Document Type

Article

Publication Date

July 2006

Comments

This article has been peer reviewed. It is the authors' final version prior to publication in Gastroenterology 131(1): 108-116, July 2006. The final version is available at http://dx.doi.org/10.1053/j.gastro.2006.03.043, copyright © 2006 American Gastroenterological Association Institute.

Abstract

Background & Aims: An increase in Rho kinase (ROK) activity has been associated with the agonist-induced sustained contraction of the smooth muscle, but its role in the pathophysiology of spontaneously tonic smooth muscle is not known.

Methods: Present studies examined the effects of ROK inhibitor Y 27632 in the tonic smooth muscle of the rat internal anal sphincter (IAS) vs. in the flanking phasic smooth muscle of the rectum (RSM). In addition, studies were performed to determine the relationship between the decreases in the basal IAS tone vs. the ROK activity. Confocal microscopic studies determined the cellular distribution of smooth muscle predominant isoform of ROK (ROCK-II) in the smooth muscle cells (SMC).

Results: In in vitro studies using neurohumoral inhibitors and tetrodotoxin, and the use of SMC demonstrate direct relaxation of the IAS SMC by Y 27632. The ROK inhibitor was more potent in the IAS than the RSM. The IAS relaxation by Y 27632 correlated specifically with the decrease in ROK activity. Confocal microscopy revealed high levels of ROCK-II towards the periphery of the IAS SMC. In in vivo studies, the lower doses of Y 27632 caused a potent and selective fall in the IAS pressures (IASP) without any adverse cardiovascular systemic effects. The ROK inhibitor also caused potent relaxation of the hypertensive IAS.

Conclusions:
1). RhoA/ROK play a crucial role in the maintenance of the basal tone in the IAS; and
2). ROK inhibitors have a therapeutic potential in the IAS dysfunction characterized by the hypertensive IAS.

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