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.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / pharmacology*
  • Animals
  • Antihypertensive Agents / pharmacology*
  • COS Cells
  • Calcium / metabolism*
  • Cell Adhesion / drug effects
  • Enzyme Inhibitors / pharmacology
  • Guinea Pigs
  • Humans
  • Hypertension / drug therapy
  • Hypertension / enzymology
  • In Vitro Techniques
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Muscle Contraction / drug effects*
  • Muscle, Smooth, Vascular / drug effects*
  • Muscle, Smooth, Vascular / metabolism*
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Pyridines / pharmacology*
  • Rabbits
  • Radioligand Assay
  • Rats
  • Rats, Wistar
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Swine
  • rho-Associated Kinases

Substances

  • Amides
  • Antihypertensive Agents
  • Enzyme Inhibitors
  • Intracellular Signaling Peptides and Proteins
  • Pyridines
  • Recombinant Proteins
  • Y 27632
  • Protein-Serine-Threonine Kinases
  • rho-Associated Kinases
  • Calcium