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ANESTHETIC PHARMACOLOGY

Rho-Kinase Inhibitors Augment the Inhibitory Effect of Propofol on Rat Bronchial Smooth Muscle Contraction

Motohiko Hanazaki, MD^*, Masataka Yokoyama, MD^*, Kiyoshi Morita, MD^*, Atsushi Kohjitani, DDS, Hiroyasu Sakai, PhD, Yoshihiko Chiba, PhD, and Miwa Misawa, PhD

From the Departments of *Anesthesiology and Resuscitology, and Dental Anesthesiology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; and Department of Pharmacology, School of Pharmacy, Hoshi University, Tokyo, Japan.

Address correspondence and reprint requests to Motohiko Hanazaki, MD, Department of Anesthesiology and Resuscitology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. Address e-mail to motohiko{at}hanazaki.com.

BACKGROUND: Airway smooth muscle contraction is not caused by the increase in intracellular Ca²⁺ ([Ca²⁺]_i) alone because agonist stimulation increases tension at the same [Ca²⁺]_i (increase in Ca²⁺ sensitivity). The small G protein RhoA and Rho-kinase (ROCK) play important roles in the regulation of Ca²⁺ 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-µL organ baths containing Krebs–Henseleit solution. After obtaining stable contraction with 30 µM acetylcholine, (1) propofol (1 µM–1 mM) was cumulatively applied; (2) cumulative doses of Y-27632 (0.01–300 µM), fasudil (0.01–100 µM), or H-1152 (0.01–100 µM) were applied; (3) propofol (1 µM–1 mM), with Y-27632, fasudil or H-1152 (0.03 µM or 0.1 µM), 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 µM Y-27632 and fasudil had no significant effect on the concentration–response curve for propofol, while 0.1 µM of both agents significantly shifted concentration–response curves to the left and decreased EC₅₀. H-1152 (both 0.03 µM and 0.1 µM) significantly sifted the concentration–response curve for propofol to the left and decreased EC₅₀.

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.