smooth muscle myosin inhibition a novel therapeutic approach for pulmonary hypertension平滑肌肌凝蛋白抑制肺动脉高压的新颖的治疗方法.pdf

Smooth Muscle Myosin Inhibition: A Novel Therapeutic Approach for Pulmonary Hypertension 2. 2. 2 3 3 2 David Ho , Li Chen , Xin Zhao , Nicquanna Durham , Malar Pannirselvam , Dorothy E. Vatner , 3 3 1,2 1,2 David J. Morgans , Fady I. Malik , Stephen F. Vatner *, You-Tang Shen 1 CV Dynamics, Inc., North Brunswick, New Jersey, United States of America, 2 Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, United States of America, 3 Cytokinetics, Inc., South San Francisco, California, United States of America 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 mg/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 63 and 28 66% from baseline in hypoxia and thromboxane pig models, respectively (p,0.01 and 0.01), while mean arterial pressure also fell and he