PLoS ONE：发现新的肺动脉高压治疗策略

肺动脉高压是各种原因引起的静息状态下右心导管测得的肺动脉平均压（mean pulmonary arterial pressure，mPAP）≥25mmHg的一组临床病理生理综合征。由于肺血管重塑引起肺循环血流动力学改变，最终可导致右心衰竭，甚至死亡。

近日，来自美国新泽西医学院的研究人员首次发现了肺动脉高压新的用药靶点--平滑肌肌球蛋白，还发现平滑肌肌球蛋白的抑制剂CK-2019165(CK-165)能够改善肺动脉高压症状。

在该实验中，母猪被用于测量肺动脉血流及包括肺血管的全身动力学研究，并利用低氧或者注入凝血烷类似物诱发肺动脉高压。在老鼠模型，慢性肺动脉高压则被野百合碱所诱导。

结果发现，CK-165减少了肺血管阻力，而平均动脉压也下降，心律则轻微上升。在缺氧模型吸入CK-16后，肺血管阻力下降，然而平均动脉压及心律没有明显改变。在慢性肺动脉高压的野百合碱模型中，与西地那非相比，吸入CK-165也会导致相似的右心室收缩压下降。

该研究表明，抑制平滑肌肌球蛋白很可能会成为肺动脉高压新的治疗策略。相关论文发表在5月1日的PLoS ONE。

doi: 10.1371/journal.pone.0036302
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Smooth Muscle Myosin Inhibition: A Novel Therapeutic Approach for Pulmonary Hypertension

David Ho, Li Chen, Xin Zhao, Nicquanna Durham, Malar Pannirselvam, Dorothy E. Vatner, David J. Morgans, Fady I. Malik, Stephen F. Vatner, You-Tang Shen.

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