Toyoshima H, Nasa Y, Hashizume Y, Koseki Y, Isayama Y, Kohsaka Y, Yamada T, Takeo S
Department of Pharmacology, Tokyo University of Pharmacy and Life Science, Hachioji, Japan.
J Cardiovasc Pharmacol. 1998 Oct;32(4):543-51. doi: 10.1097/00005344-199810000-00006.
Recent in vitro evidence shows a role of endothelial nitric oxide (NO) in the modulation of isoproterenol-induced vasorelaxation. To elucidate roles of endothelial cells and NO in cyclic adenosine monophosphate (cAMP)-mediated vasodilators we examined the effects of removal of endothelium and a NO synthase (NOS) inhibitor on relaxant responses in vitro of rat aortic strips to beta-adrenoceptor stimulants and colforsin dapropate, a water-soluble forskolin, and changes in cAMP and cyclic guanosine monophosphate (cGMP) contents. Relaxant responses of rat aorta to isoproterenol, denopamine, salbutamol, colforsin, and dibutyryl cAMP (dbcAMP) were blunted by removal of endothelial cells or treatment with NOS inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). Relaxant response of endothelium-intact segments to isoproterenol was associated with increases in tissue cAMP and cGMP contents. Removal of endothelium or treatment with L-NAME markedly reduced basal cGMP and abolished the isoproterenol-induced increase in cGMP but not cAMP content. In endothelium-removed segments, pretreatment with sodium nitroprusside (SNP) restored the diminished relaxant response to isoproterenol and increased basal cGMP (from 0.08 +/- 0.01 to 0.16 +/- 0.02 pmol/mg protein), whereas it did not affect the isoproterenol-induced increase in cAMP. The diminished relaxant response of endothelium-removed segments to dbcAMP was not restored by SNP pretreatment. The results suggest that relaxant response of rat aorta to cAMP-mediated vasodilators is mediated, in part, by NO production in endothelium and subsequent increase in cGMP in vascular smooth-muscle cells.
近期的体外实验证据表明，内皮型一氧化氮（NO）在异丙肾上腺素诱导的血管舒张调节中发挥作用。为了阐明内皮细胞和NO在环磷酸腺苷（cAMP）介导的血管舒张剂中的作用，我们研究了去除内皮和一氧化氮合酶（NOS）抑制剂对大鼠主动脉条对β-肾上腺素能受体激动剂和可福乐酯（一种水溶性福斯高林）的体外舒张反应以及cAMP和环磷酸鸟苷（cGMP）含量变化的影响。去除内皮细胞或用NOS抑制剂N(G)-硝基-L-精氨酸甲酯（L-NAME）处理后，大鼠主动脉对异丙肾上腺素、地诺帕明、沙丁胺醇、可福乐酯和二丁酰cAMP（dbcAMP）的舒张反应减弱。内皮完整节段对异丙肾上腺素的舒张反应与组织cAMP和cGMP含量增加有关。去除内皮或用L-NAME处理显著降低基础cGMP水平，并消除异丙肾上腺素诱导的cGMP增加，但不影响cAMP含量。在去除内皮的节段中，用硝普钠（SNP）预处理可恢复对异丙肾上腺素减弱的舒张反应，并增加基础cGMP（从0.08±0.01增加到0.16±0.02 pmol/mg蛋白），而不影响异丙肾上腺素诱导的cAMP增加。SNP预处理不能恢复去除内皮节段对dbcAMP减弱的舒张反应。结果表明，大鼠主动脉对cAMP介导的血管舒张剂的舒张反应部分是由内皮中NO生成以及随后血管平滑肌细胞中cGMP增加介导的。
