Fiscus R R, Zhou H L, Wang X, Han C, Ali S, Joyce C D, Murad F
Department of Physiology, Loyola University Medical Center, Maywood, Illinois 60153.
Neuropeptides. 1991 Oct;20(2):133-43. doi: 10.1016/0143-4179(91)90063-o.
The mechanism of CGRP-induced vasodilation in rat thoracic aorta was investigated using antagonists of the classical endothelium-derived vasorelaxant factor (EDRF) and comparisons with acetylcholine-induced vasodilations. The CGRP-induced relaxations of isolated rings of rat thoracic aorta were completely dependent on the presence of endothelium and were associated with increases in the levels of both cyclic AMP and cyclic GMP, the same as in our previous study using rat abdominal aorta. Maximum relaxations to CGRP, which represented 40-50% reversal of the norepinephrine-induced contractions, occurred with 100 nM CGRP. Addition of acetylcholine (ACh, 1 microM) to aortic rings, which were already maximally relaxed to CGRP, caused further relaxation to 100%, suggesting that CGRP may use a mechanism (or pool of EDRF) different from that of ACh. Both CGRP- and ACh-induced relaxations of aorta were significantly inhibited by the EDRF blocking agents, hemoglobin (10 microM), methylene blue (10 microM), and nordihydroguaiaretic acid (NDGA, 10 microM). In fact, hemoglobin and NDGA were more effective as inhibitors of CGRP-induced relaxations than ACh-induced relaxations. Hemoglobin, methylene blue and NDGA also inhibited the CGRP-induced increases in both cyclic AMP and cyclic GMP levels. On the other hand, indomethacin, a cyclo-oxygenase inhibitor, did not alter CGRP-induced vasorelaxations or increases in either cyclic AMP or cyclic GMP levels, suggesting that prostaglandins are not involved. Therefore, CGRP-induced vasodilations in rat thoracic aorta appear to involve EDRF, leading to cyclic GMP elevations in smooth muscle and ultimately vasorelaxations. However, another previously undescribed mechanism, which involves EDRF-dependent and indomethacin-resistant elevations of cyclic AMP levels, is triggered by CGRP in thoracic aorta. This novel EDRF-dependent cyclic AMP response may contribute to the CGRP-induced vasodilation in rat thoracic aorta.
利用经典的内皮源性血管舒张因子（EDRF）拮抗剂，并与乙酰胆碱诱导的血管舒张进行比较，研究了降钙素基因相关肽（CGRP）诱导大鼠胸主动脉血管舒张的机制。CGRP诱导的大鼠胸主动脉离体血管环舒张完全依赖于内皮的存在，并且与环磷酸腺苷（cAMP）和环磷酸鸟苷（cGMP）水平的升高有关，这与我们之前使用大鼠腹主动脉的研究结果相同。100 nM CGRP可使对CGRP的最大舒张达到去甲肾上腺素诱导收缩的40 - 50%的逆转。向已对CGRP最大舒张的主动脉环中加入乙酰胆碱（ACh，1 μM），可使其进一步舒张至100%，这表明CGRP可能使用了与ACh不同的机制（或EDRF池）。EDRF阻断剂血红蛋白（10 μM）、亚甲蓝（10 μM）和去甲二氢愈创木酸（NDGA，10 μM）均可显著抑制CGRP和ACh诱导的主动脉舒张。事实上，血红蛋白和NDGA作为CGRP诱导舒张的抑制剂比ACh诱导舒张的抑制剂更有效。血红蛋白、亚甲蓝和NDGA也抑制CGRP诱导的cAMP和cGMP水平升高。另一方面，环氧化酶抑制剂吲哚美辛不会改变CGRP诱导的血管舒张或cAMP和cGMP水平的升高，这表明前列腺素不参与其中。因此，CGRP诱导的大鼠胸主动脉血管舒张似乎涉及EDRF，导致平滑肌中cGMP升高并最终引起血管舒张。然而，CGRP在胸主动脉中触发了另一种先前未描述的机制，该机制涉及EDRF依赖性和吲哚美辛抗性的cAMP水平升高。这种新的EDRF依赖性cAMP反应可能有助于CGRP诱导的大鼠胸主动脉血管舒张。
