Objective:To investigate the role of ryanodine rececptor2(RyR2)in atrial fibrillation(AF)in depressed rats and to explore the mechanism of dantrolene intervention.Methods:Eighty male SD rats(180-220g)were randomized into four groups:control group(CTL=20),dantrolene group(DAN=20),depression group(CUMS=20)and depression plus dantrolene group(CD=20).These four groups were given intraperitoneal injections with saline,dantrolene,saline and dantrolene(4 mg/kg,Sigma)for 4 weeks.The CUMS group and the CD group were given chronic unexpected mild stresses for the same time to establish stable depression models.After 4 weeks,the behavioral evaluation was performed using sucrose preference test(SPT)and forced swimming test(FST).The 24 hours electrocardiograms of rats were obtained using an implanted signal telemetry system and the heart rate variability(HRV)was analyzed.Cardiac electrophysiological study was performed in a Langendorff device.ERP,APD90,ERP/APD90 were recorded in atrial tissue.Burst procedure was used to stimulate the atrium and detect the frequency and duration of atrial fibrillation.The conduction of electrical signals between myocardial cells,the conduction velocity,field potential duration and field potential duration dispersion were measured in the microelectrode arrays(MEA).Western blot was used to detect the changes of RyR2 and related proteins and Masson staining to observe the myocardial fibrosis.Results:1.Compared with the CTL group,there was no significant difference in the indicators of the DNA group(P>0.05),suggesting that dantralene has no influence on the heart of normal rats.2.The behavior evaluation of each group:Compared with the CTL group,the percentage of sucrose preference was decreased and the time of forced swimming test was prolonged in the CUMS group(P<0.05).The indexes were improved in the DNA group and CD group(P<0.05),but did not return to the normal level.3.Heart rate variability(HRV):Compared with the CTL group,the SDNN,SNADD and HF decreased,while LF and LF/HF increased In the CUMS group(P<0.05).After treatment with dantrolene,the related indicators improved(P<0.05).Although there was a difference in cSNRT between groups,it was not statistically significant(P>0.05).4.Microelectrode array results(MEA):The conduction velocity(CV)between myocardial cells was decreased,the total field potential duration(TAT)was prolonged and the field potential dispersion was increased in the CUMS group.Dantrolene administration was found to increase the CV and decrease the TAT in CD group(P<0.05).5.Electrophysiological changes:Compared with the CTL group,ERP and APD90 were significantly shorter,and the ratio of ERP/APD90 was decreased in the CUMS group and the CD group(P<0.05).Compared with the CUMS group,the above indicators improved in the CD group(P<0.05).Under Burst stimulation,the prevalence of atrial fibrillation was 100%in the CUMS group and 40%in the CD group(P<0.05).6.Western blot and Masson staining results:There was no significant difference in the expression of total RyR2 in each group(P>0.05).The expression of P-RyR2(2808)、P-RyR2(2808)、CAMKII and PKA were significantly increased,while the relative expression of SERCA2a was decreased in the CUMS group compared with other groups(P<0.05).Atrial fibrosis was evident in the CUMS group,and the fibrosis was relieved after treatment with dantrolene(P<0.05).Conclusion:Depression is closely related to AF.The abnormal function of RyR2 located on cardiac sarcoplasmic reticulum in depressed rat model may be an important cause of atrial fibrillation,and dantrolene has a therapeutic effect on dysfunctional RyR2 and reduces the risk of AF in depressed rats. |