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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.
Author: Teixeira, Cleber E
Jin, Liming
Priviero, Fernanda B M
Ying, Zhekang
Webb, R Clinton
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 microM), phenylephrine (PE, 0.01-300 microM) 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 microM), Y-27632 (1-10 microM) or HA-1077 (10 microM). 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 microM). 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 microM), H-1152 (1 microM) and HA-1077 (10 microM). The expression of RhoA, RhoGDI, leukemia-associated RhoGEF (LARG) and p115RhoGEF was similar among the detrusor, trigone and urethra, whereas Rho-kinase alpha, Rho-kinase beta 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 Ca(2+) sensitization in the lower urinary tract.
Subject: 1-(5-isoquinolinesulfonyl)-2-methylpiperazine
Adenosine Triphosphate
Blotting, Western
Calcium Signaling
Dose-response Relationship, Drug
Electric Stimulation
Enzyme Inhibitors
Guanine Nucleotide Dissociation Inhibitors
In Vitro Techniques
Intracellular Signaling Peptides And Proteins
Muscle Contraction
Muscle, Smooth
Protein-serine-threonine Kinases
Rats, Sprague-dawley
Reverse Transcriptase Polymerase Chain Reaction
Urinary Bladder
Rho-associated Kinases
Rho-specific Guanine Nucleotide Dissociation Inhibitors
Rhoa Gtp-binding Protein
Citation: Biochemical Pharmacology. v. 74, n. 4, p. 647-58, 2007-Aug.
Rights: fechado
Identifier DOI: 10.1016/j.bcp.2007.06.004
Date Issue: 2007
Appears in Collections:Unicamp - Artigos e Outros Documentos

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