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Objective To investigate the effect of U50488H on the ultrastructure and organ function in septic shock rats. Methods Forty SD male rats were randomly(random number) divided into 5 groups: sham group, septic shock group, U50488H+septic shock group, nor-BNI+U50488H+septic shock group, and nor-BNI+septic shock group, with 8 rats in each group. Cecal ligation and puncture (CLP) was performed to induce septic shock in the septic shock group. Rats in the U50488H+septic shock group were treated with U50488H injection by intravenous at the shock point, and other procedures were the same as the septic shock group. Rats in the nor-BNI+U50488H+septic shock group were treated with nor-BNI injection by intravenous 3.5 h after abdomen closed, and other procedures were the same as the U50488H+septic shock group. Except for U50488H injection, rats in the nor-BNI+septic shock group received procedures the same as the nor-BNI+U50488H+septic shock group. Albumin, cardiac troponin I (cTnI) and N terminal pro B type natriuretic peptide (NT-proBNP) in serum were measured at abdomen-closed, 3, 6, and 12 h after CLP. The changes of histology and ultramicro structure under electron microscope of lung, heart, liver and kidney of rats were observed at 12 h after CLP. Statistical analysis was performed using SPSS 19.0. Comparison among groups was carried out using ANOVA, and Student's t-test was used for multiple comparisons as post-hoc. Results At 6 and 12 h of CLP, serum albumin of the septic shock group were significantly lower than those of the sham group (P<0.01), while those in the cTnI and NT-pro BNP groups were higher at 3, 6, and 12 h of CLP (P<0.01). Compared with the septic shock group, serum albumin of the U50488H+septic shock group increased significantly (P<0.01), whereas the serum levels of cTnI and NT-pro BNP decreased remarkably at 3, 6 and 12 h of CLP (P < 0.05, P < 0.01, respectively). Compared with the sham group, the alveolar wall was severely damaged, the alveolar septum and blood vessel wall were thickened obviously; the myocardial fiber was swollen, necrotic, and the infiltration of central granulocyte was increased significantly; hepatocyte showed edema, vacuolar-like steatosis, fatty degeneration, spotty and focal necrosis; and slight edema and vacuolar degeneration were found in the glomerulus endothelial in the septic shock group. Compared with the septic shock group, the ultrastructural damage of the lung, heart, liver and kidney of the U50488H+ septic shock group was significantly improved. All the above effects of U50488H could be blocked by nor-BNI (a selective κ-opioid receptor antagonist) (P<0.01). Conclusions U50488H can promote the recovery of serum albumin, and protect organ function in septic shock rats.
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Aim To investigate the effect of U50488H(a selective κ-opioid receptor agonist)and isoproterenol(ISO,a β-adrenergic receptor agonist)on ventricular arrhythmias and Cx43 during myocardial ischemia and reperfusion in rats.Methods 60 rats were randomly divided into five groups,ie,normal control group,I/R group,ISO+I/R group,U50488H+ISO+I/R group,Nor-BNI+U50488H+ISO+I/R group.The incidence of ventricular arrhythmias and arrhythmia score were determined. The expression of Cx43mRNA was tested by RT-PCR.The expression of Cx43 protein in myocardial cell was tested by an immunohistochemical approach with a quantitative imaging system.Results ① Compared with the I/R group,arrhythmia score was increased with administration of ISO(P<0.05).U50488H intravenously injected before ISO significantly decreased the arrhythmia score(P<0.05).② Compared with the normal control group,the expression of Cx43 mRNA was decreased in the I/R group(P<0.05).With administration of ISO,the amount of Cx43 mRNA was not significantly increased.③ Compared with normal control group,total and phosphorylated Cx43 proteins were significantly decreased in the I/R group(P<0.05),and the phosphorylated Cx43 was also decreased with administration of ISO.Compared with ISO+I/R group,phosphorylated Cx43 was increased with administration of U50488H (P<0.05).Conclusion κ-opioid receptor agonist U50488 H antagonizes the arrhythmias through the regulation of Cx43 during myocardial ischemia and reperfusion via inhibiting β-adrenergic receptor pathway.
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Aim To examine the effect of ? opioid receptor agonist U50488H on the levels of interleukin-6(IL-6) and interleukin-8(IL-8) from angiotensinⅡ(AngⅡ) stimulated endothelial cells.Methods In the in vivo study,the modulation of U50488H(1.5 mg?kg~-1) intravenously on the level of AngⅡ was evaluated.In the in vitro study,endothelial cells from human umbilical vein(HUVEC) were cultured and divided into four groups:Control group,AngⅡ group,and AngⅡ plus U50488H and/or nor-BNI(a selective ? opioid receptor antagonist) group.These groups were treated respectively with phosphate buffered solution(PBS),AngⅡ(10~-9~10~-5 mol?L~-1),and AngⅡ in the presence of U50488H and/or nor-BNI for 0~24 hours.Culture supernatant and endothelial cells were collected at 0,3,6,12 and 24 h.IL-6 and IL8 levels in culture supernatant were measured by enzyme linked immunosorbent assay(ELISA).Results The level of AngⅡ in the blood was significantly decreased following U50488H intravenously,which was blocked by nor-BNI administration(2 mg?kg~-1).AngⅡ stimulated the productions of IL-6 and IL-8 from HUVEC in the dose-dependent and time-dependent manners.U50488H at 10~-5 mol?L~-1 significantly inhibited this process,and the inhibitory effect of U50488H was blocked by nor-BNI,which itself had no effect.Conclusion ? opioid receptor may play a role in the process of anti-inflammation via down regulation of AngⅡ level and inhibition of the AngⅡ-stimulated IL-6 and IL-8 productions from endothelium cells.
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Aim To investigate the anti-arrhythmic effect and mechanism of ?-opioid receptor during myocardial ischemia and reperfusion in rats,and to initially determine the regulation of U50488H(U50,a selective ?-opioid receptor agonist) to angiotensinⅡ(AngⅡ),endothelin(ET) and nitric oxide(NO) in rats.Methods Rats were randomly divided into 7 groups,i.e.,control group,ischemia/reperfusion group(I/R),U50488H+I/R group,PTX group(PTX,a Gi/o proteininhibitor),Glib group(glibenclamide,a K_(ATP) channel blocker),Che group(chelerythrine,a selective PKC inhibitor),and Gen group(Genistein,a Tyrosine kinase inhibitor) respectively.The arrhythmia occurrence and score in different groups were observed and counted.The contents of AngⅡ,ET and NO in plasma of rats were also examined.Results ① Compared with I/R group,the arrhythmia score of U50+I/R group was significantly decreased.The effect of pared with I/R group,the arrhythmia score of U50+I/R group was significantly decreased.The effect of glibenclamide and chelerythrine respectively,the anti-arrhythmic effects induced by U50488H in the rats during myocardial ischemia and reperfusion were significantly attenuated or even completely blocked.③ The anti-arrhythmic effects of U50488H were not significantly affected by pretreatment with genistein.④ In comparison with normal rats,the contents of AngⅡand ET in plasma of I/R group were significantly increased,but the content of NO was decreased.With the administration of U50488H,the contents of AngⅡand ET in plasma of rats in U50488H+I/R group were significantly decreased.Meantime the content of NO was increased.Conclusions ① U50488H-induced anti-arrhythmic effects in the rats with myocardial ischemia and reperfusion are mediated by ?-opioid receptor.The signaling pathway may be related with(Gi/o,) PKC,and K_(ATP) channel.② The activation of ?-opioid receptor may elicit anti-arrhythmic effect through the down-regulations of AngⅡ or ET and up-regulation of NO in plasma of rats.