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

• Published in: Nature (London) Vol. 389; no. 6654; pp. 990 - 994
• Main Authors: Uehata, Masayoshi, Narumiya, Shuh, Ishizaki, Toshimasa, Satoh, Hiroyuki, Ono, Takashi, Kawahara, Toshio, Morishita, Tamami, Tamakawa, Hiroki, Yamagami, Keiji, Inui, Jun, Maekawa, Midori
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 30.10.1997; Nature Publishing Group
• Subjects: Amides - pharmacology; Animals; Antihypertensive agents; Antihypertensive Agents - pharmacology; Biological and medical sciences; Calcium; Calcium - metabolism; Cardiovascular system; Cell Adhesion - drug effects; COS Cells; Enzyme Inhibitors - pharmacology; Guinea Pigs; Humans; Hypertension; Hypertension - drug therapy; Hypertension - enzymology; In Vitro Techniques; Intracellular Signaling Peptides and Proteins; Male; Medical sciences; Muscle Contraction - drug effects; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Muscles; Muscular system; Pharmacology. Drug treatments; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Proteins; Pyridines - pharmacology; Rabbits; Radioligand Assay; Rats; Rats, Wistar; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; rho-Associated Kinases; Swine; Rat; Isozyme; Cardiovascular disease; Molecular interaction; Smooth muscle; Pyridine derivatives; Calcium ion; Blood vessel; Aorta; Mechanism of action; Hypertension; Enzyme; Transferases; Rodentia; Oral administration; In vitro; In vivo; Vertebrata; Chemotherapy; Biological fixation; Mammalia; Treatment; Protein kinase; Animal; Antihypertensive agent
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/40187

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.