HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 294/3/G687    most recent 00501.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Rattan, S. Articles by Patel, C. A. Search for Related Content PubMed PubMed Citation Articles by Rattan, S. Articles by Patel, C. A.

HORMONES AND SIGNALING

Selectivity of ROCK inhibitors in the spontaneously tonic smooth muscle

Division of Gastroenterology and Hepatology, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania

Submitted 30 October 2007 ; accepted in final form 6 January 2008

The selectivity of different Rho kinase (ROCK) inhibitors in the spontaneously tonic smooth muscle has not been investigated. We examined this issue using Y-27632 [(R)-(+)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarbox anecarboxamide, 2HCl], H-1152 [(S)-(+)-(2-methyl-5-isoquinolinyl) sulfonylhomopiperazine, 2HCl], HA-1077 [(5 isoquinolinesulfonyl) homopiperazine, 2HCl], and ROCK inhibitor II [N-(4-pyridyl)-N'-(2,4,6-trichlorophenyl)urea]. We compared these inhibitors in the spontaneously tonic smooth muscle of the internal anal sphincter (IAS). ROCK, protein kinase C (PKC), and myosin light chain kinase (MLCK) activities were determined in the IAS, before and after different ROCK inhibitors. Y-27632 and H-1152 were 30-fold more potent in the IAS (IC₅₀: 4.4 x 10^–7 and 7.9 x 10^–8 M, respectively) vs. the phasic rectal smooth muscle (RSM) (IC₅₀: 1.3 x 10^–5 and 2.5 x 10^–6 M, respectively). HA-1077 and ROCK inhibitor II were equipotent in the IAS vs. RSM. In the IAS, H-1152 was the most potent whereas ROCK inhibitor II is the least. Y-27632 and H-1152 caused concentration-dependent decrease in the IAS tone that correlates directly with the decreases in ROCK activity, without significant effect in the PKC and MLCK activities. This specifically selective correlation between ROCK activity and decrease in the IAS tone was absent in the case of HA-1077 and ROCK inhibitor II, which also inhibited PKC and MLCK. We conclude that the IAS tone is critically dependent on ROCK activity, and H-1152 and Y-27632 are the most selective and potent ROCK inhibitors in the IAS.

spontaneously tonic smooth muscle; phasic smooth muscle; protein kinase C; myosin light chain kinase

This article has been cited by other articles:

				C. Camello-Almaraz, B. Macias, P. J. Gomez-Pinilla, S. Alcon, F. E. Martin-Cano, A. Baba, T. Matsuda, P. J. Camello, and M. J. Pozo Developmental changes in Ca2+ homeostasis and contractility in gallbladder smooth muscle Am J Physiol Cell Physiol, April 1, 2009; 296(4): C783 - C791. [Abstract] [Full Text] [PDF]

				P. Tourneux, M. Chester, T. Grover, and S. H. Abman Fasudil inhibits the myogenic response in the fetal pulmonary circulation Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1505 - H1513. [Abstract] [Full Text] [PDF]

				U. Rescher, C. Ludwig, V. Konietzko, A. Kharitonenkov, and V. Gerke Tyrosine phosphorylation of annexin A2 regulates Rho-mediated actin rearrangement and cell adhesion J. Cell Sci., July 1, 2008; 121(13): 2177 - 2185. [Abstract] [Full Text] [PDF]