Attenuation of pulmonary hypertension secondary to left ventricular dysfunction in the rat by Rho-kinase inhibitor fasudil.

Abstract

Pulmonary hypertension (PH) in left ventricular dysfunction is attributable not only to backward failure of the left ventricle, but also to increased pulmonary vascular resistance (PVR) in some patients. Recently, Rho-kinase has been known as a potent growth stimulator and mediator of vasoconstriction, and Rho-kinase inhibitors could ameliorate PVR, little is known about the role of Rho-kinase in left ventricular dysfunction-induced PH. We utilized the ascending aortic-banded rat and assessed the effect of Rho-kinase inhibitor fasudil on the development of PH secondary to left ventricular dysfunction. Subsequently, in rats subjected to aortic banding for 6 weeks, there were increases in mean pulmonary arterial pressure, pulmonary arteriolar medial thickness, active RhoA, Rho-kinase II, Rho-kinase activity, endothelial nitric oxide synthase (eNOS) and endothelin-1(ET-1) concomitant with decreased levels in NO and cGMP in the lung. Treatment with fasudil at a dose of 30 mg/kg/day from days 1 to 28 or from days 29 to 42 decreased the mean pulmonary arterial pressure by 57% and 56%, right ventricular hypertrophy by 31% and 30%, pulmonary arteriolar medial thickness by 50% and 50%, and pulmonary expression of Rho-kinase II by 41% and 28%, respectively, as well as augmented pulmonary expression of eNOS by 16% and 31% and NO by 50% and 76%, respectively, when compared with the vehicle controls. In conclusion, these results suggest that inhibition of Rho-kinase may provide therapeutic potential for preventing and attenuating the development of PH in left ventricular dysfunction. Further translational study in human is needed to substantiate the findings.

• Authors: Zen-Kong Dai, Bin-Nan Wu, I-Chen Chen, Chee-Yin Chai, Jiunn-Ren Wu, Shah-Hwa Chou, Jwu-Lai Yeh, Ing-Jun Chen, Mian-Shin Tan
• Journal: Pediatric pulmonology (Pediatr Pulmonol) Vol. 46 Issue 1 Pg. 45-59 (Jan 2011) ISSN: 1099-0496 [Electronic] United States
• PMID: 20717937 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Wiley-Liss, Inc.

Chemical References

• Endothelin-1
• Protein Kinase Inhibitors
• Nitric Oxide
• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
• Nitric Oxide Synthase Type III
• rho-Associated Kinases
• Cyclic GMP
• fasudil

Topics

• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (analogs & derivatives, therapeutic use)
• Animals
• Arterioles (drug effects, metabolism)
• Cyclic GMP (metabolism)
• Endothelin-1 (metabolism)
• Hypertension, Pulmonary (drug therapy, etiology, physiopathology)
• Lung (drug effects, metabolism, pathology, physiopathology)
• Male
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type III (metabolism)
• Protein Kinase Inhibitors (therapeutic use)
• Pulmonary Artery (anatomy & histology, drug effects, metabolism, pathology, physiopathology)
• Rats
• Rats, Wistar
• Treatment Outcome
• Ventricular Dysfunction, Left (complications, physiopathology)
• rho-Associated Kinases (antagonists & inhibitors)