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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Masayoshi Uehata & Toshimasa Ishizaki & Hiroyuki Satoh & Takashi Ono & Toshio Kawahara & Tamami Morishita & Hiroki Tamakawa & Keiji Yamagami & Jun Inui & Midori Maekawa & Shuh Narumiya, 1997. "Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension," Nature, Nature, vol. 389(6654), pages 990-994, October.
  • Handle: RePEc:nat:nature:v:389:y:1997:i:6654:d:10.1038_40187
    DOI: 10.1038/40187
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    Cited by:

    1. Ying Yang & Pekka Paivinen & Chang Xie & Alexis Leigh Krup & Tomi P. Makela & Keith E. Mostov & Jeremy F. Reiter, 2021. "Ciliary Hedgehog signaling patterns the digestive system to generate mechanical forces driving elongation," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    2. Béla Horváth & Gábor Lenzsér & Balázs Benyó & Tamás Németh & Rita Benkő & András Iring & Péter Hermán & Katalin Komjáti & Zsombor Lacza & Péter Sándor & Zoltán Benyó, 2010. "Hypersensitivity to Thromboxane Receptor Mediated Cerebral Vasomotion and CBF Oscillations during Acute NO-Deficiency in Rats," PLOS ONE, Public Library of Science, vol. 5(12), pages 1-6, December.
    3. Kei Yamamoto & Haruko Miura & Motohiko Ishida & Yusuke Mii & Noriyuki Kinoshita & Shinji Takada & Naoto Ueno & Satoshi Sawai & Yohei Kondo & Kazuhiro Aoki, 2021. "Optogenetic relaxation of actomyosin contractility uncovers mechanistic roles of cortical tension during cytokinesis," Nature Communications, Nature, vol. 12(1), pages 1-13, December.

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