The Vasorelaxant Mechanisms of a Rho Kinase Inhibitor DL0805 in Rat Thoracic Aorta
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 iso...
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doaj-ccdaeea32eee4dbda5dd3e0d42c93e272020-11-24T21:13:51ZengMDPI AGMolecules1420-30492012-05-011755935594410.3390/molecules17055935The Vasorelaxant Mechanisms of a Rho Kinase Inhibitor DL0805 in Rat Thoracic AortaGuanhua DuLiping WangKun SiXiaozhen JiaoPing XieLili GongLianhua FangJianhao PengRho-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 N<sup>ω</sup>-nitro-L-arginine methyl ester, the guanylate cyclase inhibitor methylene blue and the cyclooxygenase inhibitor indomethacin. The voltage-dependent K<sup>+</sup> channel blocker 4-aminopyridine remarkably attenuated DL0805-induced relaxations. However, the ATP-sensitive K<sup>+</sup> channel blocker glibenclamide and Ca<sup>2+</sup>-activated K<sup>+</sup> 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<sup>+</sup> channels.http://www.mdpi.com/1420-3049/17/5/5935DL0805vasorelaxationRho kinaseaortaendotheliumnitric oxide |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Guanhua Du Liping Wang Kun Si Xiaozhen Jiao Ping Xie Lili Gong Lianhua Fang Jianhao Peng |
spellingShingle |
Guanhua Du Liping Wang Kun Si Xiaozhen Jiao Ping Xie Lili Gong Lianhua Fang Jianhao Peng The Vasorelaxant Mechanisms of a Rho Kinase Inhibitor DL0805 in Rat Thoracic Aorta Molecules DL0805 vasorelaxation Rho kinase aorta endothelium nitric oxide |
author_facet |
Guanhua Du Liping Wang Kun Si Xiaozhen Jiao Ping Xie Lili Gong Lianhua Fang Jianhao Peng |
author_sort |
Guanhua Du |
title |
The Vasorelaxant Mechanisms of a Rho Kinase Inhibitor DL0805 in Rat Thoracic Aorta |
title_short |
The Vasorelaxant Mechanisms of a Rho Kinase Inhibitor DL0805 in Rat Thoracic Aorta |
title_full |
The Vasorelaxant Mechanisms of a Rho Kinase Inhibitor DL0805 in Rat Thoracic Aorta |
title_fullStr |
The Vasorelaxant Mechanisms of a Rho Kinase Inhibitor DL0805 in Rat Thoracic Aorta |
title_full_unstemmed |
The Vasorelaxant Mechanisms of a Rho Kinase Inhibitor DL0805 in Rat Thoracic Aorta |
title_sort |
vasorelaxant mechanisms of a rho kinase inhibitor dl0805 in rat thoracic aorta |
publisher |
MDPI AG |
series |
Molecules |
issn |
1420-3049 |
publishDate |
2012-05-01 |
description |
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 N<sup>ω</sup>-nitro-L-arginine methyl ester, the guanylate cyclase inhibitor methylene blue and the cyclooxygenase inhibitor indomethacin. The voltage-dependent K<sup>+</sup> channel blocker 4-aminopyridine remarkably attenuated DL0805-induced relaxations. However, the ATP-sensitive K<sup>+</sup> channel blocker glibenclamide and Ca<sup>2+</sup>-activated K<sup>+</sup> 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<sup>+</sup> channels. |
topic |
DL0805 vasorelaxation Rho kinase aorta endothelium nitric oxide |
url |
http://www.mdpi.com/1420-3049/17/5/5935 |
work_keys_str_mv |
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