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Avril V Somlyo - One of the best experts on this subject based on the ideXlab platform.
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the effects of the rho kinase inhibitor y 27632 on arachidonic acid gtpγs and phorbol ester induced ca2 sensitization of smooth muscle
FEBS Letters, 1998Co-Authors: Xiaohong Fu, Ming C Gong, Avril V SomlyoAbstract:Abstract The effects of the Rho-kinase inhibitor, Y-27632 [1] on Ca2+-sensitization of force induced by arachidonic acid (AA), phorbol 12,13-dibutyrate (PDBu), GTPγS, and by the stable thromboxane analog, 9,11-dideoxy-9α,11α-methanoepoxy-PGF2α (U-46619), were determined in α-toxin-permeabilized smooth muscles. Y-27632 relaxed (up to 99%) Ca2+-sensitization by GTPγS (10 μM) and U-46619 (1 μM), but not by PDBu (20 μM), and reduced GTPγS-induced myosin light chain (MLC20) phosphorylation from 28% to 17% (P=0.002). GTPγS-induced force sensitization was inhibited by Y-27632 more potently when the inhibitor was added during the plateau of force than prior to stimulation. In α-toxin-permeabilized smooth muscle, Y-27632 inhibited AA (50 μM)-induced Ca2+-sensitization of force (by 66±1.3%) and reduced MLC20 phosphorylation. In contrast, Y-27632 did not relax force Ca2+-sensitized by AA in smooth muscle permeabilized with Triton X-100. We conclude that (i) AA induces Ca2+-sensitization through dual mechanisms, one mediated by Rho-kinase (or a related kinase), and (ii) Rho-kinase is not required for phorbol ester-induced Ca2+-sensitization.
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The effects of the Rho-kinase inhibitor Y-27632 on arachidonic acid-, GTPgammaS-, and phorbol ester-induced Ca2+-sensitization of smooth muscle.
FEBS letters, 1998Co-Authors: Ming C Gong, Avril V Somlyo, T JiaAbstract:The effects of the Rho-kinase inhibitor, Y-27632 [1] on Ca2+-sensitization of force induced by arachidonic acid (AA), phorbol 12,13-dibutyrate (PDBu), GTPgammaS, and by the stable thromboxane analog, 9,11-dideoxy-9alpha,11alpha-methanoepoxy-PGF2alpha (U-46619), were determined in alpha-toxin-permeabilized smooth muscles. Y-27632 relaxed (up to 99%) Ca2+-sensitization by GTPgammaS (10 microM) and U46619 (1 microM), but not by PDBu (20 microM), and reduced GTPgammaS-induced myosin light chain (MLC20) phosphorylation from 28% to 17% (P=0.002). GTPgammaS-induced force sensitization was inhibited by Y-27632 more potently when the inhibitor was added during the plateau of force than prior to stimulation. In alpha-toxin-permeabilized smooth muscle, Y-27632 inhibited AA (50 microM)-induced Ca2+-sensitization of force (by 66 +/- 1.3%) and reduced MLC20 phosphorylation. In contrast, Y-27632 did not relax force Ca2+-sensitized by AA in smooth muscle permeabilized with Triton X-100. We conclude that (i) AA induces Ca2+-sensitization through dual mechanisms, one mediated by Rho-kinase (or a related kinase), and (ii) Rho-kinase is not required for phorbol ester-induced Ca2+-sensitization.
Kenji Hashimoto - One of the best experts on this subject based on the ideXlab platform.
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Potentiation of nerve growth factor-induced neurite outgrowth by the ROCK inhibitor Y-27632: a possible role of IP₃ receptors.
European journal of pharmacology, 2010Co-Authors: Takahiko Minase, Tamaki Ishima, Kanako Itoh, Kenji HashimotoAbstract:ROCK, a serine/threonine protein kinase that has been identified as a Rho GTP-binding protein, is a promising target for neuropsychiatric disorders. The selective ROCK inhibitor Y-27632 has been shown to induce neurite outgrowth in PC12 cells. However, the precise cellular and molecular mechanisms underlying ROCK inhibition-induced neurite outgrowth are not fully understood. In this study, we examined the roles of cellular signaling pathways in the potentiation of nerve growth factor (NGF)-induced neurite outgrowth by Y-27632. Y-27632 significantly potentiated NGF (2.5 ng/ml)-induced neurite outgrowth in PC12 cells, in a concentration-dependent manner. Furthermore, another ROCK inhibitor, H-1152, and the Rho inhibitor botulinum exoenzyme C3 also potentiated NGF (2.5 ng/ml)-induced neurite outgrowth. The effects by Y-27632 were antagonized by co-administration of inositol 1,4,5-trisphosphate (IP(3)) receptor antagonists (xestospongin C or 2-aminoethoxydiphenylborate (2-APB)). Moreover, the potentiation by Y-27632 was blocked by co-administration of the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 or an Akt inhibitor. In contrast, the specific inhibitors of phospholipase C (PLC-γ), p38MAPK, c-Jun N-terminal kinase (JNK), and the Ras/Raf/mitogen-activated protein kinase (MAPK) signaling pathways did not affect the potentiation of NGF-induced neurite outgrowth by Y-27632. The results of double-staining immunocytochemistry suggested that both ROCK1 and type-1 IP₃ receptors may be co-localized in the cell body of PC12 cells. In conclusion, these findings suggest that IP₃ receptors and PI3K-Akt signaling pathways might be involved in the mechanisms of potentiation of NGF-induced neurite outgrowth by ROCK inhibitors.
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Potentiation of nerve growth factor-induced neurite outgrowth by the ROCK inhibitor Y-27632: A possible role of IP3 receptors
European Journal of Pharmacology, 2010Co-Authors: Takahiko Minase, Tamaki Ishima, Kanako Itoh, Kenji HashimotoAbstract:ROCK, a serine/threonine protein kinase that has been identified as a Rho GTP-binding protein, is a promising target for neuropsychiatric disorders. The selective ROCK inhibitor Y-27632 has been shown to induce neurite outgrowth in PC12 cells. However, the precise cellular and molecular mechanisms underlying ROCK inhibition-induced neurite outgrowth are not fully understood. In this study, we examined the roles of cellular signaling pathways in the potentiation of nerve growth factor (NGF)-induced neurite outgrowth by Y-27632. Y-27632 significantly potentiated NGF (2.5 ng/ml)-induced neurite outgrowth in PC12 cells, in a concentration-dependent manner. Furthermore, another ROCK inhibitor, H-1152, and the Rho inhibitor botulinum exoenzyme C3 also potentiated NGF (2.5 ng/ml)-induced neurite outgrowth. The effects by Y-27632 were antagonized by co-administration of inositol 1,4,5-trisphosphate (IP(3)) receptor antagonists (xestospongin C or 2-aminoethoxydiphenylborate (2-APB)). Moreover, the potentiation by Y-27632 was blocked by co-administration of the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 or an Akt inhibitor. In contrast, the specific inhibitors of phospholipase C (PLC-γ), p38MAPK, c-Jun N-terminal kinase (JNK), and the Ras/Raf/mitogen-activated protein kinase (MAPK) signaling pathways did not affect the potentiation of NGF-induced neurite outgrowth by Y-27632. The results of double-staining immunocytochemistry suggested that both ROCK1 and type-1 IP₃ receptors may be co-localized in the cell body of PC12 cells. In conclusion, these findings suggest that IP₃ receptors and PI3K-Akt signaling pathways might be involved in the mechanisms of potentiation of NGF-induced neurite outgrowth by ROCK inhibitors.
Takahiko Minase - One of the best experts on this subject based on the ideXlab platform.
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Potentiation of nerve growth factor-induced neurite outgrowth by the ROCK inhibitor Y-27632: a possible role of IP₃ receptors.
European journal of pharmacology, 2010Co-Authors: Takahiko Minase, Tamaki Ishima, Kanako Itoh, Kenji HashimotoAbstract:ROCK, a serine/threonine protein kinase that has been identified as a Rho GTP-binding protein, is a promising target for neuropsychiatric disorders. The selective ROCK inhibitor Y-27632 has been shown to induce neurite outgrowth in PC12 cells. However, the precise cellular and molecular mechanisms underlying ROCK inhibition-induced neurite outgrowth are not fully understood. In this study, we examined the roles of cellular signaling pathways in the potentiation of nerve growth factor (NGF)-induced neurite outgrowth by Y-27632. Y-27632 significantly potentiated NGF (2.5 ng/ml)-induced neurite outgrowth in PC12 cells, in a concentration-dependent manner. Furthermore, another ROCK inhibitor, H-1152, and the Rho inhibitor botulinum exoenzyme C3 also potentiated NGF (2.5 ng/ml)-induced neurite outgrowth. The effects by Y-27632 were antagonized by co-administration of inositol 1,4,5-trisphosphate (IP(3)) receptor antagonists (xestospongin C or 2-aminoethoxydiphenylborate (2-APB)). Moreover, the potentiation by Y-27632 was blocked by co-administration of the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 or an Akt inhibitor. In contrast, the specific inhibitors of phospholipase C (PLC-γ), p38MAPK, c-Jun N-terminal kinase (JNK), and the Ras/Raf/mitogen-activated protein kinase (MAPK) signaling pathways did not affect the potentiation of NGF-induced neurite outgrowth by Y-27632. The results of double-staining immunocytochemistry suggested that both ROCK1 and type-1 IP₃ receptors may be co-localized in the cell body of PC12 cells. In conclusion, these findings suggest that IP₃ receptors and PI3K-Akt signaling pathways might be involved in the mechanisms of potentiation of NGF-induced neurite outgrowth by ROCK inhibitors.
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Potentiation of nerve growth factor-induced neurite outgrowth by the ROCK inhibitor Y-27632: A possible role of IP3 receptors
European Journal of Pharmacology, 2010Co-Authors: Takahiko Minase, Tamaki Ishima, Kanako Itoh, Kenji HashimotoAbstract:ROCK, a serine/threonine protein kinase that has been identified as a Rho GTP-binding protein, is a promising target for neuropsychiatric disorders. The selective ROCK inhibitor Y-27632 has been shown to induce neurite outgrowth in PC12 cells. However, the precise cellular and molecular mechanisms underlying ROCK inhibition-induced neurite outgrowth are not fully understood. In this study, we examined the roles of cellular signaling pathways in the potentiation of nerve growth factor (NGF)-induced neurite outgrowth by Y-27632. Y-27632 significantly potentiated NGF (2.5 ng/ml)-induced neurite outgrowth in PC12 cells, in a concentration-dependent manner. Furthermore, another ROCK inhibitor, H-1152, and the Rho inhibitor botulinum exoenzyme C3 also potentiated NGF (2.5 ng/ml)-induced neurite outgrowth. The effects by Y-27632 were antagonized by co-administration of inositol 1,4,5-trisphosphate (IP(3)) receptor antagonists (xestospongin C or 2-aminoethoxydiphenylborate (2-APB)). Moreover, the potentiation by Y-27632 was blocked by co-administration of the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 or an Akt inhibitor. In contrast, the specific inhibitors of phospholipase C (PLC-γ), p38MAPK, c-Jun N-terminal kinase (JNK), and the Ras/Raf/mitogen-activated protein kinase (MAPK) signaling pathways did not affect the potentiation of NGF-induced neurite outgrowth by Y-27632. The results of double-staining immunocytochemistry suggested that both ROCK1 and type-1 IP₃ receptors may be co-localized in the cell body of PC12 cells. In conclusion, these findings suggest that IP₃ receptors and PI3K-Akt signaling pathways might be involved in the mechanisms of potentiation of NGF-induced neurite outgrowth by ROCK inhibitors.
Abdullah T. Demiryürek - One of the best experts on this subject based on the ideXlab platform.
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Protective effects of Y-27632 on acute dichlorvos poisoning in rats
The American journal of emergency medicine, 2010Co-Authors: Nurullah Gunay, Beril Kose, Seniz Demiryürek, Nurdan Ozlu Ceylan, Ibrahim Sari, Abdullah T. DemiryürekAbstract:Anticholinesterase poisoning is an important health problem in developing countries, and understanding of its underlying mechanisms is essential for the effective treatment. This study is designed to examine the effects of Y-27632, a selective Rho-kinase inhibitor, on organophosphate-induced cardiac toxicity and mortality in rats. Rats were randomly divided into 4 groups: control (corn oil), dichlorvos (30 mg/kg intraperitoneally), and 1- and 10-mg/kg Y-27632 + dichlorvos groups. After 6 hours of intraperitoneal injection, venous blood and cardiac samples were obtained, biochemical or immunohistochemical analyses were performed, and the intensity of muscle fasciculation was recorded. Serum cholinesterase activities were suppressed with dichlorvos, and these reductions were inhibited with Y-27632 pretreatment. Serum creatine kinase, creatine kinase-MB activities, and myoglobin and N-terminal probrain natriuretic peptide concentrations were not markedly affected with poisoning or Y-27632. Although serum nitric oxide concentrations did not change with dichlorvos, cardiac nitric oxide levels were markedly increased with Y-27632 pretreatment. Cardiac glutathione levels also increased with 1 mg/kg Y-27632. There was no staining for apoptosis, and immunohistochemical analyses of inducible nitric oxide synthase showed no change in cardiac tissue for all of the groups. Both doses of Y-27632 abolished mortality in rats with acute dichlorvos exposure (100% survival). These results show that administration of Rho-kinase inhibitor can produce protective effects against dichlorvos intoxication in rats. These findings may provide new possibilities for the treatment of organophosphate poisoning.
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Effects of a selective Rho-kinase inhibitor Y-27632 on oxidative stress parameters in acute dichlorvos poisoning in rats.
Cell biochemistry and function, 2008Co-Authors: Nurullah Gunay, Beril Kose, Seniz Demiryürek, Ali Rıza Ocak, Ozcan Erel, Abdullah T. DemiryürekAbstract: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.
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Effects of Y-27632, a selective Rho-kinase inhibitor, on myocardial preconditioning in anesthetized rats.
Biochemical pharmacology, 2005Co-Authors: Seniz Demiryürek, Ali F. Kara, Ahmet Celik, Mehmet Tarakcioglu, Cahit Bagci, Abdullah T. DemiryürekAbstract:The objective of this study was to examine the effects of Y-27632, a selective Rho-kinase inhibitor, on ischemic preconditioning (IP) and carbachol preconditioning (CP) in anesthetized rats. Administration of Y-27632 (0.1 mg/kg) produced slight, but not significant, reduction in mean arterial blood pressure and suppressed the total number of ventricular ectopic beats (VEBs). IP, induced by 5 min coronary artery occlusion and 5 min reperfusion, decreased the incidence of ventricular tachycardia (VT) from 100 (n = 30) to 25% (n = 24) and abolished the occurrence of ventricular fibrillation (VF) (40% in control group) during 30 min of ischemia. The incidences of VT and VF in Y-27632 + IP group were found to be similar to IP group. Carbachol (4 μg/kg/min for 5 min) induced marked depressions in mean arterial blood pressure, heart rate and attenuated the total number of VEBs, but significant reductions in VT and VF incidences were noted in Y-27632 + CP group. Y-27632 infusion for 5 min abolished VF occurrence. Marked reductions in plasma lactate levels were observed in all treatment and preconditioning groups. IP led to marked decrease in malondialdehyde levels. Decreases in infarct size were also observed with all groups when compared to control. These results suggest that infusion of Y-27632 was able to produce cardioprotective effects on myocardium against arrhythmias, infarct size or biochemical parameters and mimic the effects of ischemic preconditioning in anesthetized rats. Therefore, it is likely that inhibition of Rho-kinase is involved in the signaling cascade of myocardial preconditioning.
Akio Fujimura - One of the best experts on this subject based on the ideXlab platform.
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Partial protective effect of Y-27632, a Rho kinase inhibitor, against hepatic ischemia-reperfusion injury in rats.
European Journal of Pharmacology, 2004Co-Authors: Atsuhiro Kawaguchi, Masami Ohmori, Akio FujimuraAbstract:Abstract (+)-( R )- trans -4-(1-aminoethyl)- N -(4-pyridyl)-cyclohexanecarboxamide dihydrochloride (Y-27632), a Rho kinase inhibitor, has a suppressive effect on the functions of polymorphonuclear leukocytes. In this study, the influence of Y-27632 on ischemia–reperfusion injury of the liver was examined in rats. Y-27632 (3 mg/kg) or vehicle alone was intravenously injected into rats 60 min before occlusion. Blood samples were obtained for 48 h after reperfusion. At the end of the experiment, the hepatic content of myeloperoxidase, which reflects the number of polymorphonuclear leukocytes in liver tissues, was determined. The increases in serum hepatic aminotransferases and inflammatory cytokines [tumor necrosis factor-α (TNF-α), interleukin (IL)-6] after reperfusion were partially, but significantly, inhibited by Y-27632. The increased hepatic myeloperoxidase content was significantly lowered by Y-27632. These results suggest that Y-27632 has a partial protective effect against hepatic ischemia–reperfusion injury through the suppression of polymorphonuclear leukocytes and inflammatory cytokines.
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The effect of a Rho kinase inhibitor Y-27632 on superoxide production, aggregation and adhesion in human polymorphonuclear leukocytes.
European journal of pharmacology, 2000Co-Authors: Atsuhiro Kawaguchi, Masami Ohmori, Kazuhiro Harada, Shuichi Tsuruoka, Koh-ichi Sugimoto, Akio FujimuraAbstract:Abstract We investigated the involvement of p160ROCK (a Rho-associated coiled coil-forming protein kinase), one of Rho kinases on superoxide anion production (O 2 − production), aggregation and adhesion of human polymorphonuclear leukocytes under physiological condition, using a selective p160ROCK inhibitor, (+)-( R )- trans -4-(1-aminoethyl)- N -(4-pyridyl)cyclohexanecarboxamide (Y-27632). Y-27632 inhibited the O 2 − production stimulated by phorbol-12-myristate-13-acetate (PMA) in a dose-dependent manner. Stauroprorine blocked the PMA-induced O 2 − production while wortmannin did not. Y-27632 also inhibited the O 2 − production by guanosine 5′- O -(3-thiotriphosphate) (GTP γ S) 100 μM. N -formyl-Met-Leu-Phe (fMLP)-induced O 2 − production was not influenced by Y-27632, but was inhibited by wortmannin. The enhanced O 2 − production by Ca-ionophore A23817 and thapsigargin was not inhibited by Y-27632. Y-27632 did not change the basal intracellular Ca 2+ concentration nor its elevation stimulated by fMLP. Polymorphonuclear leukocytes aggregation induced by PMA was dose-dependently decreased by Y-27632 while their aggregation stimulated by fMLP was enhanced by the agent. Polymorphonuclear leukocytes adhesion induced by PMA or fMLP was not influenced by Y-27632. These results suggest that p160ROCK is involved in the PMA-induced O 2 − production and aggregation in human polymorphonuclear leukocytes. This kinase might locate in downstream of protein kinase C in polymorphonuclear leukocytes.
