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Rho-kinase Inhibitor (rho-kinase + inhibitor)
Selected AbstractsRhoA/ROK Pathway Related to the Mechanism of Higher Susceptibility to Spasm in RA Than in IMAJOURNAL OF CARDIAC SURGERY, Issue 6 2009Xia Kun M.D. Methods: RA, IMA, and GSV that would otherwise have been discarded were collected from 25 patients who underwent coronary artery bypass grafting. Eleven matched rings of RA, IMA, and GSV were used to evaluate the vasodilatory properties of 10,7,10,4 mol/l of fasudil, a Rho-kinase inhibitor, by using in vitro organ chambers. Another 14 matched RA, IMA, and GSV were used to demonstrate the immunohistochemistry (IHC) of RhoA and mRNA of RhoA and Rho kinase. Results: The maximal vasodilation of RA to fasudil was significantly greater than IMA. RhoA protein IHC staining was different in IMA, RA, and GSV (RA > GSV >IMA). The expression of RhoA and Rho kinase mRNA in the RA was significantly greater than in the IMA. Conclusions: The expression of RhoA/Rho kinase mRNA and protein and function in the RA were significantly stronger than in the IMA, suggesting that RhoA/Rho kinase pathway may be one mechanism by which RA is more susceptible to spasm than IMA. Rho kinase inhibitors can be effective drug candidates to prevent and treat vasospasm. [source] Expression of RhoA mRNA and activated RhoA in urothelium and smooth muscle, and effects of a rho-kinase inhibitor on contraction of the porcine urinary bladder,,NEUROUROLOGY AND URODYNAMICS, Issue 6 2009Kimihiro Nakanishi Abstract Aims To investigate the concentration and activity of RhoA in detrusor and urothelium, as well as the effects of a Rho-kinase inhibitor, Y-27632 {(+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride}, on contraction of the pig urinary bladder. Methods The concentration of RhoA mRNA was studied by the real-time RT-PCR and activated RhoA enzyme was studied by activation assay and Western blotting. In functional studies, the response to Y-27632 was examined in bladder strips with or without urothelium. Results The concentration of RhoA mRNA (n,=,38) and activated RhoA enzyme (n,=,19) were greater in urothelium than in detrusor. Tension decrease after administration of Y-27632 (1 nM to 100 µM) was significantly greater in tissues with urothelium than in tissues without urothelium, after pre-contraction with KCl (decrease by 52.0,±,4.6% vs. 28.0,±,6.8%, respectively; P,=,0.0088) or with carbachol (decrease by 53.1,±,7.2% vs. 30.6,±,5.8%, respectively; P,=,0.0035). Maximum contraction on CRC to carbachol was reduced significantly after administration of 3, 10, and 30 µM Y-27632 (to 72.2,±,6.8%, 43.9,±,7.1%, and 25.0,±,5.5%, respectively, of the control value) in strips with intact urothelium (n,=,36), but was reduced only at 10 and 30 µM (to 66.7,±,8.3% and 85.6,±,2.6%, respectively) in tissues without urothelium (n,=,20). Inhibitory effect of Y-27632 (3,30 µM) on the response to electrical field stimulation at 20 and 50 Hz was also greater in tissues with intact urothelium than in tissues without urothelium. Conclusions The concentration of RhoA mRNA and activated RhoA enzyme were greater in urothelium than in detrusor. Y-27632 showed a stronger inhibitory effect in detrusor with intact urothelium than in dose without urothelium. Neurourol. Urodyn. 28:521,528, 2009. © 2009 Wiley-Liss, Inc. [source] Chronic inflammatory demyelinating polyneuropathy sera inhibit axonal growth of mouse dorsal root ganglion neurons by activation of rho-kinase,ANNALS OF NEUROLOGY, Issue 5 2009Junko Taniguchi MS Clinical course and prognosis are variable among patients with chronic inflammatory demyelinating polyneuropathy (CIDP), whereas the extent of axonal degeneration is the major prognostic factor. We studied the effects of sera from CIDP patients on axonal growth in cultured mouse dorsal root ganglion neurons. Compared with control sera, CIDP sera prominently suppressed axonal outgrowth of dorsal root ganglion neurons and shortened axonal length. The inhibitory activity was abolished by adding Y27632, a Rho-kinase inhibitor. These findings suggest that CIDP sera inhibit axonal elongation by Rho-kinase activation, and some serum factors may be responsible for development of axonal degeneration in CIDP. Ann Neurol 2009;66:694,697 [source] Effects of a selective Rho-kinase inhibitor Y-27632 on oxidative stress parameters in acute dichlorvos poisoning in ratsCELL BIOCHEMISTRY AND FUNCTION, Issue 7 2008N. Gunay Abstract This study examined the effects of Y-27632, a selective Rho-kinase inhibitor, on organophosphate-induced acute toxicity in rats. Rats were randomly divided into four groups as control (corn oil), dichlorvos (30,mg,kg,1 i.p.), 1 and 10,mg,kg,1 Y-27632,+,dichlorvos groups. Cholinergic signs (fatigue, tremor, cyanosis, hyper-secretion, fasciculations) were observed in all the rats in the dichlorvos group and the mortality rate was 50%. No cholinergic findings and deaths were observed in the control and Y-27632 groups. Plasma cholinesterase activities were suppressed with dichlorvos and these reductions were attenuated with Y-27632 pretreatment. There was a marked increase in plasma malondialdehyde level in the dichlorvos group, but Y-27632 pretreatment abolished this elevation. Dichlorvos markedly depressed cardiac paraoxonase activity, but these changes were not markedly modified with Y-27632. Total antioxidant capacities, total oxidant status, oxidative stress index, total free sulfhydryl groups and catalase activities in plasma and cardiac tissues were not markedly different between the groups. No significant changes were observed with cardiac myeloperoxidase activities or plasma arylesterase and ceruloplasmin activities. In conclusion, our results suggest that Rho-kinase pathway is involved in organophosphate intoxication, and a decrease in cardiac paraoxonase activities may play a role in the pathogenesis of acute organophosphate poisoning in rats. Copyright © 2008 John Wiley & Sons, Ltd. [source] Roles of P2X receptors and Ca2+ sensitization in extracellular adenosine triphosphate-induced hyperresponsiveness in airway smooth muscleCLINICAL & EXPERIMENTAL ALLERGY, Issue 6 2007T. Oguma Summary Background The release of adenosine triphosphate (ATP) from the airway epithelial cells during the inflammatory process is considered to play an important role in the pathophysiology of asthma and chronic obstructive pulmonary disease. Objective This study was designed to determine whether extracellular ATP is involved in the bronchial hyperresponsiveness as an interaction between epithelium and smooth muscle in the airways. Methods We examined the contractile response to methacholine (MCh) before and after exposure to low concentrations (10 ,m) of ATP in isolated, epithelium-denuded guinea-pig tracheal smooth muscle by measuring isometric tension. Intracellular Ca2+ concentrations ([Ca2+]i) were assessed by fluorescent intensities of fura-2. Results MCh-induced contractile force was increased with no change in [Ca2+]i after exposure to 10 ,m ATP for 15 min. The ability of ATP to enhance the MCh-induced contraction was markedly attenuated by suramin, a non-selective P2 receptor inhibitor. Pre-incubation with ATP,S, a non-hydrolysable analogue of ATP and ,,,-meATP, a P2X agonist, also enhanced the MCh-induced contraction. In contrast, uracil triphosphate, a P2Y agonist, did not affect the MCh-induced contraction. Y-27632, a Rho-kinase inhibitor, suppressed the ability of ATP to enhance the MCh-induced contraction. Moreover, PP1 and PP2, Src tyrosin kinase inhibitors, suppressed the enhancement of MCh-induced contraction by ATP. Conclusion Pre-treatment with ATP induces hyperresponsiveness to MCh mediated by Ca2+ sensitization via the P2X receptor in airway smooth muscle. The present findings suggest the possible involvement of both the Rho-kinase and Src pathways in the intracellular mechanism of this phenomenon. [source] Expression of Rho-kinase and its functional role in the contractile activity of the mouse vas deferensBRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2003Kansu Büyükaf The effects of two Rho-kinase inhibitors, Y-27632 and fasudil, were investigated on the contractions produced by electrical field stimulation (EFS, 40 V, 1 mS, 2, 4, 8 and 16 Hz, for 20 s), KCl (30 , 60 mM), phenylephrine (Phe) (10,5 , 10,4M), adenosine-3,, 5,-triphosphate (ATP) (10,4 , 10,3M) and ,,, -methylene ATP (10,5M). EFS produced frequency-dependent reproducible contractile activity, which was almost abolished by guanethidine (10,5M, for 1 h). This contraction consisted of two components (a phasic initial contraction followed by a tonic one), and it was inhibited by Y-27632 and fasudil (both at 10,5M). However, these inhibitors had no effect on resting tension of the tissue. Contractions elicited by KCl (30 , 60 mM) were insensitive to guanethidine (10,5M, for 1 h), but suppressed by Y-27632 (10,5M) and fasudil (10,5M). In addition, the contractions induced by Phe (an ,1 -adrenoceptor agonist) and ATP (a purinergic agent) were inhibited significantly by Y-27632 (10,5M). Phasic contractions evoked by the selective P2X purinoceptor agonist ,,, -methylene ATP were also suppressed by Y-27632 (10,5M). Western blot analysis revealed that the mouse vas deferens expresses Rho-kinase (ROK,, ROCK-2 isoform) protein with a molecular weight of approximately 160 kDa. As a positive control, the presence of this protein was also shown in homogenates of smooth muscle from the rat mesenteric artery. In conclusion, Rho-kinase protein is expressed in the mouse vas deferens, and it mediates neurogenic contractile activity as well as the contractions induced by KCl, Phe, ATP and ,,, -methylene ATP. Owing to the suppressive effects of Rho-kinase inhibitors on the contractile activity of the vas deferens, the possibility that these compounds might impair ejaculation must be taken into account when considering them as potential agents in the treatment of erectile dysfunction. British Journal of Pharmacology (2003) 140, 743,749. doi:10.1038/sj.bjp.0705479 [source] Expression of RhoA mRNA and activated RhoA in urothelium and smooth muscle, and effects of a rho-kinase inhibitor on contraction of the porcine urinary bladder,,NEUROUROLOGY AND URODYNAMICS, Issue 6 2009Kimihiro Nakanishi Abstract Aims To investigate the concentration and activity of RhoA in detrusor and urothelium, as well as the effects of a Rho-kinase inhibitor, Y-27632 {(+)-(R)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride}, on contraction of the pig urinary bladder. Methods The concentration of RhoA mRNA was studied by the real-time RT-PCR and activated RhoA enzyme was studied by activation assay and Western blotting. In functional studies, the response to Y-27632 was examined in bladder strips with or without urothelium. Results The concentration of RhoA mRNA (n,=,38) and activated RhoA enzyme (n,=,19) were greater in urothelium than in detrusor. Tension decrease after administration of Y-27632 (1 nM to 100 µM) was significantly greater in tissues with urothelium than in tissues without urothelium, after pre-contraction with KCl (decrease by 52.0,±,4.6% vs. 28.0,±,6.8%, respectively; P,=,0.0088) or with carbachol (decrease by 53.1,±,7.2% vs. 30.6,±,5.8%, respectively; P,=,0.0035). Maximum contraction on CRC to carbachol was reduced significantly after administration of 3, 10, and 30 µM Y-27632 (to 72.2,±,6.8%, 43.9,±,7.1%, and 25.0,±,5.5%, respectively, of the control value) in strips with intact urothelium (n,=,36), but was reduced only at 10 and 30 µM (to 66.7,±,8.3% and 85.6,±,2.6%, respectively) in tissues without urothelium (n,=,20). Inhibitory effect of Y-27632 (3,30 µM) on the response to electrical field stimulation at 20 and 50 Hz was also greater in tissues with intact urothelium than in tissues without urothelium. Conclusions The concentration of RhoA mRNA and activated RhoA enzyme were greater in urothelium than in detrusor. Y-27632 showed a stronger inhibitory effect in detrusor with intact urothelium than in dose without urothelium. Neurourol. Urodyn. 28:521,528, 2009. © 2009 Wiley-Liss, Inc. [source] | ||||||||||