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KMID : 0811720060100000340
Korean Journal of Physiology & Pharmacology
2006 Volume.10 No. 0 p.340 ~ p.0
ESTIMATION FOR INVOLVEMENT OF Rho-ASSOCIATED KINASE IN ENDOTHELIN-1- INDUCED CONTRACTION IN RAT AORTIC SMOOTH MUSCLE
Yamamura Takaki

Sakajiri Tetsuya
Abstract
In isolated rat aorta without endothelium, 100 nM endothelin-1 (ET-1) produced a long-lasting contraction corresponding to 116¡¾6.1% (mean¡¾S.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 10¥ìM, 100 nM ET-1 evoked contraction of 26.9¡¾5.5% or 23.2¡¾6.0% 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 10¥ìM. Pre-treatment with 10¥ìM Y-27632 in the Ca2+-free solution or with combination of 10¥ìM Y-27632 and 10¥ìM WM entirely prevented the ET-1-induced contraction. In pre-treatment with only 10¥ìM Y-27632, however, 100 nM ET-1 produced a contraction of 102¡¾7.1% 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 10¥ìM WM, leaving the contraction of approximately 10%. This remaining contraction was easily inhibited by 10¥ìM Y-27632. The simultaneous post-application of 10¥ìM WM and 10¥ìM 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 0.1¥ìM, 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
KEYWORD
endothelin-1, Rho-associated kinase, rat aortic smooth muscle, contraction
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