Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension

被引:2520
作者
Uehata, M [1 ]
Ishizaki, T [1 ]
Satoh, H [1 ]
Ono, T [1 ]
Kawahara, T [1 ]
Morishita, T [1 ]
Tamakawa, H [1 ]
Yamagami, K [1 ]
Inui, J [1 ]
Maekawa, M [1 ]
Narumiya, S [1 ]
机构
[1] KYOTO UNIV,FAC MED,DEPT PHARMACOL,KYOTO 60601,JAPAN
关键词
D O I
10.1038/40187
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Abnormal smooth-muscle contractility may be a major cause of disease states such as hypertension, and a smooth-muscle relaxant that modulates this process would be useful therapeutically. Smooth-muscle contraction is regulated by the cytosolic Ca2+ concentration and by the Ca2+ sensitivity of myofilaments(1): the former activates myosin light-chain kinase and the latter is achieved partly by inhibition of myosin phosphatase(1-3). The small GTPase Rho and its target, Rho-associated kinase, participate in this latter mechanism in vitro(4-6), but their participation has not been demonstrated in intact muscles. Here we show that a pyridine derivative, Y-27632, selectively inhibits smooth-muscle contraction by inhibiting Ca2+ sensitization. We identified the Y-27632 target as a Rho-associated protein kinase, p160ROCK(7). Y-27632 consistently suppresses Rho-induced, p160ROCK-mediated formation of stress fibres in cultured cells and dramatically corrects hypertension in several hypertensive rat models. Our findings indicate that p160ROCK-mediated Ca2+ sensitization is involved in the pathophysiology of hypertension and suggest that compounds that inhibit this process might be useful therapeutically.
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页码:990 / 994
页数:5
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