title: Smooth muscle myosin inhibition: a novel therapeutic approach for pulmonary hypertension.
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.
  
  
  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%).
  
  
  CONCLUSIONS
  Inhibition of smooth muscle myosin may be a novel therapeutic target for treatment of pulmonary hypertension.
authors.affiliation: Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, United States of America.
authors.forename: David
authors.initials: D
authors.lastname: Ho
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Xin
authors.initials: X
authors.lastname: Zhao
authors.forename: Nicquanna
authors.initials: N
authors.lastname: Durham
authors.forename: Malar
authors.initials: M
authors.lastname: Pannirselvam
authors.forename: Dorothy E
authors.initials: DE
authors.lastname: Vatner
authors.forename: David J
authors.initials: DJ
authors.lastname: Morgans
authors.forename: Fady I
authors.initials: FI
authors.lastname: Malik
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Vatner
authors.forename: You-Tang
authors.initials: YT
authors.lastname: Shen
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D000860:Hypoxia / Q000503:physiopathology; D066298:In Vitro Techniques; D016686:Monocrotaline; D009599:Nitroprusside / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D011687:Purines / Q000494:pharmacology; D051381:Rats; D000068677:Sildenafil Citrate; D024745:Smooth Muscle Myosins / Q000037:antagonists & inhibitors*; D013450:Sulfones / Q000494:pharmacology; D013552:Swine; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000959:Antihypertensive Agents; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014665:Vasodilator Agents; D009599:Nitroprusside; D016686:Monocrotaline; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000068677:Sildenafil Citrate; D011464:Epoprostenol; D024745:Smooth Muscle Myosins; C427248:treprostinil