCGRP(8 - 37)(10(-6) M)与αCGRP(8 - 37)(10(-6) M)具有相同的作用,但对αCGRP、AM和胰淀素浓度-反应曲线的右移作用较弱。6. 用“化合物1”(10(-7)-10(-5) M)和AM(22 - 52)(10(-6) M)预孵育无明显拮抗作用。7. 总之,构成CGRP和AM受体的组件存在于猪LAD中,而胰淀素受体的组件不存在。αCGRP、βCGRP、AM和胰淀素通过CGRP受体介导血管舒张。未检测到通过肾上腺髓质素受体对肾上腺髓质素的功能反应。

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