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

Masayoshi Uehata (), Toshimasa Ishizaki, Hiroyuki Satoh, Takashi Ono, Toshio Kawahara, Tamami Morishita, Hiroki Tamakawa, Keiji Yamagami, Jun Inui, Midori Maekawa and Shuh Narumiya ()
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Masayoshi Uehata: Discovery Research (Tokyo), Yoshitomi Pharmaceutical Industries Ltd
Toshimasa Ishizaki: Faculty of Medicine, Kyoto University
Hiroyuki Satoh: Discovery Research (Tokyo), Yoshitomi Pharmaceutical Industries Ltd
Takashi Ono: Discovery Research (Tokyo), Yoshitomi Pharmaceutical Industries Ltd
Toshio Kawahara: Discovery Research (Tokyo), Yoshitomi Pharmaceutical Industries Ltd
Tamami Morishita: Discovery Research (Tokyo), Yoshitomi Pharmaceutical Industries Ltd
Hiroki Tamakawa: Discovery Research (Tokyo), Yoshitomi Pharmaceutical Industries Ltd
Keiji Yamagami: Discovery Research (Tokyo), Yoshitomi Pharmaceutical Industries Ltd
Jun Inui: Discovery Research (Tokyo), Yoshitomi Pharmaceutical Industries Ltd
Midori Maekawa: Discovery Research (Tokyo), Yoshitomi Pharmaceutical Industries Ltd
Shuh Narumiya: Faculty of Medicine, Kyoto University

Nature, 1997, vol. 389, issue 6654, 990-994

Abstract: Abstract 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 myofilaments1: the former activates myosin light-chain kinase and the latter is achieved partly by inhibition of myosin phosphatase1,2,3. The small GTPase Rho and its target, Rho-associated kinase, participate in this latter mechanism in vitro4,5,6, 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, p160ROCK7. 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.

Date: 1997
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DOI: 10.1038/40187

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