title: Mitochondrial nitric oxide synthase participates in septic shock myocardial depression by nitric oxide overproduction and mitochondrial permeability transition pore opening.
abstract: The aim of this study was to determine whether mitochondrial nitric oxide (NO) synthase (NOS) is involved in septic shock myocardial depression. The cecal ligation and puncture (CLP) method was used to induce septic shock. There was a significant depression of hemodynamic parameters recorded in the septic shock stage. After using nonselective NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME), inducible NOS inhibitor aminoguanidine (AMG), and neuronal NOS inhibitor 7-nitroindazole (7-NI), depression of the parameters was partly attenuated. Nitric oxide production in isolated cardiac mitochondria increased obviously in the CLP-septic shock stage, L-NAME and 7-NI both decreased NO production significantly. Nitrite/nitrate (NOx) production in the septic shock stage was much greater than those in the corresponding sham groups, and NOx production in the cytosol by inducible NOS was greater. Treatment with AMG suppressed NOx production in the cytosol by iNOS, whereas treatment with 7-NI decreased NOx production in the mitochondria. Mitochondrial NOS expression increased significantly in the septic shock stage, and its overexpression was attenuated using 7-NI. There was no significant decrease in the mitochondrial permeability transition pore measurement in the CLP-septic shock group, whereas a significant decrease was observed in those treated with L-NAME or 7-NI. These results indicate that overexpression of mitochondrial NOS is involved in myocardial depression.
authors: National Chengdu Center for Safety Evaluation of Drugs, West China Hospital of Sichuan University, Chengdu, China.
authors: Ce
authors: C
authors: Xu
authors: Chenju
authors: C
authors: Yi
authors: Huiping
authors: H
authors: Wang
authors: Iain C
authors: IC
authors: Bruce
authors: Qiang
authors: Q
authors: Xia
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007191:Indazoles / Q000494:pharmacology; D008297:Male; D008929:Mitochondria, Heart / Q000201:enzymology* / Q000473:pathology; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000378:metabolism* / Q000473:pathology
chemical_list: D004791:Enzyme Inhibitors; D007191:Indazoles; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D024101:Mitochondrial Proteins; D009124:Muscle Proteins; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; C080122:7-nitroindazole; D019331:NG-Nitroarginine Methyl Ester