1. Academic Validation
  2. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension

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

  • Nature. 1997 Oct 30;389(6654):990-4. doi: 10.1038/40187.
M Uehata 1 T Ishizaki H Satoh T Ono T Kawahara T Morishita H Tamakawa K Yamagami J Inui M Maekawa S Narumiya
Affiliations

Affiliation

  • 1 Discovery Research (Tokyo), Yoshitomi Pharmaceutical Industries Ltd, Saitama, Japan. uehata@yoshitomi.co.jp
PMID: 9353125 DOI: 10.1038/40187
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 myofilaments: the former activates Myosin light-chain kinase and the latter is achieved partly by inhibition of myosin Phosphatase. The small GTPase Rho and its target, Rho-associated kinase, participate in this latter mechanism in vitro, 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. 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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