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Rho-Kinase Inhibitors

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Pharmacotherapy of Pulmonary Hypertension

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 218))

Abstract

Pulmonary arterial hypertension (PAH) is a fatal disease with poor prognosis characterized by progressive elevation of pulmonary arterial pressure and vascular resistance due to pulmonary artery hyperconstriction and remodeling; however, the precise mechanism of PAH still remains to be elucidated. Although anticoagulant agents, pulmonary vasodilators, and lung transplantation are currently used for the treatment of PAH, more effective treatment needs to be developed. Rho-kinase causes vascular smooth muscle hyperconstriction and vascular remodeling through inhibition of myosin phosphatase and activation of its downstream effectors. In a series of experimental and clinical studies, it has been demonstrated that Rho-kinase-mediated pathway plays an important role in various cellular functions not only in vascular smooth muscle hyperconstriction but also in actin cytoskeleton organization, cell adhesion and motility, cytokinesis, and gene expressions, all of which may be involved in the pathogenesis of arteriosclerosis. Rho-kinase is activated in animal models of PAH (monocrotaline and chronic hypoxia) associated with enhanced pulmonary vasoconstriction and proliferation, impaired endothelial vasodilator functions, and pulmonary remodeling. Therapeutic application of Rho-kinase inhibitors reverses established experimental pulmonary hypertension. Further, administration or inhalation of Rho-kinase inhibitors exerts acute pulmonary vasodilation in patients with PAH who were refractory to conventional therapies. Taken together, Rho-kinase is a novel and important therapeutic target of PAH, and Rho-kinase inhibitors are a promising new class of drugs for this fatal disorder.

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Acknowledgments

The authors’ works presented in this article were supported in part by the grants-in-aid from the Japanese Ministry of Education, Culture, Sports, Science, and Technology, Tokyo, Japan, grants-in-aid for Scientific Research on Innovative Areas (Research in a Proposed Research Area), MEXT, Japan, and Tohoku University Global COE for Conquest of Signal Transduction Diseases with Network Medicine, Sendai, Japan.

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan

    Yoshihiro Fukumoto & Hiroaki Shimokawa

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  1. Yoshihiro Fukumoto
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  2. Hiroaki Shimokawa
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Correspondence to Hiroaki Shimokawa .

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Editors and Affiliations

  1. Faculte´ de Me´decine, Univ Paris-Sud, Le Kremlin Bicêtre, France

    Marc Humbert

  2. Dep of Anasthesia and Critical Care, Harvard Medical School Massachusetts General Hospital, Boston, Massachusetts, USA

    Oleg V. Evgenov

  3. Cardiovascular Research, Bayer Pharma AG, Wuppertal, Germany

    Johannes-Peter Stasch

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Fukumoto, Y., Shimokawa, H. (2013). Rho-Kinase Inhibitors. In: Humbert, M., Evgenov, O., Stasch, JP. (eds) Pharmacotherapy of Pulmonary Hypertension. Handbook of Experimental Pharmacology, vol 218. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-38664-0_14

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