| Background and Objective:Today,almost all the cardiac surgery completed under the support of cardiopulmonary bypass(CPB).which may directly initiate the inflammatory response and the redundancy of the inflammatory cascades occurs to produce multiorgan system dysfunction.Cardiac dysfunction is a frequent complication during the postoperative course after cardiac surgery using CPB,and myocardial ischemia reperfusion injury (MIRI) is one of the most important factor.Myocardial inflammatory response was induced during ischemia and was extended during reperfusion.When cells were stimulated by oxidative stress and proinflammatory cytokines,the nuclear factor kappa B(NF-κB) complex moves to the nucleus where it binds to specific sequences in the promoter regions of genes(eg.ICAM-1,TNF-a,IL-1).Activation of neutrophil, endothelium and myocardium contribute to myocardium damage.The strategies to control the ischemia reperfusion injury following opened cardiac surgery and to protect the cardiac function is the focus of considerable research efforts.Penehyclidine Hydrochoride main selectively acts on the M1 and M3 acceptor which most exists in the visceral smooth muscle and the gland,and has no or less action on the M2 receptor which distributing presynaptic membrane and cordis.Penehyclidine Hydrochoride injection had the effect of protecting cells like other anticholine medicine,can improve the cells' toleration ischemia and hypoxia,stabilize subcellular structure of cytolysosome and chondriosome,reduce the releasing of lysosomal enzyme,inhibit the information of metabolite of arachidonic acid and shock factors, release the inflammatory response.Animal researches have revealed that Penehyclidine Hydrochoride injection can inhibit the expression of NF-κB obviously after cerebral ischemia reperfusion in rats. The present study was to investigate the effects and mechainsms of Penehyclidine Hydrochloride on myocardial ischemia reperfusion injury in patients undergoing heart valve replacement with CPB.Materials and Methods:Sixty adult patients with rheumatic heart valve disease scheduled for valve replacement were studied.Inclusion criteria were:(1) ASAⅡ～Ⅲ,(2) age＜65,(3) left ventricular ejection fraction＞40%.No patients received other corticosteroids preoperatively and intraoperatively.Patients with significant lung,liver,renal diseases and inflammatory were excluded.All patients were selected randomly and divided into control group(group C), penehyclidine hydrochloride group 1(group P1),and Penehyclidine Hydrochloride group 2(group P2),each with twenty cases.Patients were premedicated with intramuscular hyoscine 0.3mg and morphine(8～10)mg.Anesthesia was induced with 0.05 mg·kg-1 midazolam,10μg·kg-1 fentanyl and 0.1mg·kg-1 pipecuronium intravenously,and maintained with(10～20μg)·kg-1 fentanyl,(8～10)mg·kg-1·h-1 propofol and(0.04～0.06)mg·kg-1·h-1pipecuronium.All patients underwent valve replacement with CPB using bubble oxygenator.The pump was primed with lactated Ringer's solution and hydroxyethyl starch.Systemic heparinization was achieved with intravenous 400U·kg-1 heparin maintaining activated coagulation time(ACT)＞480s.Cardiopulmonary bypass was performed using standard hypothermia (28-32)℃which was instituted at a flow rate of(2.0～2.5)L·min-1·m-2 body surface area.Before operation,Penehyclidine Hydrochloride was injected into the central vein with the dose of 0.05mg·kg-1 and 0.1mg·kg-1 in group P1 and group P2(both diluted to 10ml),and saline 10ml in group C,respectively. Then myocardium samples of right auricle that had not been ligated and nipped were collected at different time points(T1:befbre CPB,T2:30min after aortic clamping,T3:30min after aortic unclamping) to observe the myocardium histopathology changes,and the expression of NF-κB was investigate by immunohistochemical method.Blood samples were drawn from radial artery at different five time points(T1,T2,T3,T4:4h after aortic unclamping,T5:24h after aortic unclamping),soluble intercellular adhesion molecule-1(sICAM-1) and tumor necrosis factor-alpha(TNF-α) in blood plasma were measured by enzyme linked immunosorbent assay(ELISA).Recordings of heart rate(HR),mean arterial pressure(MAP) and central venous pressure(CVP) were measured at each measuring point,and the time of tracheal extubation and the period of staying at ICU were recorded.Statistical analysis was performed with SPSS 10.0 software.All measurement data were expressed as mean±SD.Analysis of variance(ANOVA) was used to test the difference of the means and q test was used to test the difference between groups. Theαwas set at 0.05.Results:1.There was no significant difference among three groups in patients' information and intraoperative events(P＞0.05).2.There was no significant difference among three groups in the time of tracheal extubation and the period of staying at ICU(P＞0.05).3.There was no significant difference in the patients' heart rate(P＞0.05). Compared with T1,all the patients' mean artery pressure and central venous pressure increased sharply at T3-T5(P＜0.05).4.The plasma level of TNF-αComparation with groups:Compared with T1,the plasma level of TNF-αincreased sharply at T3 and reached at peak value at T5(P＜0.01).Comparation among groups:There was no significant difference among three groups at T1 and T2,but at T3-T5 the plasma level of TNF-αdecreased significantly in group P1 and P2(P＜0.05).And there was no significant difference between group P1 and P2(P＞0.05).5.The plasma level of sICAM-1Comparation with groups:Compared with T1,the plasma level of sICAM-1 increased sharply at T3 and reached at peak value at T4(P＜0.01).Comparation among groups:There was no significant difference among three groups at T1 and T2,but at T3-T5 the plasma level of sICAM-1 decreased significantly in group P1 and P2(P＜0.05).And there was no significant difference between group P1 and P2(P＞0.05).6.Myocardium histopathology changesCompared with group C:The myocardium injury was slight in group P1 and P2, the celluar swelling was unconspicuous and areas of necrosis were relatively smaller.7.Transcription activity of nuclear factor kappa BComparation with groups:Compared with T1,all the patients' transcription activity of nuclear factor kappa B increased sharply at T2 and T3(P＜0.01).Comparation among groups:There was no significant difference among three groups at T1,but at T2 and T3 the transcription activity of nuclear factor kappa B in group P1 and P2 decreased significantly(P＜0.05).And there was no significant difference between group P1 and P2(P＞0.05).Conclusions:1.The period of myocardial ischemia reperfusion can activate the transcription of nuclear factor kappa B and increase the plasma levels of TNF-αand sICAM-1 in patients undergoing heart valve replacement with CPB.2.Penehyclidine Hydrochloride can protect myocardium through inhibiting the transcription activity of NF-κB and the expression of TNF-αand sICAM-1 in the plasma.3.The hemodynamics are stabile in patients when injected penehyclidine hydrochloride with the dose of 0.05mg·kg-1 and 0.1mg·kg-1,and the heart rate does not increase significiantly. |
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