| Objective Atrial fibrillation (AF) may lead to a marked decrease in the atrial effective refractory period (AERP), action potential duration (APD) and in ERP adaptation to rate as well as a decrease in atrial conduction velocity (CV) called AER. Intra-cellular calcium overload is now regarded as an central mechanism of atrial electrophysiologic remodeling (AER). The mechanisms of AF have been investigating in animal models and in humans in recent years and the rapid atrial pacing (RAP) can trigger similar state to AER. Most scholars considered chronic rapid atrial activation reduces INa current densities (CDs) and gene and protein expressions in the animal models of AF but can not change them in the AF patients. Recent studies indicated activation of renin-angiotensin system (RAS) played important role in the development, progression and recurrence of AF and Ang II plays a central roles in the process of AER which is induced by intra-cellular calcium overload through Ica-L activation or phosphatidyl inositol (IP) pathway and Ang II inhibition can prevent the AER. Some studies with non-antiarrhythmic drugs interfering with the renin-angiotensin system (RAS) have demonstrated a positive effect to prevent episodes of AF both in animals and in humans, suggesting a possible role of the RAS as a mediator of atrial remodeling in AF. Ang-(1-7) is a bioactive component of RAS which can counterbalance most of the effects of AngⅡ. Our laboratory had worked on the effects of ACEI (enalapril), ARB (irbesartan) and Ang-(1-7) on Ica-L, Ito and their gene expressions in a canine model of chronic AF and concluded counterbalance the Ang II actions may prevent atrial ionic remodeling, but little information is available about the effects of ACEI, ARB and Ang-(1-7) on INa and mRNA expression in the model. Therefore, in the present study, we examined the effects of the ACEI enalapril, ARB irbesartan and Ang-(1-7) on INa CDs and Navl.5 mRNA expression induced by RAP in the dog model of chronic AF.Methods For this study,30 mongrel dogs of either sex weighing between 11 and 15kg were randomly assigned to the sham-operated (the sham group), paced (the control group), paced+irbesartan (the enalapril group), paced+irbesartan (the irbesartan group) and paced+ Ang-(1-7) [the Ang-(1-7) group] group,6 dogs in each. A programmable pacemaker was inserted in a subcutaneous pocket, and an atrial pacing lead was positioned in the right atrial through right jugular vein of each dog. In the group C, EN, IB and A, pacing at 500 beats per minute was maintained for 2 weeks. The dogs in the enalapril, irbesartan and Ang-(1-7) treated groups received enalapril (2mg·Kg-1·d-1), irbesartan (60 mg·Kg-1·d-1) or Ang-(1-7) (6μg·Kg-1·h-1) during the pacing respectively. The sham-operated dogs underwent pacemakers and electrodes insertion, but the pacemakers were not activated to provide atrial pacing. At the end of the experiments, the whole-cell patch-clamp technique was used to record left atrial INa currents and RT-PCR was applied to assess possible changes in cardiac gene expression of Navl.5 a subunit in right atrial tissue.Results INa CDs were significantly reduced by 46.96% in control group (P<0.05 vs. sham). Enalapril [-44.11±16.76 pA/pF (n=11)], irbesartan [-65.24±14.79pA/pF (n=13)] and Ang-(1-7) [-66.56±18.08 pA/pF (n=11)] increased INa by 35.10%, 99.82% and 103.86%, respectively (P<0.05) compared with the control (P<0.05). Ang-(1-7) increased INa (P<0.05 vs. control) but had no effects on gene expression (P>0.05 vs. control). The half-activation voltage (V1/2act) was not altered in control group (P>0.05 vs. sham). Enalapril, irbesartan and Ang-(1-7) hyperpolarized V1/2act compared with sham and control. The three agents and RAP had no effects on half-inactivation voltage (V1/2inact) RAP did not change Vi/2act [membrane voltage (Vm) at which half-activation occurs] compared with sham group. The application of enalapril, irbesartan and Ang-(1-7) caused V1/2act more negative versus sham and control group (P<0.05). The difference of INa activation slope factor Kact had no statistical significance among five groups indicating that RAP, enalapril, irbesartan and Ang-(1-7) have no effects on INa activation Kact. The difference among five groups of INa V1/2inact (Vm at which half-inactivation occurs) and inactivation slope factor Kinact had no statistical significance, which indicats that RAP, enalapril, irbesartan and Ang-(1-7) have no effects on V1/2inact and inactivationκinact of INa.Compared with the sham-operated dogs, Nav1.5αsubunit mRNA abundance decreased dramatically in the control group dogs after 14 days of RAP (P<0.05). Enalapril and irbesartan prevented the decrease of Navl.5 a subunit mRNA expression compared with the control group (P<0.05). Ang-(1-7) had no effects on the decrease of Navl.5αsubunit mRNA expression in the atria of paced dogs (P>0.05 vs. control).Conclusions:RAP can decrease INa CDs by downregulating the Nav1.5αsubunit gene expression. Enalapril and irbesartan increase INa by the way of the gene expression upregulation and facilitation of activation characters of INa.Ang-(1-7) can increase INa CDs by the hyperpolarization of V1/2act but has no effects on Navl.5αsubunit gene expression. The increase of INa CDs may contribute to improve electrical impulses CV and have a remarkable inhibiting effect to AER.
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