Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension

Fukumoto, Yoshihiro; Matoba, Tetsuya; Ito, Akira; Tanaka, Hiroshi; Kishi, Takuya; Hayashidani, Shunji; Abe, Kohtaro; Takeshita, Akira; Shimokawa, Hiroaki

doi:10.1136/hrt.2003.029470

Cited by 270 publications

(200 citation statements)

References 5 publications

(2 reference statements)

Supporting

Mentioning

191

Contrasting

Unclassified

Order By: Relevance

“…Our findings are consistent with the results of previous clinical trials. The Rock inhibitor fasudil, which is approved in Japan and China for the treatment of cerebral vasospasms following surgery for subarachnoidal hemorrhage (7), has been well tolerated without major adverse events in Ͼ100,000 patients treated so far (9,(22)(23)(24)(25)(26).…”

Section: Discussionmentioning

confidence: 99%

Rho‐associated kinases are crucial for myofibroblast differentiation and production of extracellular matrix in scleroderma fibroblasts

Akhmetshina¹,

Dees²,

Pileckytė³

et al. 2008

Arthritis & Rheumatism

109

View full text Add to dashboard Cite

Conclusion. Our findings demonstrate that Rock potently stimulates the differentiation of resting fibroblasts into myofibroblasts and the production of ECM at biologically relevant concentrations without cell toxicity. These findings, along with the beneficial effects of Rock inhibition on vascular disease, indicate that inhibition of Rock might be an interesting novel therapeutic approach for the treatment of SSc.

show abstract

Section: Discussionmentioning

confidence: 99%

Rho‐associated kinases are crucial for myofibroblast differentiation and production of extracellular matrix in scleroderma fibroblasts

Akhmetshina¹,

Dees²,

Pileckytė³

et al. 2008

Arthritis & Rheumatism

109

View full text Add to dashboard Cite

show abstract

“…Third, the so-called "pleiotropic" effects of statins may be mediated, at least in part, by their inhibitory effects on Rho with a resultant inhibition on Rho-kinase (Takemoto and Liao 2001;Shimokawa 2000;Shimokawa and Takeshita 2005). Indeed, we were recently able to demonstrate the roles of the Rho-kinase pathway in the pathogenesis of PAH (Shimokawa 2002;Abe et al 2004;Fukumoto et al 2005;Abe et al 2006;Jiang et al 2007;Tawara et al 2007). In this article, we will briefly summarize the recent progress in the treatment of PAH, with a special reference to Rho-kinase inhibitors.…”

Section: Opedmentioning

confidence: 99%

“…Indeed, prostacyclin lacks direct inhibitory effects on Rho-kinase ) and the combination of oral prostacyclin analogue, beraprost, and a Rho-kinase inhibitor, fasudil, is more effective than each monotherapy for ameliorating monocrotaline-induced PH in rats ). Finally, we were recently able to demonstrate the acute beneficial effects of intravenous fasudil in patients with severe PAH without adverse effects (Fukumoto et al 2005).…”

Section: Potential Importance Of Rho-kinase Inhibitors For the Treatmmentioning

confidence: 99%

“…We have recently demonstrated that Rhokinase is a novel therapeutic target not only in ischemic heart disease and essential hypertension but also in PAH (Shimokawa 2002;Abe et al 2004;Fukumoto et al 2005;Abe et al 2006;Jiang et al 2006;Tawara et al 2007). Fasudil is a potent and selective inhibitor of Rho-kinase (Uehata et al 1997;Shimokawa et al 1999) with its inhibitory effect on Rho-kinase being 100 times and 1,000 times more potent than on protein kinase C and myosin light chain kinase, respectively (Shimokawa et al 1999;Shimokawa 2002;Shimokawa and Rashid 2007).…”

Section: Potential Importance Of Rho-kinase Inhibitors For the Treatmmentioning

confidence: 99%

See 1 more Smart Citation

Recent Progress in the Treatment of Pulmonary Arterial Hypertension: Expectation for Rho-Kinase Inhibitors

Tawara

Shimokawa

2007

Tohoku J. Exp. Med.

View full text Add to dashboard Cite

Pulmonary arterial hypertension (PAH) is a 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, vasodilators (e.g., prostaglandins, sildenafil, and bosentan), 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, we have demonstrated that Rhokinase-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 expression, all of which may be involved in the pathogenesis of arteriosclerosis. We also have recently demonstrated that Rho-kinase is activated in animal models of PAH with different etiologies (monocrotaline and chronic hypoxia) associated with enhanced pulmonary vasoconstricting and proliferating responses, impaired endothelial vasodilator functions, and pulmonary remodeling. Indeed, we were able to demonstrate that intravenous fasudil, a selective Rho-kinase inhibitor, exerts acute pulmonary vasodilator effects in patients with severe PAH who were refractory to conventional therapies. Taken together, our findings indicate that Rho-kinase is a novel and important therapeutic target of PAH in humans and that Rho-kinase inhibitors are a promising new class of drugs for the fatal disorder.pulmonary arterial hypertension; pulmonary arteriosclerosis; pulmonary arterial hyperconstriction; Rho-kinase © 2007 Tohoku University Medical Press Pulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure greater than 25 mmHg at rest or greater than 30 mmHg during exercise (Barst et al. 2004). Pulmonary arterial hypertension (PAH) is characterized by progressive elevation of pulmonary artery pressure and vascular resistance with poor prognosis (Barst et al.

show abstract

“…[115][116][117][118] ROCK inhibitors have been shown to decrease PA pressures and PVR both in experimental models of PH and in PAH patients. [119][120][121] The best-characterized action of ROCK is the phosphorylation of the myosin-binding subunit of myosin light chain phosphatase (MLCP), thereby inhibiting MLCP and thus increasing phosphorylation of myosin light chains, which serves to augment contraction. However, since ROCK inhibition also prevents ET-1-induced activation of NHE in normoxic settings, it is likely that the ET-1/ROCK pathway contributes to remodeling as well.…”

Section: Mechanisms Controlling Nhe1 Activity and Expression In Pasmcmentioning

confidence: 99%

Na⁺/H⁺ Exchange and Hypoxic Pulmonary Hypertension

Huetsch

Shimoda

2015

Pulm. circ.

View full text Add to dashboard Cite

Intracellular pH (pH i ) homeostasis is key to the functioning of vascular smooth muscle cells, including pulmonary artery smooth muscle cells (PASMCs). Sodium-hydrogen exchange (NHE) is an important contributor to pH i control in PASMCs. In this review, we examine the role of NHE in PASMC function, in both physiologic and pathologic conditions. In particular, we focus on the contribution of NHE to the PASMC response to hypoxia, considering both acute hypoxic pulmonary vasoconstriction and the development of pulmonary vascular remodeling and pulmonary hypertension in response to chronic hypoxia. Hypoxic pulmonary hypertension remains a disease with limited therapeutic options. Thus, this review explores past efforts at disrupting NHE signaling and discusses the therapeutic potential that such efforts may have in the field of pulmonary hypertension.

show abstract

Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension

Cited by 270 publications

References 5 publications

Rho‐associated kinases are crucial for myofibroblast differentiation and production of extracellular matrix in scleroderma fibroblasts

Rho‐associated kinases are crucial for myofibroblast differentiation and production of extracellular matrix in scleroderma fibroblasts

Recent Progress in the Treatment of Pulmonary Arterial Hypertension: Expectation for Rho-Kinase Inhibitors

Na⁺/H⁺ Exchange and Hypoxic Pulmonary Hypertension

Contact Info

Product

Resources

About

Acute vasodilator effects of a Rho-kinase inhibitor, fasudil, in patients with severe pulmonary hypertension

Cited by 270 publications

References 5 publications

Rho‐associated kinases are crucial for myofibroblast differentiation and production of extracellular matrix in scleroderma fibroblasts

Rho‐associated kinases are crucial for myofibroblast differentiation and production of extracellular matrix in scleroderma fibroblasts

Recent Progress in the Treatment of Pulmonary Arterial Hypertension: Expectation for Rho-Kinase Inhibitors

Na+/H+ Exchange and Hypoxic Pulmonary Hypertension

Contact Info

Product

Resources

About

Na⁺/H⁺ Exchange and Hypoxic Pulmonary Hypertension