平滑肌肌球蛋白抑制：肺动脉高压的一种新治疗方法。

Smooth muscle myosin inhibition: a novel therapeutic approach for pulmonary hypertension.

机构信息

Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, United States of America.

出版信息

PLoS One. 2012;7(5):e36302. doi: 10.1371/journal.pone.0036302. Epub 2012 May 1.

DOI:10.1371/journal.pone.0036302

PMID:22563487

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3341368/

Abstract

OBJECTIVE

Pulmonary hypertension remains a major clinical problem despite current therapies. In this study, we examine for the first time a novel pharmacological target, smooth muscle myosin, and determine if the smooth muscle myosin inhibitor, CK-2019165 (CK-165) ameliorates pulmonary hypertension.

MATERIALS AND METHODS

Six domestic female pigs were surgically instrumented to measure pulmonary blood flow and systemic and pulmonary vascular dynamics. Pulmonary hypertension was induced by hypoxia, or infusion of the thromboxane analog (U-46619, 0.1 µg/kg/min, i.v.). In rats, chronic pulmonary hypertension was induced by monocrotaline.

RESULTS

CK-165 (4 mg/kg, i.v.) reduced pulmonary vascular resistance by 22±3 and 28±6% from baseline in hypoxia and thromboxane pig models, respectively (p<0.01 and 0.01), while mean arterial pressure also fell and heart rate rose slightly. When CK-165 was delivered via inhalation in the hypoxia model, pulmonary vascular resistance fell by 17±6% (p<0.05) while mean arterial pressure and heart rate were unchanged. In the monocrotaline model of chronic pulmonary hypertension, inhaled CK-165 resulted in a similar (18.0±3.8%) reduction in right ventricular systolic pressure as compared with sildenafil (20.3±4.5%).

CONCLUSION

Inhibition of smooth muscle myosin may be a novel therapeutic target for treatment of pulmonary hypertension.

摘要

目的

尽管目前已有多种治疗方法，但肺动脉高压仍然是一个主要的临床问题。在这项研究中，我们首次研究了一种新型的药理学靶点——平滑肌肌球蛋白，并确定平滑肌肌球蛋白抑制剂 CK-2019165（CK-165）是否能改善肺动脉高压。

材料和方法

六只国内雌性猪接受了手术，以测量肺血流量和体循环及肺血管动力学。通过缺氧或静脉输注血栓素类似物（U-46619，0.1μg/kg/min）诱导肺动脉高压。在大鼠中，通过给予单环素来诱导慢性肺动脉高压。

结果

CK-165（4mg/kg，静脉注射）使缺氧和血栓素猪模型的肺血管阻力分别降低了 22±3%和 28±6%（p<0.01 和 0.01），同时平均动脉压也略有下降，心率略有升高。当 CK-165 在缺氧模型中通过吸入给药时，肺血管阻力降低了 17±6%（p<0.05），而平均动脉压和心率保持不变。在慢性肺动脉高压的单环素模型中，与西地那非（20.3±4.5%）相比，吸入 CK-165 可使右心室收缩压降低相似的 18.0±3.8%。