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

Abstract

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.

Combination Therapy With Fasudil and Sildenafil Ameliorates Monocrotaline-Induced Pulmonary Hypertension and Survival in Rats

“…[13][14][15][16][17][18] Additionally, Rho-kinase causes VSMC proliferation, vascular contraction and remodeling by multiple mechanisms. 19, 20 We have previously demonstrated that Rho-kinase is substantially involved in the pathogenesis of pulmonary hypertension (PH) in animal models. 21-23 Indeed, Rho-kinase is an important therapeutic target in cardiovascular diseases, 14 and Rho-kinase inhibition ameliorates PH in animals and humans.…”

Recent Progress in the Management of Pulmonary Hypertension

“…5, 45 High altitude and infections should also be avoided because the former may produce hypoxic pulmonary vasoconstriction and the latter are fatal in some patients. 5 In general, pregnancy is also not recommended in young women with PAH, because of the high mortality. 3,5…”

“…4 PH is characterized by elevated PAP and increased pulmonary vascular resistance (PVR), frequently leading to right-sided heart failure (HF) and death. [4][5][6] The classification of PH has been recently updated 2 to include 5 major categories of the disorder ( Figure 1, Table 1). Group 1, pulmonary arterial hypertension (PAH), is a clinical condition defined as mean PAP ≥25 mmHg and pulmonary capillary wedge pressure (PCWP) ≤15 mmHg, which is characterized by the presence of pre-capillary PH in the absence of other causes of pre-capillary PH, such as PH because of lung diseases, chronic thromboembolic PH (CTEPH) or other rare diseases ( Figure 1, Table 1).…”

Hypertension Promotes Phosphorylation of Focal Adhesion Kinase and Proline-Rich Tyrosine Kinase 2 in Rats: Implication for the Pathogenesis of Hypertensive Vascular Disease

“…In hypertension, vascular remodeling can be induced by both elevated blood pressure and enhanced circulating humoral factors (Lehoux and Tedgui 1998;Fukumoto et al 2007). It has been shown that the mechanical stress generate intracellular signals through several growth factor receptors, ion-channels, cytoskeletons, all of which are the candidates of sensing mechanical stress and among them, integrins are important mechanosensors (Lehoux and Tedgui 1998;Li and Xu 2000;Ali and Schumacker 2002;Shyy and Chien 2002).…”