Study Of Butorphanol Tartrate On Inflammatory Response In Rat Models With Septic Shock And Myocardial Ischemia Reperfusion Injury

PART 1 Effects of butorphanol tartrate on inflammatory response in septic ratsObjective:To investigate the effects of butorphanol tartrate on inflammatory cytokines in septic rats.Methods:Forty adult male SD rats weighing 200～250 g were randomly divided into sham-operated group (group C), operated group (group CLP), operated and butorphanol group (group CLP+B) and butorphanol group(group B). Septic shock model was induced by cecal ligation puncture (CLP). Thirty minutes before CLP 5 ml·kg-1 saline and 0.5 mg·kg-1 butorphanol were injected intravenously in group CLP and group CLP+B respectively. Group C and group B only received saline (5 ml·kg-1) and butorphanol (0.5 mg·kg-1) respectively. Mean artery pressure (MAP) and heart rate (HR) were monitored via the right femoral artery. Tumor necrosis factor-α(TNF-α), interleukin-6 (IL-6) and interleukin-10 (IL-10) in serum were measured at 4 h,12 h and 20 h after CLP.Results:MAP decreased progressively after CLP in group CLP and group CLP+B, while HR increased at first and decreased afterwards in group CLP. The decrease of MAP was inhibited, and the changes of HR were slight in group CLP+B. TNF-α, IL-6 and IL-10 concentrations in group CLP were higher than those in group C at 4,12 and 20 hours after CLP (P<0.05). TNF-a and IL-6 concentrations in group CLP+B were lower than those in group CLP(P<0.05).IL-10 concentrations in group CLP+B were higher than those in group CLP(P<0.05). There were no significant effects on TNF-α、IL-6 and IL-10 concentrations between group C and group B(P>0.05).Conclusions:Butorphanol tartrate has protective effects on septic shock rats by decreasing pro-inflammatory cytokines TNF-α, IL-6 concentrations and increasing anti-inflammatory cytokine IL-10 concentrations. Butorphanol tartrate has no significant effect on the TNF-α, IL-6 and IL-10 concentrations of normal rats. PART 2 Effects of butorphanol tartrate on myocardial ischemia reperfusion injury in ratsObjective To observe the effects of butorphanol on myocardial infarct size,malondialdehyde and myocardial structure following myocardial ischemia-reperfusion (I/R) in rats.Methods Forty healthy male SD rats weighing 200-250 g were randomly divided into five groups with 8 in each group:control group(group A);I/R group(group B); low dosage butorphanol group (group C); moderate dosage butorphanol group(group D) and high dosage butorphanol group(group E). In group B,C,D and E myocardial ischemia-reperfusion was produced by occlusion of left anterior descending artery (LAD) for 30 min followed by 120 min reperfusion.In group C,D and E butorphanol 25μg·kg-1,50μg·kg-1and 100μg·kg-1 was given respectively IV 10 min before occlusion of LAD. The myocardial infarct size was determined by TTC method and the changes of myocardial microstructure were observed under light-microscope. The tissue concentrations of malondialdehyde were measured.Results The myocardial infarct sizes were both significantly reduced in all butorphanol groups compared with those in I/R group (P<0.05), and myocardial infarct sizes in high dosage butorphanol group were lower than those in low dosage butorphanol group. The myocardial structures of rats in all butorphanol groups were better than those in I/R group, and in moderate dosage butorphanol group and high dosage butorphanol group the myocardial structures were generally normal. Concentrations of malondialdehyde in myocardial ischemia-reperfusion groups were higher than those in control group (P<0.05),Malondialdehyde concentrations in all butorphanol groups were reduced compared with those in I/R group (P<0.05).Conclusion Butorphanol provide a protective effect on rat heart in a dose-dependent manner following myocardial ischemia-reperfusion. PART 3 Effects and mechanisms of butorphanol tartrate on inflammatory response in myocardial ischemia-reperfusion ratsObjective To investigate the effect and mechanism of butorphanol tartrate on inflammatory cytokines in myocardial ischemia-reperfusion(I/R) rats.Methods Forty healthy male SD rats weighing 200～250 g were randomly divided into 5 groups (n=8):control group (group A); I/R group (group B); butorphanol group (group C); Nor-BNI group (group D) and glibenclamide group (group E). In group B,C,D and E myocardial ischemia-reperfusion was produced by occlusion of left anterior descending artery (LAD) for 30 min followed by 120 min reperfusion. In group C,D and E butorphanol 25μg·kg-1 was givenⅣ10min before occlusion of LAD.In group D Nor-BNI 2mg·kg-1 was given IV 20 min before occlusion of LAD.In group E glibenclamide 1 mg·kg-1 was given IV 10 min before occlusion of LAD.In group A and B butorphanol were replaced by normal saline 5 ml·kg-1 followed 5 ml·kg-1-h-1. Blood samples were taken at 120 min of reperfusion for determination of serum TNF-α·IL-6 and IL-10 concentrations.Result Compared with control group, the concentrations of TNF-a,IL-6 and IL-10 were increased in all myocardial ischemia-reperfusion groups (P <0.01).Compared with I/R group, TNF-αand IL-6 concentrations were decreased and IL-10 concentrations were increased in all butorphanol groups (P<0.05). Compared with butorphanol group, TNF-αand IL-6 concentrations were higher and IL-10 concentration was lower than those in Nor-BNI group and glibenclamide group (P <0.05).Conclusion Serum TNF-αIL-6 and IL-10 levels were increased following myocardial ischemia reperfusion. Butorphanol decrease pro-inflammatory cytokines TNF-α, IL-6 concentrations and increase anti-inflammatory cytokine IL-10 concentrations. And the effects on cytokines of butorphanol may be attenuated by Nor-BNI or glibenclamide.