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The Protection of Dantrolene on Myocardial Ischemia-reperfusion Injury in Rats

Author: ZhaoXiaoLi
Tutor: YuGongYuan
School: Tianjin Medical University
Course: Biochemistry and Molecular Biology
Keywords: Myocardial ischemia Reperfusion injury Energy metabolism Dantrolene
CLC: R965
Type: Master's thesis
Year: 2011
Downloads: 37
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Abstract

Objective: To investigate the protective effect of dantrolene on ischemic reperfusion myocardial injury. Concept Chadan sertraline ischemia-reperfusion myocardial infarct size, LDH activity, hemodynamic changes to evaluate the degree of myocardial damage; detection of myocardial cells in high-energy phosphate compounds, purine metabolites adenosine, inosine, xanthine, hypoxanthine, changes in the levels of uric acid and purine nucleotide metabolic pathway enzymes: 5'-nucleotidase (5'-nucleotidase, 5'-NT), adenosine deaminase (adenosine deaminase ADA) purine nucleoside phosphorylase (purine nucleoside phosphorylase, PNP) and xanthine oxidase (xanthine oxidase, XO) and the purine salvage pathway the key enzymes: hypoxanthine (guanine) phosphoribosyl transferase (HGPRT) and adenine phosphoribosyl transferase (APRT) activity changes, to study the effects of dantrolene on ischemia-reperfusion myocardial energy metabolism. Methods: 72 healthy male Wistar rats (n = 72) were randomly divided into three groups: control group, ischemia-reperfusion group and dantrolene treated, Langendorff isolated heart perfusion model. Each group are first perfused with Krebs solution balance 30min normal control group continued perfusion 90min ischemia-reperfusion group balance 30min after global ischemia 30min reperfusion 60min; the dantrolene treatment group Krebs solution gradually the amount Jiaru Dan song forest, the circulation system of the final concentration of 5μmol / L, and then ischemia 30min reperfusion 60min. Determination of dantrolene different concentrations, heart rate, aortic flow, coronary flow and cardiac output changes; HPLC detection of myocardial tissue high-energy phosphate compounds, purine metabolites content and nucleotide metabolism pathway enzyme activity the change; the ultraviolet spectroscopy detection perfusate LDH activity; tetrazolium chloride (TTC) staining observed myocardial infarct size after reperfusion. Results: 1. Affect its myocardial protective effect of dantrolene on cardiac hemodynamics: Dantrolene reduces ischemia-reperfusion myocardial infarct size (P lt; 0.05) of LDH release was significantly reduced (P lt; 0.01 ). Dantrolene on cardiac ischemia-reperfusion hemodynamic no apparent effect, just slight increase coronary flow (P lt; 0.05). Dantrolene on ischemic reperfusion myocardial energy metabolism of dantrolene treatment group of high-energy phosphate compounds content was significantly higher than the ischemia-reperfusion group (P lt; 0.05). The dantrolene infusion after release of purine metabolites were significantly lower (P lt; 0.05). Dantrolene purine nucleotide metabolic pathways and remedial synthesis pathway activity the dantrolene treatment group compared with the ischemia-reperfusion group, 5'-nucleotidase, adenosine deaminase, xanthine oxidase activity were significantly increased (P lt; 0.05), purine nucleoside phosphorylase activity was significantly decreased (P lt; 0.05). HGPRT and APRT activity of dantrolene treatment group was significantly lower than the ischemia-reperfusion group (P lt; 0.05). Conclusion: 1. Dantrolene significantly delayed myocardial ischemic reperfusion injury. Dantrolene myocardial ischemia-reperfusion the apparent hemodynamic effects, only a slight increase in coronary blood flow. Dantrolene has a negative inotropic effect, but also have a protective effect on myocardial unclear. Energy depletion is the originating factor of myocardial ischemia-reperfusion injury, myocardial contraction depends on the trigger RyR channels in the sarcoplasmic reticulum terminal pool open Ca2 flow from the extracellular space, cytoplasm increased activation of Ca2 contractile system. ATP synthesis blocked due to myocardial ischemia, as well as the Ca2 overload leads to myocardial contracture excessive, exacerbating ATP depletion. Dantrolene inhibition of Ca2 release, reducing Ca2 overload, reducing myocardial two main enzymes: myosin ATP enzyme and sarcoplasmic reticulum Ca2 ATP activity, ATP consumption is reduced to ease the heart from excessive contracture promote ischemia reperfusion myocardial energy recovery. Due to myocardial ischemia, purine nucleotide degradation followed by ATP-ADP-AMP-adenosine - inosine - hypoxanthine - xanthine - uric acid, uric acid is the end product. Ischemia reperfusion leads to the accumulation of various substrates, the purine metabolites increase that purine nucleotide degradation accelerated, ATP resynthesis reduce the. The dantrolene reduce the purine metabolites content (P lt; 0.05), suggesting that dantrolene to facilitate the recovery of the purine metabolism. Myocardial ischemia reperfusion a significant feature of Ca2 overload. Ca2 overloading activated calpains -1, caused by the degradation of the proteins and cytoskeletal proteins of the composition of the myocardial fibers, resulting in myocardial cell integrity damage, the enzyme within the cell is released. Dantrolene reduces the concentration of cytosolic Ca2, inhibit the activation of calpain, reduce the degradation of the calpain protein and structural proteins of membrane skeleton, helps to maintain the cell integrity, less release of intracellular enzymes, and is therefore ischemia-reperfusion group as compared dantrolene treatment group showed high activity and stability. ATP degradation products hypoxanthine and adenine phosphate transfer enzyme pathways involved in ATP resynthesis. Under the conditions of the experiment, the the dantrolene treatment group APRT and HGPRT activity was significantly lower than the ischemia-reperfusion group, suggesting phosphotransferase enzyme pathway on ischemia-reperfusion myocardial ATP resynthesis contribution not.

The Protection of Dantrolene on Myocardial Ischemia-reperfusion Injury in Rats

Abstract

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