Rho-kinase inhibitors augment the inhibitory effect of propofol on rat bronchial smooth muscle contraction.
BACKGROUND
Airway smooth muscle contraction is not caused by the increase in intracellular Ca(2+) ([Ca(2+)](i)) alone because agonist stimulation increases tension at the same [Ca(2+)](i) (increase in Ca(2+) sensitivity). The small G protein Rho A and Rho-kinase (ROCK) play important roles in the regulation of Ca(2+) sensitivity. In this study, we investigated the effects of three ROCK inhibitors (fasudil, Y-27632, and H-1152) on rat airway smooth muscle contraction and the effects of ROCK inhibitors on propofol-induced bronchodilatory effects.


METHODS
Ring strips from intrapulmonary bronchus of male Wistar rats were placed in 400-microL organ baths containing Krebs-Henseleit solution. After obtaining stable contraction with 30 microM acetylcholine, (1) propofol (1 microM-1 mM) was cumulatively applied; (2) cumulative doses of Y-27632 (0.01-300 microM), fasudil (0.01-100 microM), or H-1152 (0.01-100 microM) were applied; (3) propofol (1 microM-1 mM), with Y-27632, fasudil or H-1152 (0.03 microM or 0.1 microM), was cumulatively applied.


RESULTS
(1) Propofol produced concentration-dependent relaxation of rat bronchial smooth muscle. (2) All ROCK inhibitors produced concentration-dependent relaxation. (3) 0.03 microM Y-27632 and fasudil had no significant effect on the concentration-response curve for propofol, while 0.1 microM of both agents significantly shifted concentration-response curves to the left and decreased EC(50). H-1152 (both 0.03 microM and 0.1 microM) significantly sifted the concentration-response curve for propofol to the left and decreased EC(50).


CONCLUSIONS
ROCK inhibitors, especially H-1152, can attenuate the contraction of rat airway smooth muscle. The combined use of ROCK inhibitors and propofol causes greater relaxation.
Hanazaki
Motohiko
M
Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. motohiko@hanazaki.com
Yokoyama
Masataka
M
Morita
Kiyoshi
K
Kohjitani
Atsushi
A
Sakai
Hiroyasu
H
Chiba
Yoshihiko
Y
Misawa
Miwa
M
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000577:Amides / Q000494:pharmacology; D000818:Animals; D001980:Bronchi / Q000187:drug effects* / Q000201:enzymology; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D001993:Bronchodilator Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000201:enzymology; D015742:Propofol / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
C459092:2-methyl-1-((4-methyl-5-isoquinolinyl)sulfonyl)homopiperazine; D000577:Amides; D016085:Bronchoconstrictor Agents; D001993:Bronchodilator Agents; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C108830:Y 27632; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D054460:rho-Associated Kinases; D000109:Acetylcholine; C049347:fasudil; D015742:Propofol