Ohbayashi H, Yamaki K, Suzuki R, Takagi K
Second Department of Internal Medicine, Nagoya University School of Medicine, Japan.
Life Sci. 1998;62(20):1833-44. doi: 10.1016/s0024-3205(98)00149-0.
Uroguanylin and guanylin are isolated mainly from the gastrointestinal tract and are activators of guanylyl cyclase C receptor (GC-C), which mediates the production of intracellular cyclic guanosine 3',5'-monophosphate (cyclic GMP). The bronchodilator effects of agents that raise cyclic GMP levels, such as atrial natriuretic peptide, have been reported, and uroguanylin mRNA has recently been detected in extra-gastrointestinal tissues, including the lung, suggesting their role in pulmonary activity. In the first step of this study, we examined the relaxant effects of uroguanylin and guanylin on isolated tracheal smooth muscle of guinea-pigs, and measured tissue cyclic GMP levels by means of enzymeimmunoassay. Uroguanylin produced concentration-dependent relaxant effects on resting tone and significant elevated cyclic GMP levels. Guanylin produced the same, but less potent, effects. In this study, we first investigated the effects of uroguanylin and guanylin on antigen-induced bronchoconstriction and airway microvascular leakage in actively sensitized guinea-pigs. Anesthetized male guinea-pigs, ventilated via a tracheal cannula, were placed in a plethysmograph to measure pulmonary mechanics for 10 min after challenging with 1 mg/kg of ovalbumin. Evans blue dye was then extravasated into their airway tissues to measure microvascular leakage. Intravenous pretreatment with uroguanylin significantly inhibited ovalbumin-induced bronchoconstriction and microvascular leakage in a dose-dependent manner. These inhibitory effects were mimicked by 8-bromoguanosine 3', 5'-cyclic monophosphate. This study is the first to show that uroguanylin not only had a potent bronchodilatory effect but also inhibited microvascular leakage. These results encouraged us to continue the above experimental and clinical studies in bronchial asthma.
尿鸟苷素和鸟苷素主要从胃肠道分离出来，是鸟苷酸环化酶C受体（GC-C）的激活剂，该受体介导细胞内环磷酸鸟苷（cGMP）的产生。据报道，提高cGMP水平的药物（如心房利钠肽）具有支气管扩张作用，最近在包括肺在内的胃肠道外组织中检测到了尿鸟苷素mRNA，提示它们在肺部活动中发挥作用。在本研究的第一步中，我们检测了尿鸟苷素和鸟苷素对豚鼠离体气管平滑肌的舒张作用，并通过酶免疫测定法测量组织cGMP水平。尿鸟苷素对静息张力产生浓度依赖性舒张作用，并显著提高cGMP水平。鸟苷素也有同样的作用，但效力较弱。在本研究中，我们首先研究了尿鸟苷素和鸟苷素对主动致敏豚鼠抗原诱导的支气管收缩和气道微血管渗漏的影响。经气管插管通气的麻醉雄性豚鼠，在给予1mg/kg卵清蛋白激发后，置于体积描记器中测量肺力学10分钟。然后将伊文思蓝染料渗入其气道组织以测量微血管渗漏。尿鸟苷素静脉预处理以剂量依赖性方式显著抑制卵清蛋白诱导的支气管收缩和微血管渗漏。这些抑制作用被8-溴环磷酸鸟苷模拟。本研究首次表明尿鸟苷素不仅具有强大的支气管扩张作用，而且还能抑制微血管渗漏。这些结果鼓励我们继续进行上述关于支气管哮喘的实验和临床研究。
