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The Vasorelaxant Mechanisms of a Rho Kinase Inhibitor DL0805 in Rat Thoracic Aorta
Beijing City Key Laboratory of Drug Target Identification and Drug Screening, State Key Laboratory for Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China
Beijing Chao-Yang Hospital affiliated with Beijing Capital Medical University, Beijing 100020, China
Department of Macromolecular Science and Engineering, Case Western Reserve University, Cleveland, OH 44106, USA
* Authors to whom correspondence should be addressed.
Received: 26 March 2012; in revised form: 11 May 2012 / Accepted: 11 May 2012 / Published: 18 May 2012
Abstract: Rho-kinase has been suggested as a potential therapeutic target in the treatment of cardiovascular diseases. The Rho-kinase signaling pathway is substantially involved in vascular contraction. The aim of the present study was to evaluate the vasorelaxant effects of Rho kinase inhibitor DL0805 in isolated rat aortic rings and to investigate its possible mechanism(s). It was found that DL0805 exerted vasorelaxation in a dose-dependent manner in NE or KCl-induced sustained contraction and partial loss of the vasorelaxation under endothelium-denuded rings. The DL0805-induced vasorelaxation was significantly reduced by the nitric oxide synthase inhibitor Nω-nitro-L-arginine methyl ester, the guanylate cyclase inhibitor methylene blue and the cyclooxygenase inhibitor indomethacin. The voltage-dependent K+ channel blocker 4-aminopyridine remarkably attenuated DL0805-induced relaxations. However, the ATP-sensitive K+ channel blocker glibenclamide and Ca2+-activated K+ channel blocker tetraethylammonium did not affect the DL0805-induced relaxation. In the endothelium-denuded rings, DL0805 also reduced NE-induced transient contraction and inhibited contraction induced by increasing external calcium. These findings suggested that DL0805 is a novel vasorelaxant compound associated with inhibition of Rho/ROCK signaling pathway. The NO-cGMP pathway may be involved in the relaxation of DL0805 in endothelium-intact aorta. The vasorelaxant effect of DL0805 is partially mediated by the opening of the voltage-dependent K+ channels.
Keywords: DL0805; vasorelaxation; Rho kinase; aorta; endothelium; nitric oxide
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MDPI and ACS Style
Gong, L.; Peng, J.; Fang, L.; Xie, P.; Si, K.; Jiao, X.; Wang, L.; Du, G. The Vasorelaxant Mechanisms of a Rho Kinase Inhibitor DL0805 in Rat Thoracic Aorta. Molecules 2012, 17, 5935-5944.
Gong L, Peng J, Fang L, Xie P, Si K, Jiao X, Wang L, Du G. The Vasorelaxant Mechanisms of a Rho Kinase Inhibitor DL0805 in Rat Thoracic Aorta. Molecules. 2012; 17(5):5935-5944.
Gong, Lili; Peng, Jianhao; Fang, Lianhua; Xie, Ping; Si, Kun; Jiao, Xiaozhen; Wang, Liping; Du, Guanhua. 2012. "The Vasorelaxant Mechanisms of a Rho Kinase Inhibitor DL0805 in Rat Thoracic Aorta." Molecules 17, no. 5: 5935-5944.