Long-Term Treatment With a Rho-Kinase Inhibitor Improves Monocrotaline-Induced Fatal Pulmonary Hypertension in Rats

• Published in: Circulation research 2004-02, Vol.94 (3), p.385-393
• Main Authors: Abe, Kohtaro, Shimokawa, Hiroaki, Morikawa, Keiko, Uwatoku, Toyokazu, Oi, Keiji, Matsumoto, Yasuharu, Hattori, Tsuyoshi, Nakashima, Yutaka, Kaibuchi, Kozo, Sueishi, Katsuo, Takeshit, Akira
• Format: Article
• Language: English
• Subjects: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - analogs & derivatives; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - blood; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - metabolism; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - pharmacology; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine - therapeutic use; Animals; Biological and medical sciences; Dose-Response Relationship, Drug; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiopathology; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Fundamental and applied biological sciences. Psychology; Hypertension, Pulmonary - chemically induced; Hypertension, Pulmonary - mortality; Hypertension, Pulmonary - prevention & control; Hypertrophy, Right Ventricular - physiopathology; Hypertrophy, Right Ventricular - prevention & control; Intracellular Signaling Peptides and Proteins; Male; Medical sciences; Monocrotaline; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - pathology; Muscle, Smooth, Vascular - physiopathology; Pneumology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Pulmonary Artery - drug effects; Pulmonary Artery - pathology; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Rats; Rats, Sprague-Dawley; rho-Associated Kinases; Survival Rate; Time Factors; Vertebrates: cardiovascular system
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.RES.0000111804.34509.94

ABSTRACT—Primary pulmonary hypertension is a fatal disease characterized by endothelial dysfunction, hypercontraction and proliferation of vascular smooth muscle cells (VSMCs), and migration of inflammatory cells, for which no satisfactory treatment has yet been developed. We have recently demonstrated that intracellular signaling pathway mediated by Rho-kinase, an effector of the small GTPase Rho, is involved in the pathogenesis of arteriosclerosis. In the present study, we examined whether the Rho-kinase–mediated pathway is also involved in the pathogenesis of fatal pulmonary hypertension in rats. Animals received a subcutaneous injection of monocrotaline, which resulted in the development of severe pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular lesions in 3 weeks associated with subsequent high mortality rate. The long-term blockade of Rho-kinase with fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil after oral administration, markedly improved survival when started concomitantly with monocrotaline and even when started after development of pulmonary hypertension. The fasudil treatment improved pulmonary hypertension, right ventricular hypertrophy, and pulmonary vascular lesions with suppression of VSMC proliferation and macrophage infiltration, enhanced VSMC apoptosis, and amelioration of endothelial dysfunction and VSMC hypercontraction. These results indicate that Rho-kinase–mediated pathway is substantially involved in the pathogenesis of pulmonary hypertension, suggesting that the molecule could be a novel therapeutic target for the fatal disorder.