Activation of MEK1/ERK1/2/iNOS/sGC/PKG pathway associated with peroxynitrite formation contributes to hypotension and vascular hyporeactivity in endotoxemic rats
| Autor: | A. Tuncay Demiryurek, Tuba Cuez, Seyhan Sahan-Firat, Belma Korkmaz, Kemal Buharalioglu, Bahar Tunctan |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Cancer Research Physiology Clinical Biochemistry MAP Kinase Kinase 1 Nitric Oxide Synthase Type II Receptors Cytoplasmic and Nuclear Aorta Thoracic Blood Pressure Pharmacology Biochemistry Nitric oxide Norepinephrine (medication) Norepinephrine chemistry.chemical_compound Soluble Guanylyl Cyclase Heart Rate Peroxynitrous Acid Cyclic GMP-Dependent Protein Kinases medicine Animals Enzyme Inhibitors Rats Wistar Protein kinase A Nitrites Mitogen-Activated Protein Kinase 3 Nitrotyrosine Vasodilator-stimulated phosphoprotein Endotoxemia Rats Endotoxins Enzyme Activation Oxidative Stress chemistry Guanylate Cyclase cardiovascular system Tyrosine Hypotension Soluble guanylyl cyclase cGMP-dependent protein kinase Peroxynitrite Signal Transduction medicine.drug |
| Zdroj: | Nitric Oxide. 24:160-172 |
| ISSN: | 1089-8603 |
| DOI: | 10.1016/j.niox.2011.02.004 |
| Popis: | Increased production of inducible nitric oxide (NO) synthase (iNOS)-derived NO contributes to fall in blood pressure and vascular reactivity during endotoxemia. We investigated whether an increase in protein expression and activity of the enzymes involved in mitogen-activated protein kinase kinase 1 (MEK1)/extracellular signal-regulated kinase 1/2 (ERK1/2)/iNOS/soluble guanylyl cyclase (sGC)/protein kinase G (PKG) pathway associated with peroxynitrite production would contribute to endotoxin-induced decrease in mean blood pressure (MAP) and vascular reactivity in rats. A selective iNOS inhibitor, 1,3-PBIT (10 mg/kg, i.p.), or a selective inhibitor ERK1/2 phosphorylation by MEK1, U0126 (5 mg/kg, i.p.), prevented endotoxin (10 mg/kg, i.p.)-induced decrease in MAP and vascular reactivity to norepinephrine (0.001–100 μM) in endothelium-intact and -denuded arteries associated with increased levels of nitrite (an index for NO production), cyclic GMP (an index for sGC activity), phosphorylated vasodilator stimulated phosphoprotein (an index for PKG activity), and nitrotyrosine (an index for peroxynitrite production). Endotoxin-induced increase in the phosphorylated MEK1 protein levels were not changed by 1,3-PBIT or U0126. U0126 prevented the endotoxin-induced increase in phosphorylated ERK1/2 and iNOS expressions. A selective sGC inhibitor, ODQ (3 μM), prevented the endotoxin-induced decrease in the Emax values and increase in the EC50 values of norepinephrine in endothelium-intact aortic rings isolated from endotoxemic rats in vitro. ODQ also reversed the effect of endotoxin on the increase in the EC50 values of norepinephrine in endothelium-denuded rings. A selective PKG inhibitor, KT5823 (1 μM), only prevented the endotoxin-induced decrease in the Emax values of norepinephrine in arteries with endothelium. These results suggest that activation of MEK1/ERK1/2 pathway leading to an increase in iNOS protein expression and NO production associated with an increase in sGC and PKG activity and peroxynitrite formation results in hypotension and vascular hyporeactivity in endotoxemic rats. However, further study is needed to confirm the involvement of PKG to the fall in vascular reactivity in the rat model of endotoxemia. |
| Databáze: | OpenAIRE |
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