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Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension | | M Uehata
; T Ishizaki
; H Satoh
; T Ono
; T Kawahara
; T Morishita
; H Tamakawa
; K Yamagami
; J Inui
; M Maekawa
; S Narumiya
; | | Date: |
30 Oct 1997 | | Journal: | Nature, 389 (6654), 990-4 | | 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. | | Source: | PubMed, pmid9353125 doi: 10.1038/40187 | | Services: | Forum | Review | Favorites | |
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