| bjective: Atrial fibrillation(AF)is one of the most common clinical arrhythmia and is associated with increasing cardiovascular mortality and excessive disability.AF is a progressive disease that is closely related to age and can worsen underlying heart disease.The mechanism of AF has so far been unknown,and many hypotheses have been presented,such as the AF focal origin hypothesis,the multiple subwave reentry hypothesis,focal drive elicited conduction accompanied with fibrillation and pulmonary vein conduction triggering hypothesis,but no one can explain all the phenomena of AF.Although the triggering and reentry mechanism of AF have been accepted gradually,there are still a lot of problems about AF maintenance.Recently studies have provided evidence that the small conductance Ca2+-activated K+ channel subtype 2(SK2)is associated with the occurrence of AF.SK2 is a potassium channel family members that present highly intracellar Ca2+ sensitivity and insensitive to voltage.It has been demonstrated that the electrical remodeling of AF is involved in intracellular Ca2+ overload,and the increasing the concentration of angiotensin ? in blood or tissue can lead to further augment intracellular Ca2+,which leads to the aggravation of AF.The SK2 channel is highly sensitive to intracellular calcium,so we speculate that Ang ? may lead to increased AF which involv in the regulation of the SK2 channel,but no reports are presented.Therefore,the purpose of this study is to investigate the role of Ang? in the regulation of SK2 during development of AF.Methods: 25 healthy adult beagle dogs were randomly divided into 5 groups(n=5): sham operation group(Sham group),pacing group(Pacing group),pacing+angiotensin? group(Pacing+Ang? group),pacing+valsartan group(Pacing+Val group),pacing+angiotensin?+valsartan group(Pacing+Ang?+ Val group).The blood pressure was measured before and after drug treatment in each group,and the average value was calculated by measured three times.The dosing group before pacing were respectively treated with subcutaneous continuous micro pump(Ang? 110ng/kg/min)or(and)oral Valsartan(30mg /kg/d)for 2 weeks.After 2 weeks drug treatment,all dogs were anesthetized with pentobarbital sodium and then mechanical ventilation with endotracheal intubation,measured ECG during all the experiment time.The right atrial pacing electrode was inserted from the right femoral vein,which was coupled to the electrophysiological recording system.The other groups except Sham group were treated with rapid atrial pacing(frequency 600 beats / min)for 8 hours.Before and after each pacing,measured the Atrial effective refractory period(AERP)and AF frequency and AF duration.The serum and left and right atrial tissue concentrations of angiotensin? was measured.Western Blotting method was used to detect the protein expression level of SK2 channel.Results: 1.The change of blood pressure,after 2 weeks drug treatment,compared with Sham group,the blood pressure of Pacing+Ang? group was increase 45±3.53 mmHg,statistically significant(p<0.01);the difference between the other groups and the Sham group was not statistically significant(p>0.05).2.The change of the AERP after pacing,compared with sham group,the AERP was significantly shortened in Pacing group,Pacing+ Ang? group,and Pacing+Ang?+Val group(p<0.01),the shortening of Pacing+Ang? group was most significant,Pacing +Val group no significant shorten(p>0.05);compared with Pacing group,the AERP was shortened in pacing+Ang? group(p<0.01),Pacing+Val group,Pacing+Ang?+Val group AERP were prolonged(p<0.01).3.The change of after pacing serum and left and right atrial tissues Ang? concentrations,compared with Sham group,the Ang? concentrations of serum and right atrial tissue in Pacing group were increased significantly(p<0.01),Left atrial tissue also increased(p<0.05),Pacing+Val group although the Ang? concentrations in serum and atrial tissue were increased,but no significant difference(p>0.05).4.The frequency and time of burst stimulation AF induced in each group,compared with Sham group,the frequency and time of AF induced in Pacing group,Pacing+Ang? group were increased significantly(p<0.01),Pacing+Val group had no significant difference(p>0.05);compared with the pacing group,the frequency and duration of AF induced by Pacing+Ang? group was increased(p<0.01),Pacing+Val group and Pacing+Ang?+Val group were significant decreased(p<0.01).6.Western blotting measured results of the relative expression of SK2 channel protein in each groups,compared with Sham group,Pacing group,pacing+Ang? group,Pacing+Ang?+Val group were downregulation significantly(p<0.01),Pacing+Ang? group was the most significant downregulation,Pacing+Val group were decrease the expression,but no other groups downregulation significantly(p<0.05);compare to pacing group,the protein in Pacing+Ang?group was decreased(P<0.01),Pacing+Val group was increased(P<0.01),Pacing+Ang?+Val group also increased(P<0.05).Conclusion: 1.Rapid pacing can lead to atrial electrical remodeling.Ang? can aggravate atrial electrical remodeling,whereas Valsartan can reduce atrial electrical remodeling and reduce the occurrence of AF.2.Rapid pacing can lead to an increase in the concentration of Ang? in serum and atrial tissue,which may be one of the possible mechanism for the occurrence and maintenance of AF.3.SK2 channel is involved in the process of atrial electrical remodeling,rapid pacing can lead to down regulate the expression of SK2 channel protein in myo cardial tissue,Ang? further downregulation SK2 channel protein expression,which may be the cause of frequent recurrence of atrial fibrillation. |
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