| General anesthetics (inhalation anesthetics and intravenous anesthetics) have inotropic and chronotropic effects on cardiac muscle cells,such as inhibiting cardiac muscle cells and changing cardiac rhythm.Intravenous anesthetics lead to cardiac rhythm changing mainly caused by disturbing the balance of autonomic nerve system(ANS). Electrical stability of cardiac muscle cells depend on the balance among vagus nerve, sympathetic nerve and humoral regulation.Sympathetic nerves release norepinephrine and epinephrin (almost the former one) to combine with acceptors. Adenylate cyclases are acted with cAMP changing when agitating the acceptors,therefore K+、Ca+、Na+ ion channels’ activities change following.Vagus nerve endings release acetycholine,which act the cardiac M acceptors (mainly the M2 acceptors subtype), inhibit the activities of adenylate cyclase,deduce the cAMP produce, modulate the currents of cell membrane ion channel,thus influence the eletric cardiac actvities. Most of the vagus nerve distribute at the Sinus node, followed by the atrioventricular node, the least at the ventricular innervation. While the sympathetic postganglionic fibers distribute throughout the heart. Cardiovascular autonomic nervous modulate the heart rhythm through the cardiovascular reflex which is made from the baroreceptors, cardiopulmonary receptors,chemical ceptors. If the sympathetic and vagal nerve mutual restraint mechanisms can not achieve balance, it will make the function of the cardiac conduction system changes.To achieve certain depth of anesthesia,anesthetist use many kinds of anaesthetics in perioperative period. The negative frequency and negative conduction of heart caused by most anesthetics,leading to significant changes of hemodynamics during anesthesia. In recent twenty years, there are increasing reports and research gradually in ventricular arrhythmia, sinus bradycardia, atrioventricular block caused by anesthetics. Tension and balance of ANS play an important role in anesthetics-induced arrhythmia.Hight cardiac sympathetic nerve tension can cause tachycardia, ventricular tachycardia ventricular fibrillation;Hight vagus nerve tension can cause dysfunction of sinus node, the atrioventricular node, which will lead to tardy cardiac arrhythmias and conduction block. Arrhythmia induced by anesthesia will bring risks to patients, therefore, it have importantly clinical significance to fully understand mechanism of anesthetic-induced negative chronotropic effects.Dexmedetomidine(Dex) is a new, efficient and highly selective α2 adrenergic receptor agonist (α2-AR). In 1999 the US Food and Drug Administration approved it for ICU sedation, there have been some clinical trials about the effectiveness and safety of auxiliary general anesthesia in China. Application of Dex in the ICU and perioperative anesthesia has shown superiority and value.Now it is clearly that Dex play sedative and hypnotic effects by acting on the brain locus coeruleus.To play an anti-nociceptive effect mainly through acting on the spinal dorsal horn. To play an anti-sympathetic activity effect through acting on the peripheral and central nerve synergistically. Dex has the unique " conscious sedation " feature,When patients receive long-term mechanical ventilation in ICU, Dex has better effects than midazolam and propofol to maintain light to moderate degree sedation.There are an increasing number of sthdies about Dex in recent twenty years,from WangFang database show that in 2010 made the 4.78 per million journal articles to article 225.78 per million in 2014. The advantages of Dex were reported by ninety percent of domestic articles. Application of Dex in perioperative indicated that Dex have effect on Hemodynamic stability, inhibiting the stress response, reducing the dose of anesthetic drugs and opioids, also have the potential organ protection function. In addition to pay attention to the curative effect of Dex, clinicians should pay more attention to its security and promote its reasonable application.Foreign literatures reported that hypotension and bradycardia were the most normal adverse reactions of Dex. It was reported in a research that Dex in recommended clinical dose might significantly inhibit the functions of sinus node and the atrioventricular node in children cardiac conduction system. Recently,there are some case reports that cardiac arrest happened after clinical recommended dose Dex were used.What is clearly is that Dex inhibits sympathetic activities to make vagus nerve dominant result in the change of cardiac conduction system function. However,mechanisms of cardiac vagal activity directly increasing have not been definitive. The one part clinical trial observed the influences of clinical recommended dose Dex in healthy volunteers’ heart rate, atrioventricular conduction time, intraventricular conduction time, QT interval, corrected QT interval, the sinus node and the atrioventricular node function though electrocardiogram and transesophageal cardiac electrophysiology.Another part of clinical trials observed the changes of heart rate variability of 36 young patients who use Dex in two kinds of loading dose and continuous dose in their selective operations, and the variations of autonomic nervous function drugs caused by Dex were analysised. Effects of Dex on cardiac conduction system researchs datas were obtained through the clinical trials study.Datas will provide objective basis in order to predict adverse reaction in the process of Dex administered.The gap junction(GJ) mediate electrical coupling between cardiomyocytes, that composite the pathway between cell for electricity excitation spreading sequentially, thus control cardiac muscle synchronous contraction. Redistribution and the quantity of gap junction channels may lead to changes in conduction velocity and direction of the corresponding parts of the myocardial tissue changes. In Part three, we investigate the effects of Dex on rabbit heart rate in isolate heart and vivo heart, and Dex concentration-response relationship effects on heart rate were studied. Drug dose was obtained to prepare sinus bradycardia in rabbits In Part four, we investigated the changes of gap junction protein Cx45,Cx31.9,Cx40 expression by making model of rabbit sinus bradycardia,and discussed preliminarily whether the negative frequency and negative conduction caused by Dex were related to the expression change of connexin.Part One Effects of dexmedetomidine on healthy volunteers’ Cardiac conduction systemObjective To investigate the effects of clinical recommended dose dexmedetomidine(Dex) in healthy volunteers’ heart rate, atrioventricular conduction time, intraventricular conduction time, QT interval, corrected QT interval, the sinus node function and the atrioventricular node function.Methods To compare variables at baseline and at subsequent infusion time of Dex through own-control,20 healthy volunteers were pump injected Dex1.0μg/kg, and then continuously pump injected Dex 0.5μg·kg-1·h-1. Electrocardiograph monitored resting 12-lead ECG, analysed and recorded the heart rate, PR interval, width of QRS,QT interval, corrected QT interval before pump injection Dex(t0),after pump injection Dex 20min (t1), after pump injection Dex 40min (t2). SBP,DBP,SPO2 were recorded at to, t1, t2.Sinus Nodal Recover Time (SNRT), Corrective Sinus Nodel Recovery Time (CSNRT), and Total Recovery Time (TRT) were measured by transesophageal cardiac electrophysiology before and after r pump injection Dex (30±5) min. Wenckbech cycle length of AVN, atrioventricular node prequel 2:1 block point were mearsured by transesophageal cardiac electrophysiology before pump injection Dex (T0), after pump injection Dex 15～20min (T1),and after pump inj ection Dex 35～40min (T2).Atrioventricular node relative refractory period (AVNRRP), Atrioventricular node effective refractory period (AVNERP) were measured before pump injection Dex (T0), after pump injection Dex (20±5) min (T1),and after pump injection Dex (50±5) min (T2)Results (1) Resting 12-lead ECG index:the heart rate significantly reduced and the PR interval significantly prolonged after administrating Dex (P<0.05), width of QRS significantly prolonged (P<0.05),The QT interval significantly prolonged after administrating Dex (P<0.05),and the corrected QT interval were no significantly prolonged (P>0.05) (2) The parameter of sinus node’s function:Compare with baseline,R-R interval,SNRT,CSNRT,TRT were significantly prolonged at subsequent Infusion (30±5) min time of Dex (P<0.05).(3) The parameter of Atrioventricular node’s function:Compare with baseline, the wenckbech cycle length of AVN, atrioventricular node prequel 2:1 block point significantly advanced at subsequent Infusion T1, T2 time of Dex (P< 0.05), AVNRRP and AVNERP were significantly prolonged at subsequent Infusion T1, T2 time of Dex (P<0.05)Conclusion The heart rate significantly reduced and the PR, width of QRS,the QT interval nterval significantly prolonged after administrating Dex, and the corrected QT interval are no significantly prolonged, the function of sinus node and the atrioventricular node are inhibited by Dex, indicators have not reached basic pathological anomaly threshold of clinical cardiac conduction system change. The heart conduction system adverse reaction inducing by Dex exist obvious individual differences, Clinical recommended doses of Dex can lead to serious bradycardia and atrioventricular block among basic vagus tension subjects.Part Two Clinical study of effect of dexmedetomidine on young people’s heart rate variability.Objective To investigate the effects of dexmedetomidine(Dex) on young patients’heart rate variability (HRV), and to discuss the change of autonomic nervous system(ANS) tension and balance of ANS.Methods Twenty-four young patients undergoing elective surgery were randomly divided into two groups. The subjects of the control group were inject physiological saline (group C).Twelve young patients were pump injected Dex1.0μg/kg, and then continuously pumped Dex 0.5μg-kg-1·h-1 (group Ⅰ).The change of HRV time-domain index (5 min heart beats total, the average rate of ventricular,SDNN,RMSSM,PNN50) and frequency-domain index (LFnorm,HFnorm, LF/HF) were monitored by the workstation of digital ECG before pump injection of Dex (To), after pump injection of Dex 15～20min (T1),and after pump injection of Dex 45～50min (T2)Results (1) There were no significant differences in gender composition,age, weight, height,BMI (P>0.05). (2) There were no significant differences in SBP,DBP (P>0.05),SPO2 were decreased in the process of Dex administration in Experimental groups (P<0.05),but it was still in the clinical normal range.(3) The variation trends of HRV time-domain indexs over time:Compared with To they were no significant differences over time:in C group (P>0.05), they were significant differences over time in group Ⅰ (P<0.05).5 min heart beats total and the average rate of ventricular of T1 and T2 were decreased than To in group Ⅰ(P<0.05). SDNN of T2 were increased than To in group Ⅰ (P<0.05).RMSSD and PNN50 of T1 and T2 were significantly increased than To in group Ⅰ (P<0.05). HRV time-domain indexs in groups comparison:Compared with C group,they were no significant differences at To(P>0.05),5 min heart beats total and the average rate of ventricular were decreased at T1 and T2 in group Ⅰ (P<0.05), SDNN,RMSSD and PNN50 were significantly increased at T1 and T2 in group Ⅰ (P<0.05).(4) The variation trends of HRV frequency-domain indexs over time:Compared with To,they were no significant differences over time in C group (P>0.05), LFnorm were no significant differences over time in group Ⅰ (P>0.05). HFnorm of T1 were increased than To in group Ⅰ (P<0.05). LF/HF of T1 in group I were decreased than To (P<0.05), it was recovered to baseline at T2 (P>0.05). HRV frequency-domain indexs in group comparison:they were no significant differences at To (P>0.05). Compared with C group, HFnorm were increased at T1 and T2 in group Ⅰ (P<0.05), LF/HF were significantly decreased at T1 in groups Ⅰ (P<0.05), it was recovered to baseline at T2 (P>0.05)Conclusion HRV indexs show that the tension of vagus nerves are increased and the tension of sympathetic nerve are decreased in the process of Dex administration. The balance ratio of the autonomic nerve decreased. The slowest rate and the highest vagus nerve tension are time after pump injection of Dex load dose.Part Three Effects of dexmedetomidine on rabbit heart rate in isolate heart and vivo heart.Objective To investigate the effects of dexmedetomidine(Dex) on rabbit heart rate in isolate heart and vivo heart, to clarify the mechanism of Dex-induced bradyarrhythmias.Methods Twenty-four isolate rabbit hearts were randomly divided into three groups (n=8). Rabbits were anesthesia and heparinized,and the removed hearts was connected to the a Langendorff technique.The isolated hearts were allowed to equilibrate for 15 min with oxygenated Kreb-Hensleit (K-H) buffer solution (95% 02+5%C02). After perfusion 5 min,Ventricular pressure balloon was put into the left ventricle through the left atrium and mitral valve, and the balloon was connected to the biological signal collection and processing system,the HR, LVSP, LVDP,± dP/dtmax were monitored. Then the isolated hearts were perfused with K-H buffer in group C, with K-H buffer containing Dex 3,30 ng/ml in group E1,E2, respectively for 30 minutes. All parameter were monitoring at perfusion for 15 minutes(T0), perfusion for 30 minutes(T1), perfusion for 60 minutes(T2). Rabbits were pump injected different dose of Dex (3、6、9、12、15μg/kg) by ear marginal vein in vivo model. The HR, MAP were monitored before pump injection of Dex (T0), after pump injection of Dex 15 min (T1),and after pump injection of Dex 45min (T2), and Dex concentration-response relationship effects on heart rate were studied.Results (1) In isolate heart model group:Compare with indexs of different time points in same group, HR、LVSP、LVDP、±dP/dtmax were significant differences over time in three groups (P< 0.05). Compare with indexs of different groups at same time points, HR、LVSP、LVDP、±dP/dtmax were no significant differences in groups (P>0.05). Left heart function gradually decreasesd over time in isolate heart, but it was no significant difference between three groups (P>0.05).(2) In vivo heart model group:heart rate decreased significantly at 10-15 min after Dex of loading dose administration excluding 3 μg/kg group.The heart rate of 6,9 μg/kg loading dose groups were recovered to baseline at 40 min (P>0.05), The heart rate of 12,15μg/kg loading dose groups were not recovered to at 40 min after Dex administration (P <0.05).Different dose of Dex were Linear positively related with heart rate change (T1-T0/T0) after Dex administration (F=203.8243,P<0.001), the correlation coefficient, r=0.948, determination coefficient R2= 0.899.Conclusion There was no significant effect on HR, LVSP, LVDP, ±dP/dtmax of isolate heart in perfusion fluid with diffierent concentration of Dex, Dex can not directly suppress function of sinus node and myocardial.different dose of Dex are Linear positively related with the degree of decreaseing heart beat in vivo model of keeping autonomic nerves, autonomic nerves plays an important role in Dex-induced bradyarrhythmias.Part Four The expression changes of Cx45,Cx31.9 and Cx40 on sinus bradycardia model caused by dexmedetomidine in rabbitObjective:To investigate the express changes of Cx45,Cx31.9 and Cx40 on rabbits’ sinus bradycardia model caused by dexmedetomidine(Dex). and to discuss whether the negative frequency and negative conduction caused by Dex are related to the expression change of connexin.Methods:48 healthy adult New Zealand rabbits were divided into two groups, and 24 rabbits were randomly divided into three subgroups (n=8). To prepared sinus bradycardia in rabbits by intravenous injecting Dex through ear vein. animal models in which heart rate of rabbit decreased more than 30% of baseline is success. After rabbits were anesthesia by sodium pentobarbital, basic operations were quickly were completed in order to measure cardiac electrophysiology index,MAP and ECG. Rabbits in the group C were injected physiological saline. Rabbits in group Di were pump injected loading dose Dex 10μg/kg, and then continuously pumped Dex 5μg·kg-1·h-1. Rabbits in group D2 were pump injected loading dose Dex 60μg/kg, and then continuously pumped Dex 30 μg·kg-1·h-1After observation 60 min of Dex pump injection,hearts were quickly removed and divided accurately the sinus node. The average optical density of sinus node Cx45、Cx31.9、Cx40 in the first goup were detected by immunohistochemistry, and Genes the relative expression of sinus node Cx45、Cx31.9、Cx40 in the second groups were detected by the Real-time quantitative.Results:The comparison between different groups:(1) MAP,HR were no significant differences at To (P>0.05).MAP,HR in D1,D2 groups were lower than the control group at ti,t2,t3 (P<0.05). HR in D2 group were lower than D1 group at t1,t2,t3 (P<0.05).(2) Changes in the relative amounts of gene expression:Cx45 relative gene expression of group D2 showed remarkable increase than group C, group D] (P<0.05),there were no significant difference between group D1 and C (P>0.05) Cx31.9 relative gene expression of group Di showed remarkable increase than group C (P<0.05), there were no significant difference between group D2 and C,D1 and D2 (P>0.05). Cx40 relative gene expression of group D2 showed remarkable increase than group C (P<0.05), there were no significant difference between group Di and C,Diand D2 (P>0.05). (3) Changes in the average optical density:Cx45 average optical density of group D2 showed remarkable increase than group C, group D1 (P<0.05),there were no significant difference between group D1 and C (P>0.05).Cx31.9 average optical density of group D1、D2 showed remarkable increase than group C (P<0.05), there were no significant difference between group Di and D2 (P>0.05). Cx40 average optical density of group D1、D2 showed remarkable increase than group C (P<0.05), group D2 showed remarkable increase than group D1 (P<0.05)Conclusion:More than 10μg/kg dose of Dex will cause rabbit sinus bradycardia and significantly.drop in blood pressure Dex possibly changes the gap junction protein expression to impact the the electrophysiological function of the heart. The variation trends of cardiac conduction velocity in sinus node are slowing down.The increasing of low electrical conductivity connexin and low electrical conductivity heterotypic gap junction channels formed of Cx31.9/Cx40 may be connected with negative cardiac frequency and negative conduction caused by Dex. |
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