Heart and Vascular Center, Semmelweis University, 1122 Budapest, Hungary.
Cyclolab Ltd., 1097 Budapest, Hungary.
Int J Mol Sci. 2024 Jul 22;25(14):7981. doi: 10.3390/ijms25147981.
Numerous research projects focused on the management of acute pulmonary hypertension as Coronavirus Disease 2019 (COVID-19) might lead to hypoxia-induced pulmonary vasoconstriction related to acute respiratory distress syndrome. For that reason, inhalative therapeutic options have been the subject of several clinical trials. In this experimental study, we aimed to examine the hemodynamic impact of the inhalation of the SIN-1A formulation (N-nitroso-N-morpholino-amino-acetonitrile, the unstable active metabolite of molsidomine, stabilized by a cyclodextrin derivative) in a porcine model of acute pulmonary hypertension. Landrace pigs were divided into the following experimental groups: iNO (inhaled nitric oxide, n = 3), SIN-1A-5 (5 mg, n = 3), and SIN-1A-10 (10 mg, n = 3). Parallel insertion of a PiCCO system and a pulmonary artery catheter (Swan-Ganz) was performed for continuous hemodynamic monitoring. The impact of iNO (15 min) and SIN-1A inhalation (30 min) was investigated under physiologic conditions and U46619-induced acute pulmonary hypertension. Mean pulmonary arterial pressure (PAP) was reduced transiently by both substances. SIN-1A-10 had a comparable impact compared to iNO after U46619-induced pulmonary hypertension. PAP and PVR decreased significantly (changes in PAP: -30.1% iNO, -22.1% SIN-1A-5, -31.2% SIN-1A-10). While iNO therapy did not alter the mean arterial pressure (MAP) and systemic vascular resistance (SVR), SIN-1A administration resulted in decreased MAP and SVR values. Consequently, the PVR/SVR ratio was markedly reduced in the iNO group, while SIN-1A did not alter this parameter. The pulmonary vasodilatory impact of inhaled SIN-1A was shown to be dose-dependent. A larger dose of SIN-1A (10 mg) resulted in decreased PAP and PVR in a similar manner to the gold standard iNO therapy. Inhalation of the nebulized solution of the new SIN-1A formulation (stabilized by a cyclodextrin derivative) might be a valuable, effective option where iNO therapy is not available due to dosing difficulties or availability.
许多研究项目都集中在急性肺动脉高压的管理上，因为 2019 年冠状病毒病（COVID-19）可能导致与急性呼吸窘迫综合征相关的缺氧诱导性肺血管收缩。因此，吸入治疗选择已成为多项临床试验的主题。在这项实验研究中，我们旨在检查在急性肺动脉高压的猪模型中吸入 SIN-1A 制剂（N-亚硝基-N-吗啉基-氨基乙腈，米索地尔的不稳定活性代谢物，由环糊精衍生物稳定）对血流动力学的影响。长白猪分为以下实验组：iNO（吸入一氧化氮，n = 3），SIN-1A-5（5mg，n = 3）和 SIN-1A-10（10mg，n = 3）。为连续血流动力学监测并行插入 PiCCO 系统和肺动脉导管（Swan-Ganz）。在生理条件下和 U46619 诱导的急性肺动脉高压下研究 iNO（15 分钟）和 SIN-1A 吸入（30 分钟）的作用。这两种物质均使平均肺动脉压（PAP）短暂降低。SIN-1A-10 在 U46619 诱导的肺动脉高压后与 iNO 具有可比的作用。SIN-1A-10 降低 PAP 和 PVR 的效果与 iNO 相似。与 iNO 治疗相比，SIN-1A 给药不会改变平均动脉压（MAP）和全身血管阻力（SVR），但会导致 MAP 和 SVR 值降低。因此，iNO 组的 PVR/SVR 比值显著降低，而 SIN-1A 则没有改变该参数。结果表明，吸入 SIN-1A 的肺血管扩张作用呈剂量依赖性。较大剂量的 SIN-1A（10mg）以与金标准 iNO 治疗相似的方式降低 PAP 和 PVR。由于剂量困难或可用性，在无法使用 iNO 治疗的情况下，吸入新型 SIN-1A 制剂（由环糊精衍生物稳定）的雾化溶液可能是一种有价值且有效的选择。
