Effects Of Angiotensin-(1-7),Angiotensin â…¡,Valsartan And Captopril On Potassium Channel Currents In Atrial Myocytes In Canine Model Of Atrial Electrial Remodeling

Objectives: Atrial fibrillation (AF) is the most common arrhythmia in clinical practice. Its incidence rapidly increases with age. Therefore, it is the most intensively studied disease in cardiology while its still remaining a major challenge. There has been some progress in the management of AF, but not to radical cure AF until now. The renin-angiotensin-system (RAS) possibly has a critical role in electrical and structure remodeling of AF by present opinion. Treatment with ACEI or ARB can block the renin-angiotensin-system, so may prevent occurrence of AF by reversing atrial remodeling. Angiotensin-(1-7) is a new nember of RAS and may be opposite in physiological activity compared with angiotensin II. It is not known that if Ang-(1-7) has an important role in atrial electrical and structure remodeling of AF until now. Furthermore, it is initiating that studying the role of RAS in occurrence and development of AF in domestic. We are intending to study on two direction: (1) Studying the effects of Ang-(1-7), AngII, Valsartan and Captopril on potassium channel currents in normal canine atrial myocytes respectively. (2)We first establish a canine model by rapid right atrial pacing (RAP). Then were studying the effects of Ang-(1-7), AngII, Valsartan and Captopril on potassium channel currents in RAP canine atrial myocytes respectively. The results are assistance to investigate the mechanism of the involvement of Angiotensin II in occurrence and development of AF, the effects of Angiotensin II antagonist on the atrial remodeling and provide new method for intervention of AF.Methods: (1) Normal canine cellular electrophysiology study: By establishing awhole-cell-clamp model on the enzymatically isolated single canine atrial myocytes, used V-clamp mode to observe the effects of Ang-(l-7)> Anglic Valsartan and Captopril on mainly repolarization potassium ionic currents (Ikr> Iks> Ikur arid It0) in normal canine atrial myocytes respectively. (2) RAP canine cellular electrophy-siology study: To establish a canine acute atrial fibrillation model by RAP for 8 hours. By establishing a whole-cell-clamp model on the enzymatically isolated single canine atrial myocytes, used V-clamp mode to observe: (Dthe effects of 1^ l^ Ikur and It0 in canine atrial myocytes by RAP. (2) the effects of Ang-(l-7)> AnglK Valsartan and Captopril on Iko Iks> Ikur and It0 in RAP canine atrial myocytes respectively.Results: (1) Normal canine cellular electrophysiology study results: ? 1 jxmol/L Ang-(l-7) can respectively inhibit I^ (inhibiting Ikr density by 31.83 + 11.87 %, P<0.05)> Iks (inhibiting Iks density by 24.85 + 6.37%, P<0.05), while increase It0 (increasing It0 density by 41.10+10.62%, P<0.05), has no effect on 1^. (2) 0.5umol/L Angll can respectively increase Ikr (increasing Ikr density by 22.35 + 7.98 %, P<0.05^ Iks (increasing 1^ density by 30.02±8.08%, P<0.01), while inhibit It0 (inhibiting It0 density by 42.74+10.77%, P<0.05), has no effect on Ikur. ?5umol/L Valsartan can respectively inhibit Ikr (inhibiting Ikr density by 21.73 + 10.66%, P< 0.05)> Iks (inhibiting Iks density by 24.37+11.22%, P<0.05)^ W (inhibiting Ikur density by 23.82 + 9.67%, P<0.01) and I,o (inhibiting It0 density by 40.67+5.10%, P<0.05). ?5umol/L Captopril has no significant effects on Ikr> Ifco Ikur and It0(all P >0.05). (2) RAP canine cellular electrophysiology study results: ? There is significantly decrease It0 density in RAP canine atrial myocytes compared with normal canine's (P<0.01) and no change in Ikr>Iks and Ikur(all P>0.05). (2)lumol/L Ang-(l-7) can respectively inhibit 1^ (inhibiting I^ density by 33.22 + 12.02%, P<0.05), Iks (inhibiting 1^ density by 23.88+6.36%, P<0.05), increase Ito (increasing It0 density by 38.16 + 12.62%, P<0.05), has no effect on l^. (3)0.5umol/L Angll can respectively increase Ikr (increasing Ikr density by 32.65±5.23% P<0.05)> Iks (increasing 1^ density by 27.94+12.53%, P<0.01), inhibit It0(inhibiting It0 density by 52.24+10.63%, P < 0.05), no effect on Ikur. ?5umol/L Valsartan can respectively inhibition I^ (inhibiting I^ density by 26.50+5.49%, P<0.05)> Iks (inhibiting Iks density by 27.33 + 3.32%, P<0.05), 1^ (inhibiting Ikur density by 24.47 + 9.99%, P<0.01) and It0 (inhibiting It0 density by 35.70+7.82%, P<0.01). ?5p.mol/L Captopril respectively inhibit I^r (inhibiting Ikur density by 26.08+7.92 %, P<0.05) and Ito (inhibiting It0 density by 39.21+3.74%, P<0.05), has no effect on Ikr and Iks (all P>0.05). ?Both Ang-(l-7) and Angll make It0 significantly lower in RAP group than in normal group(all P<0.05), have no significant difference about effects of Ikr> Iks and Ikur compared with two groups (all P>0.05). The effects of Valsartan on Ikr> Iks> Ikur and It0 in two groups have no significant difference (all P >0.05). Captopril makes Ikur and It0 significantly lower in RAP group than in normal group (all P<0.05), has no significant difference about effects of Ikr and IkS compared with two groups (all P>0.05).Conclusion: (1) the canine atrial myocytes acutely isolated from normal and model of RAP canine have the typical morphological % cellular biological-, electrophysiological features of atrial myocytes. It is provide experimental basis for advanced to study the molecular biology, electrophysiology> gene expression and signal conduction of canine atrial myocytes. (2) RAP makes It0 decreased and not change Iko It0 and Ikur- (3) Angiotensin-(l-7) and Angiotensin II have significant effects on the electrophysiology of the atrial myocytes by influencing Ib-% Iks and It0. Angiotensin II may promote atrial electrical remodeling of AF by effects of outwardpotassium currents. As endogenous antagonism of Angiotensin II, Angiotensin-(l-7) may antagonize the electrophysiological effects of Angiotensin II. (4) Valsartan can respectively inhibit 1^ Iks> Ikur and It0 of canine atrial myocytes. Captopril has no significant effects on outward potassium currents of normal canine atrial myocytes but can inhibit Ikur and It0 of RAP atrial myocytes. Valsartan and Captopril may improve the shorten of action potential duration by inhibiting outward potassium currents, block atrial electrical remodeling of AF and provide partial experimental basis for therapeutic atrial arrhythmia.