Fiscus R R, Hao H, Wang X, Arden W A, Diana J N
Department of Physiology and Biophysics, University of Kentucky College of Medicine, Lexington 40536-0230.
Neuropeptides. 1994 Feb;26(2):133-44. doi: 10.1016/0143-4179(94)90104-x.
Rat calcitonin gene-related peptide (rCGRP) causes endothelium-dependent vasorelaxations via a dual signal transduction mechanism involving elevations of both cyclic AMP and cyclic GMP levels in rat aorta. These responses are all dependent on de novo synthesis of nitric oxide (NO) in endothelial cells and appear to involve a mechanistic link between cyclic GMP and cyclic AMP responses in smooth muscle cells. The present study determined whether NO from an exogenous source (i.e. added nitroglycerin) could substitute for endogenous NO in rCGRP-induced responses in endothelium-denuded aorta. Nitroglycerin (1 microM) significantly elevated cyclic GMP levels by 20-fold and 3.3-fold and cyclic AMP levels by 26% and 22% at 1 and 2 min, respectively. By itself, rCGRP (100 nM) did not significantly elevate cyclic AMP levels. In combination, however, nitroglycerin and rCGRP caused more-than-additive cyclic AMP elevations (41% above basal at 1 and 2 min). Nitroglycerin also potentiated rCGRP-induced vasorelaxations in endothelium-denuded rings, thus uncovering a direct (endothelium-independent) relaxant effect of rCGRP in rat aorta. The data indicate that exogenous NO can substitute for endogenous NO in rCGRP-induced relaxant and cyclic AMP responses in aorta. This nitroglycerin-induced potentiation of CGRP effects likely involves inhibition of cyclic-GMP-inhibited-phosphodiesterase in smooth muscle cells, thus allowing cyclic AMP to accumulate and mediate the direct vasodilator effects of rCGRP.
大鼠降钙素基因相关肽（rCGRP）通过一种双重信号转导机制引起内皮依赖性血管舒张，该机制涉及大鼠主动脉中环状AMP和环状GMP水平的升高。这些反应均依赖于内皮细胞中一氧化氮（NO）的从头合成，并且似乎涉及平滑肌细胞中环状GMP和环状AMP反应之间的机制联系。本研究确定了外源性来源的NO（即添加的硝酸甘油）是否可以替代内皮剥脱主动脉中rCGRP诱导反应中的内源性NO。硝酸甘油（1 microM）在1分钟和2分钟时分别使环状GMP水平显著升高20倍和3.3倍，使环状AMP水平分别升高26%和22%。单独使用时，rCGRP（100 nM）并未显著升高环状AMP水平。然而，硝酸甘油和rCGRP联合使用会导致环状AMP升高超过相加效应（1分钟和2分钟时比基础水平高41%）。硝酸甘油还增强了rCGRP诱导的内皮剥脱环的血管舒张，从而揭示了rCGRP在大鼠主动脉中的直接（不依赖内皮）舒张作用。数据表明，外源性NO可以替代主动脉中rCGRP诱导的舒张和环状AMP反应中的内源性NO。这种硝酸甘油诱导的CGRP效应增强可能涉及平滑肌细胞中环状GMP抑制性磷酸二酯酶的抑制，从而使环状AMP积累并介导rCGRP的直接血管舒张作用。
