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


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

1997-10

AUTHORS

M Uehata, T Ishizaki, H Satoh, T Ono, T Kawahara, T Morishita, H Tamakawa, K Yamagami, J Inui, M Maekawa, S Narumiya

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. More... »

PAGES

990-994

Journal

TITLE

Nature

ISSUE

6654

VOLUME

389

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/40187

    DOI

    http://dx.doi.org/10.1038/40187

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1014459412

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/9353125


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