Kanazawa H, Hirata K, Yoshikawa J
First Department of Internal Medicine, Osaka City University Medical School, Osaka, Japan.
Am J Respir Crit Care Med. 1999 Jan;159(1):165-8. doi: 10.1164/ajrccm.159.1.9803076.
Losartan is the first angiotensin II type 1 (AT1) receptor antagonist to become available for the treatment of hypertension. However, recent reports have revealed several cases of losartan-induced bronchoconstriction. We investigated to determine the mechanism of losartan-induced bronchoconstriction, considering in particular the involvement of endogenous nitric oxide (NO). In this study, we examined the effects of losartan on airway obstruction and endogenous NO production using anesthetized guinea pigs and cultured airway epithelial cells. Five minutes after administration of angiotensin II (Ang II), the bronchoconstriction induced by acetylcholine was not changed. In contrast, Ang II in the presence of losartan caused a significant increase in the acetylcholine responsiveness. Pretreatment with L-N omega-nitroarginine-methylester (L-NAME) potentiated acetylcholine-induced bronchoconstriction 5 min after administration of Ang II, and L-arginine reversed this action of L-NAME on the acetylcholine responsiveness. Moreover, Ang II administration increased NO concentration in expired air (12.5 +/- 1.5 ppb for saline, 40 +/- 5 ppb for Ang II, p < 0.01), and losartan significantly inhibited Ang II-stimulated NO release (20 +/- 3.5 ppb) from guinea pig airway. In cultured airway epithelial cells, Ang II also increased NO release (160 +/- 25 nM), and the effect of this Ang II-induced NO release was significantly inhibited by pretreatment with losartan (25 +/- 8 nM, p < 0.01). These findings suggest that losartan-induced bronchoconstriction may result from inhibition of endogenous NO release in the airway.
氯沙坦是首个可用于治疗高血压的血管紧张素II 1型（AT1）受体拮抗剂。然而，最近的报告显示了几例氯沙坦诱发支气管收缩的病例。我们进行了研究以确定氯沙坦诱发支气管收缩的机制，尤其考虑内源性一氧化氮（NO）的作用。在本研究中，我们使用麻醉的豚鼠和培养的气道上皮细胞，研究了氯沙坦对气道阻塞和内源性NO生成的影响。给予血管紧张素II（Ang II）5分钟后，乙酰胆碱诱发的支气管收缩未发生变化。相反，在氯沙坦存在的情况下，Ang II使乙酰胆碱反应性显著增加。用L-Nω-硝基精氨酸甲酯（L-NAME）预处理可增强Ang II给药5分钟后乙酰胆碱诱发的支气管收缩，而L-精氨酸可逆转L-NAME对乙酰胆碱反应性的这种作用。此外，给予Ang II可增加呼出气中的NO浓度（生理盐水组为12.5±1.5 ppb，Ang II组为40±5 ppb，p<0.01），氯沙坦可显著抑制Ang II刺激的豚鼠气道NO释放（20±3.5 ppb）。在培养的气道上皮细胞中，Ang II也增加了NO释放（160±25 nM），氯沙坦预处理可显著抑制这种Ang II诱导的NO释放（25±8 nM，p<0.01）。这些发现提示，氯沙坦诱发的支气管收缩可能是由于气道内源性NO释放受到抑制所致。
