Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension.
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.
Uehata
M
M
Discovery Research (Tokyo), Yoshitomi Pharmaceutical Industries Ltd, Saitama, Japan. uehata@yoshitomi.co.jp
Ishizaki
T
T
Satoh
H
H
Ono
T
T
Kawahara
T
T
Morishita
T
T
Tamakawa
H
H
Yamagami
K
K
Inui
J
J
Maekawa
M
M
Narumiya
S
S
D000577:Amides / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D019556:COS Cells; D002118:Calcium / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000201:enzymology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013552:Swine; D054460:rho-Associated Kinases
D000577:Amides; D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011725:Pyridines; D011994:Recombinant Proteins; C108830:Y 27632; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D002118:Calcium