RAS阻断剂对实验性高甲状腺素毒性兔心房电生理和离子通道表达的影响

Effect of renin angiotensin system blocker on atrial electrophysiology and ion channel expression in hyperthyroid rabbits

目的研究肾素-血管紧张素系统(renin angiotensin system,RAS)在甲状腺素诱导的心房电重构和离子通道重构中的作用,探讨RAS阻断剂对甲状腺素诱导的心房重构的影响。方法 40只新西兰大白兔分为4组(n=10):正常对照、甲状腺素、贝那普利及厄贝沙坦干预组。腹腔注射左旋甲状腺素(Levothyroxine,L-Thy)建立兔甲状腺素毒性模型,贝那普利组和厄贝沙坦组同时给予贝那普利或厄贝沙坦。4周后,通过心内电生理仪测定心房有效不应期,连续高频刺激诱发心房颤动(atrial fibrillation,AF),评价心房频率适应性和AF诱发率,荧光定量PCR检测L型Ca2+通道(Cav1.2和Cav1.3亚基)和Ito电流相关亚基(kv1.4、kv4.2和kv4.3)mRNA表达,Western blot检测L型Ca2+通道α亚基和kv4.2蛋白表达。结果贝那普利和厄贝沙坦明显降低AF诱发率并明显改善高甲状腺素诱导的频率适应性变化。贝那普利组(76.63±4.44)ms和厄贝沙坦组(79.00±4.95)ms心房有效不应期较甲状腺素组(75.13±5.41)ms无明显延长(P>0.05)。L型Ca2+通道蛋白表达在贝那普利组(1.15±0.24)和厄贝沙坦组(1.08±0.17)明显高于甲状腺素组(0.56±0.11)(P<0.01),但对高甲状腺素引起的Ito电流相关亚基变化无明显抑制作(P>0.05)。结论 RAS可能参与了高甲状腺素性诱导的心房电生理和离子通道改变,贝那普利和厄贝沙坦可以改善L-Thy诱导的心房电重构和离子通道重构,并降低高甲状腺素致AF性。

Objective To investigate the effect of renin angiotensin system（RAS） on thyroxine-induced atrial electrical remodeling and ion channel remodeling in experimental hyperthyroid rabbits and the effect of RAS blocker on thyroxine-induced atrial remodeling.Methods Forty New Zealand white rabbits were assigned to four groups（n=10）： a normal control group,a thyroxine group,a benazepril group,and an irbesartan group.In the thyroxine group,benazepril group,and irbesartan group,levothyroxine（L-Thy） was given to the rabbits by intraperitoneal injection to establish a rabbit model of hyperthyroidism,and benazepril and irbesartan were administered orally in combination with L-Thy in the benazepril group and irbesartan group,respectively.Four weeks later,burst stimulation was used to induce atrial fibrillation（AF）.Electrophysiological testing was performed to measure atrial effective refractory period（AERP） and evaluate AERP frequency adaptability and AF vulnerability.Real-time PCR was used to measure the mRNA expression levels of L-Ca2＋ channel-related subunits（Cav1.2 and Cav1.3） and Ito channel-related subunits（kv1.4,kv4.2,and kv4.3）.Western blot was used to measure the protein expression levels of Cav1.2 and kv4.2.Results No significant difference was found in AERP among the thyroxine group（75.13±5.41 ms）,benazepril group（76.63±4.44 ms）,and irbesartan group（79.00±4.95 ms）（P0.05）.Benazepril or irbesartan could significantly decrease AF vulnerability and significantly increase AERP frequency adaptation.The protein expression of L-Ca2＋ channel-related subunit Cav1.2 was significantly increased in the benazepril group（1.15±0.24） and irbesartan group（1.08±0.17）,as compared with that in the thyroxine group（0.56±0.11）（P0.01）.Benazepril and irbesartan did not markedly inhibit the effect of L-Thy on the mRNA and protein expression of Ito channel-related subunits（P0.05）.Conclusion RAS may play an important role in thyroxine-induced atrial electrical remodeling and ion channel remodeling.Benazepril or irbesartan may reduce thyroxine-induced atrial electrical remodeling and ion channel remodeling and the increase of AF vulnerability attributed to thyroxine.