e0188 Enalapril, Irbesartan and Ang-(1-7) prevent atrial tachycardia-induced sodium channel remodelling

Purpose Recent studies indicated that the activation of renin-angiotensin system (RAS) played an important role in the development and recurrence of atrial fibrillation (AF). Angiotensin II (Ang II) plays a central role in the process of atrial electrical remodelling (AER). Some studies on interfering with RAS have demonstrated positive effects to prevent episodes of AF both in animals and in humans. Angiotension-(1-7) (Ang-(1-7)) is a bioactive component of RAS which can counterbalance most of effects of Ang II. In the present study, the effects of ACEI enalapril, ARB irbesartan and Ang-(1-7) on Na+ current (INa) densities and Na+ channel (Nav1.5) mRNA expression were examined in a canine chronic model of AF induced by rapid atrial pacing. Methods For this study, 30 mongrel dogs of either sex weighing between 11 and 15 kg were randomly assigned to sham, paced, paced+enalapril, paced+irbesartan and paced+Ang-(1-7) group, six dogs in each. Rapid atrial pacing at 500 bpm was maintained for 2 weeks, while the dogs in sham group underwent pacemaker implantation, but the pacemakers were not activated to provide atrial pacing. During the pacing, the dogs in enalapril, irbesartan or Ang-(1-7) group received enalapril (2 mg/Kg/d), irbesartan (60 mg/Kg/d) or Ang-(1-7) (6 μg/Kg/h), respectively. The whole-cell patch-clamp technique was used to record INa and RT-PCR was applied to assess possible underlying changes in cardiac Na+ channels. Results INa densities were reduced by 46.96% in paced group (-32.65±10.92 pA/pF) compared with sham group (-61.56±14.17 pA/pF, p<0.05). The half-activation voltage (V1/2act) and half-inactivation voltage (V1/2inact) of INa were not altered in paced group (p>0.05 vs sham). Enalapril (-44.11±16.76 pA/pF), irbesartan (-65.24±14.79pA/pF) and Ang-(1-7) (-66.56 ±18.08 pA/pF) increased INa by 35.10%, 99.82% and 103.86% (p<0.05 vs paced group), respectively. Enalapril, irbesartan and Ang-(1-7) hyperpolarized V1/2act compared with sham and paced group (p<0.05). The difference of V1/2inact among five groups had no statistical significance. Compared with sham group, Nav1.5 α subunit mRNA abundance decreased dramatically in paced group (p<0.05). Enalapril and irbesartan prevented the decrease of Nav1.5 α subunit mRNA expression compared with paced group (p<0.05). Ang-(1-7) had no effects on the decrease of Nav1.5 α subunit mRNA expression (p>0.05 vs paced group). Conclusion Enalapril, irbesartan and Ang-(1-7) increase INa densities and contribute to improving intra-atrial conduction and decreasing the likelihood AF maintains. Hence, counterbalance the Ang II actions may represent an important tool to prevent atrial ionic remodelling, and perhaps a novel therapeutic approach to the prevention of AF.