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KMID : 0811720060100000340
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Korean Journal of Physiology & Pharmacology
2006 Volume.10 No. 0 p.340 ~ p.0
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ESTIMATION FOR INVOLVEMENT OF Rho-ASSOCIATED KINASE IN ENDOTHELIN-1- INDUCED CONTRACTION IN RAT AORTIC SMOOTH MUSCLE
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Yamamura Takaki
Sakajiri Tetsuya
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Abstract
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In isolated rat aorta without endothelium, 100 nM endothelin-1 (ET-1) produced a long-lasting contraction corresponding to 116±6.1% (mean±S.D) of the contraction induced by 72.7 mM (high K+). In Ca2+-free solution or in the presence of the myosin light chain kinase (MLCK) inhibitor wortmannin (WM) of 10μM, 100 nM ET-1 evoked contraction of 26.9±5.5% or 23.2±6.0% of the high K+-induced contraction, respectively. The Ca2+-free- and WM-insensitive contractions were rapidly and completely inhibited by post-application of the Rho-associated kinase (Rho-kinase) inhibitor Y-27632 of 10μM. Pre-treatment with 10μM Y-27632 in the Ca2+-free solution or with combination of 10μM Y-27632 and 10μM WM entirely prevented the ET-1-induced contraction. In pre-treatment with only 10μM Y-27632, however, 100 nM ET-1 produced a contraction of 102±7.1% of the high K+-induced contraction at the peak, and then the contraction very slowly reversed to the basal level. The ET-1 (100 nM)-induced contraction in the normal salt solution was incompletely inhibited by the post-application of 10μM WM, leaving the contraction of approximately 10%. This remaining contraction was easily inhibited by 10μM Y-27632. The simultaneous post-application of 10μM WM and 10μM Y-27632 smoothly and completely inhibited the ET-1-induced contraction. These results suggest that the ET-1-induced contraction includes contraction due to MLC phosphorylation by Rho-associated kinase besides MLCK. The activator of adenylate cyclase forskolin of 0.1μM, which indirectly activates MLC phosphatase (MLCP), showed a little inhibitory effect on both the Ca2+-free-contraction and the WM-insensitive contraction, although this reagent completely inhibited the ET-1-induced contraction, but in a trailing contraction form last 13% to the basal level.
In conclusions: Rho-kinase is involved in ET-1-induced contraction of rat aorta by means of MLCP inhibition and MLC phosphorylation. Contribution of the MLC phosphorylation by Rho-kinase to the ET-1 (100 nM)-induced contraction was about 14% of the high K+-induced contraction, but as the MLCK activation pathway was inhibited, the MLC phosphorylation activity of Rho-kinase increased, resulting in the contraction of 23～26%. In the ET-1-induced contraction of rat aortic smooth muscle, when the Ca2+-calmodulin-dependent MLCK pathway normally functions, the contribution to the contraction by the MLC phosphorylation by Rho-kinase is considerably miner. However, this miner contraction was considerably resistant to forskolin. It is interesting that the contraction has how physiologically significant role in the ET-1-induced contraction.
Source: Korean J Physiol Pharmacol.2006 Oct;10(Suppl II):246
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KEYWORD
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endothelin-1, Rho-associated kinase, rat aortic smooth muscle, contraction
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