肾上腺髓质素和降钙素基因相关肽对大鼠主动脉和猪冠状动脉收缩的影响。

Effects of adrenomedullin and calcitonin gene-related peptide on contractions of the rat aorta and porcine coronary artery.

作者信息

Yoshimoto R, Mitsui-Saito M, Ozaki H, Karaki H

机构信息

Department of Veterinary Pharmacology, Graduate School of Agriculture and Life Sciences, The University of Tokyo, Japan.

出版信息

Br J Pharmacol. 1998 Apr;123(8):1645-54. doi: 10.1038/sj.bjp.0701805.

DOI:10.1038/sj.bjp.0701805

PMID:9605572

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC1565343/

Abstract

Effects of adrenomedullin and alpha-calcitonin gene-related peptide (CGRP) on the contractions and cytosolic Ca2+ concentrations ([Ca2+]i) of the rat aorta and porcine coronary artery were investigated. Characteristics of the receptors mediating the effects of adrenomedullin and alpha-CGRP were also investigated. 2. Adrenomedullin and alpha-CGRP caused a concentration-dependent relaxation in the rat aorta contracted with noradrenaline. The IC50 values for adrenomedullin and alpha-CGRP were 2.4 nM and 4.0 nM, respectively. The relaxant effects of these peptides were abolished by removal of the endothelium and significantly attenuated by an inhibitor of nitric oxide synthase, NG-monomethyl-L-arginine (L-NMMA, 100 microM), but not by a cyclo-oxygenase inhibitor, indomethacin (10 microM). 3. Adrenomedullin and alpha-CGRP increased the endothelial [Ca2+]i in the rat aorta with endothelium, whereas they did not change [Ca2+]i in the smooth muscle. 4. An antagonist of the CGRP1 receptor, CGRP (8-37), antagonized the relaxant effects of alpha-CGRP and the beta-isoform of CGRP (beta-CGRP) but not those of adrenomedullin in the rat aorta. 5. In the porcine coronary artery contracted with U46619, adrenomedullin and alpha-CGRP caused a concentration-dependent relaxation with an IC50 of 27.6 and 4.1 nM, respectively. Removal of the endothelium altered neither the IC50 values nor the maximal relaxations induced by adrenomedullin or alpha-CGRP. When the artery was contracted with high K+ solution (72.7 mM), these peptides caused a small relaxation. 6. Adrenomedullin and alpha-CGRP increased cyclic AMP content and decreased the smooth muscle [Ca2+]i in the porcine coronary artery. 7. CGRP (8-37) significantly antagonized the relaxant effects of adrenomedullin and alpha-CGRP in the porcine coronary artery. However, it had little effect on the relaxations induced by the beta-isoform of CGRP (beta-CGRP). 8. These results suggest that in the rat aorta, adrenomedullin and alpha-CGRP increase the endothelial [Ca2+]i, activate nitric oxide synthase and release nitric oxide, without a direct inhibitory action on smooth muscle. In the porcine coronary artery, in contrast, adrenomedullin and alpha-CGRP directly act on smooth muscle, increase cyclic AMP content, decrease the smooth muscle [Ca2+]i and inhibit contraction. The rat aortic endothelium seems to express the CGRP receptor which is sensitive to alpha-CGRP, beta-CGRP and CGRP (8-37) and the adrenomedullin specific receptor. The porcine coronary smooth muscle, in contrast, seems to express two types of CGRP receptor; one of which is sensitive to alpha-CGRP, CGRP (8-37) and adrenomedullin and the other is sensitive only to beta-CGRP.

摘要

研究了肾上腺髓质素和α-降钙素基因相关肽（CGRP）对大鼠主动脉和猪冠状动脉收缩及胞质钙离子浓度（[Ca2+]i）的影响。还研究了介导肾上腺髓质素和α-CGRP作用的受体特性。2. 肾上腺髓质素和α-CGRP使去甲肾上腺素收缩的大鼠主动脉产生浓度依赖性舒张。肾上腺髓质素和α-CGRP的半数抑制浓度（IC50）值分别为2.4 nM和4.0 nM。去除内皮后，这些肽的舒张作用消失，一氧化氮合酶抑制剂NG-单甲基-L-精氨酸（L-NMMA，100 μM）可使其显著减弱，但环氧化酶抑制剂吲哚美辛（10 μM）对其无影响。3. 肾上腺髓质素和α-CGRP使有内皮的大鼠主动脉内皮细胞[Ca2+]i升高，而对平滑肌细胞[Ca2+]i无影响。4. CGRP1受体拮抗剂CGRP（8-37）可拮抗α-CGRP和CGRPβ异构体（β-CGRP）对大鼠主动脉的舒张作用，但不拮抗肾上腺髓质素的舒张作用。5. 在U46619收缩的猪冠状动脉中，肾上腺髓质素和α-CGRP产生浓度依赖性舒张，IC50分别为27.6和4.1 nM。去除内皮既不改变IC50值，也不改变肾上腺髓质素或α-CGRP诱导的最大舒张程度。当动脉用高钾溶液（72.7 mM）收缩时，这些肽引起轻微舒张。6. 肾上腺髓质素和α-CGRP可增加猪冠状动脉中环磷酸腺苷（cAMP）含量，并降低平滑肌细胞[Ca2+]i。7. CGRP（8-37）可显著拮抗肾上腺髓质素和α-CGRP对猪冠状动脉的舒张作用。然而，它对CGRPβ异构体（β-CGRP）诱导的舒张作用影响很小。8. 这些结果表明，在大鼠主动脉中，肾上腺髓质素和α-CGRP可增加内皮细胞[Ca2+]i，激活一氧化氮合酶并释放一氧化氮，而对平滑肌无直接抑制作用。相比之下，在猪冠状动脉中，肾上腺髓质素和α-CGRP直接作用于平滑肌，增加cAMP含量，降低平滑肌细胞[Ca2+]i并抑制收缩。大鼠主动脉内皮似乎表达对α-CGRP、β-CGRP和CGRP（8-37）敏感的CGRP受体以及肾上腺髓质素特异性受体。相比之下，猪冠状动脉平滑肌似乎表达两种类型的CGRP受体；其中一种对α-CGRP、CGRP（8-37）和肾上腺髓质素敏感，另一种仅对β-CGRP敏感。