Cinaciguat, a soluble guanylate cyclase activator, causes potent and sustained pulmonary vasodilation in the ovine fetus
Cinaciguat, a soluble guanylate cyclase activator, causes potent and sustained pulmonary vasodilation in the ovine fetus
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DOI：
10.1152/ajplung.00062.2009
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发表时间：
2009-08-01
影响因子：
4.9
通讯作者：
Abman, Steven H.
中科院分区：
文献类型：
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作者：
Chester, Marc;Tourneux, Pierre;Abman, Steven H.
Chester M，Tourneux P，Seedorf G，Grover TR，吉安J和Abman SH.西那西瓜是一种可溶性鸟苷酸环化酶激活剂，可引起羊胎儿强效且持续的肺血管舒张。Am J Physiol Lung Cell Mol Physiol 297：L318-L325，2009.首次发表于2009年5月22日; doi：10.1152/ajplung.00062.2009.-受损的一氧化氮-cGMP信号传导导致出生后严重的肺动脉高压，这可能部分是由于可溶性鸟苷酸环化酶（sGC）活性降低。Cinaciguat（BAY 58-2667）是一种新型sGC激活剂，即使在存在氧化血红素或无血红素sGC的情况下也会引起血管舒张，但尚未在围产期肺中研究其血流动力学效应。我们对8只胎羊（妊娠126 +/- 2天）（足月= 147天）进行了手术，并在主肺动脉、主动脉和左心房中放置导管以测量压力。将超声流量传感器放置在左肺动脉上以测量血流量，并将导管放置在左肺动脉中以进行药物输注。Cinaciguat（0.1-100 μ g，10分钟）引起肺血流量的剂量相关性增加，超过基线的4倍，并使肺血管阻力降低80%。用1H-[1，2，4]恶二唑并[4，3-a]喹喔啉-1-酮（ODQ）（一种sGC氧化抑制剂）治疗可使西那西呱诱导的肺血管舒张增强> 120%。西那西呱的肺血管扩张作用延长，在短暂输注后降低肺血管阻力>1.5小时。ODQ处理后用西那西呱体外刺激羊胎肺动脉平滑肌细胞，与非ODQ处理的细胞相比，cGMP增加了14倍。我们的结论是，西那西呱导致有效的和持续的胎儿肺血管扩张，在氧化sGC的存在下增强，并推测西那西呱可能具有治疗严重新生儿肺动脉高压的潜力。
Chester M, Tourneux P, Seedorf G, Grover TR, Gien J, and Abman SH. Cinaciguat, a soluble guanylate cyclase activator, causes potent and sustained pulmonary vasodilation in the ovine fetus. Am J Physiol Lung Cell Mol Physiol 297: L318-L325, 2009. First published May 22, 2009; doi:10.1152/ajplung.00062.2009.-Impaired nitric oxide-cGMP signaling contributes to severe pulmonary hypertension after birth, which may in part be due to decreased soluble guanylate cyclase (sGC) activity. Cinaciguat (BAY 58-2667) is a novel sGC activator that causes vasodilation, even in the presence of oxidized heme or heme-free sGC, but its hemodynamic effects have not been studied in the perinatal lung. We performed surgery on eight fetal (126 +/- 2 days gestation) lambs (full term = 147 days) and placed catheters in the main pulmonary artery, aorta, and left atrium to measure pressures. An ultrasonic flow transducer was placed on the left pulmonary artery to measure blood flow, and a catheter was placed in the left pulmonary artery for drug infusion. Cinaciguat (0.1-100 mu g over 10 min) caused dose-related increases in pulmonary blood flow greater than fourfold above baseline and reduced pulmonary vascular resistance by 80%. Treatment with 1H-[1,2,4] oxadiazolo[4,3-a] quinoxalin-1-one (ODQ), an sGC-oxidizing inhibitor, enhanced cinaciguat-induced pulmonary vasodilation by >120%. The pulmonary vasodilator effect of cinaciguat was prolonged, decreasing pulmonary vascular resistance for >1.5 h after brief infusion. In vitro stimulation of ovine fetal pulmonary artery smooth muscle cells with cinaciguat after ODQ treatment resulted in a 14-fold increase in cGMP compared with non-ODQ-treated cells. We conclude that cinaciguat causes potent and sustained fetal pulmonary vasodilation that is augmented in the presence of oxidized sGC and speculate that cinaciguat may have therapeutic potential for severe neonatal pulmonary hypertension.