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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
  • Animals
  • Antihypertensive Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Epoprostenol / analogs & derivatives
  • Epoprostenol / pharmacology
  • Female
  • Hypertension, Pulmonary / chemically induced
  • Hypertension, Pulmonary / drug therapy*
  • Hypertension, Pulmonary / physiopathology
  • Hypoxia / physiopathology
  • In Vitro Techniques
  • Monocrotaline
  • Nitroprusside / pharmacology
  • Piperazines / pharmacology
  • Pulmonary Artery / drug effects*
  • Pulmonary Artery / metabolism
  • Pulmonary Artery / physiopathology
  • Purines / pharmacology
  • Rats
  • Sildenafil Citrate
  • Smooth Muscle Myosins / antagonists & inhibitors*
  • Sulfones / pharmacology
  • Swine
  • Vascular Resistance / drug effects
  • Vasoconstriction / drug effects
  • Vasodilator Agents / pharmacology

Substances

  • Antihypertensive Agents
  • Piperazines
  • Purines
  • Sulfones
  • Vasodilator Agents
  • Nitroprusside
  • Monocrotaline
  • 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
  • Sildenafil Citrate
  • Epoprostenol
  • Smooth Muscle Myosins
  • treprostinil