Acute Vasodilator Effect of Fasudil, a Rho-kinase Inhibitor, in Monocrotaline-Induced Pulmonary Hypertension in Rats

Abstract

Pulmonary arterial hypertension is a progressive and fatal disease for which Rho-kinase may be substantially involved. In this study, we examined the acute vasodilator effects of fasudil, a Rho-kinase inhibitor, in monocrotaline (MCT)-induced pulmonary hypertension (PH) in rats. Three weeks after a single subcutaneous injection of MCT (60 mg/kg), hemodynamic variables were measured under conscious and free-moving conditions before and after oral administration of fasudil. MCT caused a significant elevation of mean pulmonary arterial pressure (mPAP). Although a low dose of fasudil (3 mg/kg) had no effect on mPAP, a middle dose (10 mg/kg) caused a significant reduction in mPAP without change in mean systemic arterial pressure (mSAP), and a high dose (30 mg/kg) significantly reduced both mPAP and mSAP. Rho-kinase activity was significantly increased by MCT injection in pulmonary arteries but not in the aorta. Fasudil (10 mg/kg) inhibited only the Rho-kinase activity in pulmonary arteries without any effect in the aorta. Plasma concentration of hydroxyfasudil, a metabolite of fasudil, was within its clinical range in humans. These results demonstrate that fasudil exerts effective and selective vasodilatation of pulmonary arteries in rats with MCT-induced PH at a given dose, suggesting its usefulness for the treatment of the fatal disorder.

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

“…29, 54 In contrast, fasudil directly inhibits Rho-kinase through dephosphorylation of myosin phosphatase. 40 In the present study, we were able to demonstrate a significant inhibition of Rho-kinase activity in the PA by the combination therapy compared with each monotherapy. Thus, we propose additive and synergistic Rhokinase inhibition by the combination therapy with fasudil and sildenafil (Figure 7).…”

“…39 Fasudil suppresses Rho-kinase-mediated vasoconstriction by dephosphorylation of myosin phosphatase in PA of rats. 40 In addition, sildenafil increases the cGMP level through PDE5 inhibition and causes vasodilation of PA in rats. 41 In severe PH, increased pulmonary vascular resistance causes RV pressure overload and develops an imbalance between RV oxygen demand and supply, resulting in RV failure.…”

“…43, 44 Importantly, Rho-kinase activity is increased in most of the cardiovascular diseases, including myocardial ischemia and remodeling. 45 Rho-kinase inhibition by fasudil protects phatase, 40 and sildenafil causes relaxation by a cGMP-dependent mechanism. 29 Consistently, we demonstrated a significant inhibition of Rho-kinase-mediated MYPT phosphorylation by combination therapy with fasudil and sildenafil.…”

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

“…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.…”

Effect of All-Trans-Retinoic Acid on the Development of Chronic Hypoxia-Induced Pulmonary Hypertension

“…26 There is also evidence that Rho-kinase-mediated vasoconstriction contributes substantially to the increased pulmonary arterial pressure in the monocrotaline model. 27, 28 Hypoxia activates Rho-kinase in vascular smooth muscle and induces vasoconstriction. 29 In patients with PH, Rho-kinase activity is increased.…”