Effects Of Enalapril, Irbesartan And Angiotensin-(1-7) On The Atrial Remodeling In Canine Model Of Chronic Atrial Fibrillation

Objective:The purpose of the present study was to observe atrial remodeling, including atrial electrical remodeling(AER)and atrial structural remodeling(ASR)of both atria,induced by rapid atrial pacing of the right atrium at 500 beats/min for two weeks in dogs,and to evaluate the effects of Enalapril,Irbesartan and Angiotensin-(1-7)[Ang-(1-7)]on chronic atrial remodeling in atrial fibrillation(AF). Meanwhile,the relationship of expressions of angiotensin converting enzyme 1 (ACE1),angiotensinⅡtype 2 receptor(AT2R)and extracellular signal-regulated kinase(ERK)to the atrial remodeling of AF were investigated.Methods:30 healtly mature mongrel dogs were randomly enrolled in control group (sham operation),pacing group,ACEI group(pacing and Enalapril),ARB group (pacing and Irbesartan)and Ang-(1-7)group[pacing and Ang-(1-7)].A programmable pacemaker was inserted in a subcutaneous pocket,and a atrial pacing lead was positioned in the right atrium through right jugular vein of each dog. Sustained AF was induced by rapid right atrial pacing of 500 beats per minute for two weeks in each group beside control group.Enalapril(2mg/kg/day),Irbesartan (60mg/kg/day)was administered orally for three days before rapid pacing and was continued for two weeks.Ang-(1-7)(6μg/kg/h)was released into left internal jugular vein by osmotic pumps.Six bipolar recording electrodes were sutured to 6 sites of both atrial when electrophysiologic studies beginning.Some electrophysiological index were measured,including atrial effective refractory period(AERP),frequency adaptability,dispersion of AERP,inducibility and duration of induced AF under different basic pacing cycle length(BCL:300ms,250ms,200ms).At the end of the experiments,the right auricular muscular tissues(free wall)were dislodged.Some of muscular tissues were fixed in 10%formalin liquid for pathological examination.The sample would be made histological section.After hematoxyln eosin(HE)and Masson trichrome stain,the histological section would be observed under light microscope. Another was stored with low temperature for molecular biological experiment.The study of gene and protein expression of ACE1,AT2R and ERK1/ERK2 would be carried out according to extract total ribonucleic acid(RNA),reverse transcription (RT),polymerase chain reaction(PCR),production analysis and PCR sequencing, step by step.Results:1.Electrophysiology:Contrast with control group and three drug groups,the AERP was significantly shortened at all three BCL in pacing group(P＜0.05 or＜0.01), frequency adaptability of the AERP was lost,and the dispersion of the AERP was significantly increased(all P＜0.05).The incidence and mean duration of induced AF were also increased(P＜0.01 or＜0.001)or prolonged(P＜0.05 or＜0.01)significantly in pacing group.Compared with control group,the AERP was shorter(P＜0.05)and the incidence of induced AF was increased significantly(P＜0.01)at long BCL in ACEI group.However,there were no significant differences of these parameters at short BCL.The physiological frequency adaptability of the AERP was maintained and the dispersion of the AERP was not significantly increased.The mean duration of induced AF was significantly shorter at three BCL compared with pacing group (P＜0.05 or＜0.01).In ARB and Ang-(1-7)group,the AERP was significantly increased at all three BCL compared with others(all P＜0.01).The physiological frequency adaptability of the AERP was maintained and the dispersion of the AERP was not significantly increased.The incidence of induced AF was not significantly increased and the mean duration of induced AF was significantly shorter(P＜0.05 or＜0.01)than that in pacing group.2.Pathology:In control,ARB and Ang-(1-7)group, the cellular morphology and tissular structure were complete.The significant interstitial fibrosis was not to be observed.However,the significant interstitial fibrosis and adipose tissue infiltration were observed in pacing group,evidenced by Masson trichrome stain.At the same time,heterogeneity in the size and arrangement of atrial myocytes was found in these tissues.In ACEI group,the cellular morphology and tissue structure were still complete.The interstitial fibrosis was merely.3. Molecular biological experiment:In pacing group,the expression of ACE1,AT2R, ERK1 and ERK2 mRNA were increased significantly compared with others(P＜0.05). In addition,photodensity were increased at electrophoretogram in pacing group. There were no significant differences of these parameters between control and each of drug groups.Conclusions:Sustained AF by rapid right atrial pacing of 500 beats per minute for two weeks can produce the phenomenon of atrial remodeling in a canine model, including AER and ASR.Enalapril,Irbesartan and Angiotensin-(1-7)can attenuate the fibrosis of atria by suppressing the expression of ACE1,AT2R,ERK1 and ERK2. So the atrial remodeling can be prevented by them.The inhibitory action of Enalapril on AER was inconspicuous,but the effects of Irbesartan and Ang-(1-7)on the AER induced by chronic AF were significant.