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|Type:||Artigo de periódico|
|Title:||Comparative pharmacological analysis of Rho-kinase inhibitors and identification of molecular components of Ca2+ sensitization in the rat lower urinary tract|
|Abstract:||We aimed to compare the expression and function of molecular components of the RhoA/ Rho-kinase signaling pathway in the contractile responses of detrusor, trigonal and urethral smooth muscle, using selective Rho-kinase inhibitors. Contractility studies and molecular approaches were employed to demonstrate the expression patterns and functional activity of the RhoA/Rho-kinase signaling pathway in the lower urinary tract. Frequency-response curves (1-32 Hz) and concentration-response curves (CRC) to carbachol (CCh, 0.01-30 mu M), phenylephrine (PE, 0.01-300 mu M) and endothelin-1 (ET-1, 0.01-100 nM) were significantly attenuated (p < 0.01) following incubation with the Rho-kinase inhibitors H-1152 (0.1-1 mu M), Y-27632 (1-10 mu M) or HA-1077 (10 mu M). Addition of Rho-kinase inhibitors also markedly reduced (p < 0.01) the contractions evoked by either KCl (80 mM) or alpha,beta-methylene ATP (alpha,beta-mATP, 10 mu M). Among the Rho-kinase inhibitors tested, H-1152 was approximately 9-16 times more potent than Y-27632 or HA-1077. In addition, basal tone of detrusor and trigonal strips was reduced following addition of Y-27632 (10 mu M), H-1152 (1 mu M) and HA-1077 (10 mu M). The expression of RhoA, RhoGDI, leukemia-associated RhoGEF (LARG) and p115RhoGEF was similar among the detrusor, trigone and urethra, whereas Rho-kinase a, Rho-kinase p and PDZ-RhoGEF protein levels were significantly lower in the urethra. Components of the RhoA/Rho-kinase signaling are expressed in detrusor, trigonal and urethral smooth muscle and dynamically regulate contraction and tone. Manipulation of RhoGEF expression may provide further understanding of mechanisms involving Ca2+ sensitization in the lower urinary tract. (C) 2007 Elsevier Inc. All rights reserved.|
|Editor:||Pergamon-elsevier Science Ltd|
|Appears in Collections:||Artigos e Materiais de Revistas Científicas - Unicamp|
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