神经生长因子对陈旧性心梗兔非梗死区心肌细胞及交感神经作用机制的研究
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摘要
背景及目的从整体和细胞水平研究了NGF及p75NTR在心梗后对交感神经及心肌细胞电生理的作用,以揭示心梗后室性心律失常的发生机制。
第一部分神经生长因子对陈旧性心梗兔交感神经分布及室颤阈值的影响
方法
日本大耳兔按体重随机分为四组,每组10只：陈旧性心梗(HMI)组、给予NGF刺激p75NTR作为p75NTR激活组、给予p75NTR受体单克隆抗体抑制p75NTR作为p75NTR抑制组、假手术(sham)组。实验组兔结扎冠状动脉左回旋支。10w后测各组兔的室颤阈值(VFT)。用免疫组织化学技术标记,检测S-100蛋白阳性和TH阳性的神经纤维的分布及其密度。
结果
HMI组的VFT与Sham组比较显著降低；p75 NTR激活组的VFT与HMI组和Sham组比较明显降低；p75 NTR抑制组VFT与p75 NTR激活组相比有显著性差异。HMI组的神经纤维密度与Sham组比较增加明显；p75 NTR激活组的神经纤维密度较Sham组和HMI组显著增加。
结论
1.陈旧性心梗兔VFT降低,交感神经纤维密度增加。
2.NGF可能通过与p75NTR结合后促进心梗后交感神经增生,降低VFT,增加发生恶性心律失常的风险。
3. p75NTR抑制剂可部分逆转NGF的上述作用,提高陈旧性心梗兔的VFT,抑制非梗死区交感神经增生。
第二部分神经生长因子对陈旧性心梗兔心肌细胞动作电位时程和复极电流的影响
方法
日本大耳兔按体重随机分为3组：HMI组,HMI+NGF组,Sham组。8w后,从非梗死区的心肌壁分离出心肌细胞,并应用全细胞膜片钳技术检测这些细胞的动作电位和Ito、ICa,L、IKr、及IKs等电流的情况。
结果
HMI组和HMI+NGF组的APD与对照组比较显著延长。HMI+NGF组及HMI组的Ito电流密度明显降低,HMI+NGF组激活曲线右移,失活后通道恢复减慢。HMI+NGF组ICa,L电流较HMI组及Sham组明显增大。HMI+NGF的ICa,L半激活电压左移,通道失活后恢复加速。HMI+NGF组IKr,tail电流密度降低显著,稳态失活曲线向负电位移动,失活后恢复时间常数延长。HMI+NGF组心肌细胞的IKs,tail幅值明显变小,电流在各个电位下均显著降低,且随着电位增加电流密度降低幅度相对更大,NGF使通道失活曲线向更负的方向移动,从而加速通道失活,NGF使灭活时间常数降低。
结论
1.陈旧性心梗兔模型非梗死区心肌细胞的APD延长,NGF使APD延长更加明显,而APA和RMP基本不变。
2.NGF使陈旧性心梗兔非梗死区心肌细胞的Ito明显降低,其门控机制可能与激活曲线右移,通道开放减少,关闭态失活增加有关。
3.NGF使陈旧性心梗兔非梗死区心肌细胞钙通道的失活减慢,恢复加快,进而导致ICa,L电流增大。
4. NGF可降低陈旧性心梗兔非梗死区心肌细胞的IKr,tail电流,主要通过加速通道失活,减慢通道恢复所致。
5.NGF使陈旧性心梗兔非梗死区心肌细胞的IKs.tail降低,机制可能为加快通道失活和灭活动力学所致。
Sympathetic hyperinnervation in healed-infarction is an important factor for triggering ventricular arrhythmias by binding to p75NTR, which is thought to be due to sudden cardiac death during the post-infarction period. We examined the effect of NGF and p75NTR on the action potential in cardiomyocytes.
The first part Effects of Nerve Growth Factor on the Ventricular Fibrillation Threshold and the Distribution of Sympathetic Nerve in a Rabbit Model of Healed Myocardial Infarction
Methods:Forty rabbits were divided into four groups as HMI group, p75 NTR activation group, p75 NTR inhibition group and the sham group. Rabbits with occlusion of the left circumflex coronary artery were prepared and allowed to recover for ten weeks. The VFTs in rabbit heart with HMI and sham group were studied. The distribution and densities of S-100 protein and tyrosine hydroxylase(TH) in ventricle were detected with immunohistochemical technique.
Results:The VFT of p75 NTR activation group were lower significantly than those of HMI and sham groups. Comparing with those in sham and HMI groups, the distribution of sympathetic nerve fibers in p75 NTR activation group increased significantly (P<0.05). The distributions of nerve fibers in p75 NTR inhibition group were significantly reduced than those of p75 NTR activation and HMI groups.
Conclusions:The VFT decreased and the densities of sympathetic nerve increased in the noninfarcted myocardium in a rabbit model of healed Myocardial Infarction. NGF is essential for enhanced sympathetic hyperinnervation and decreased VFT that may be mediated by binding to p75NTR in a rabbit model of healed Myocardial Infarction. These changes were partly reversed by p75 NTR inhibition.
The second part Effects of Nerve Growth Factor on the Action Potential Duration and Repolarizing Currents in a Rabbit Model of Healed Myocardial Infarction
Methods:Rabbits with occlusion of the left anterior descending coronary artery were prepared and allowed to recover for eight weeks (HMI group). During ligation surgery of the left coronary artery, a polyethylene pipe was placed near the left stellate ganglion in the subcutis of the neck for the purpose of administering NGF 400 U/day for eight weeks (HMI+NGF group). Cardiomyocytes were isolated from regions of the noninfarcted left ventricular wall and the action potentials and ion currents in these cells were recorded using whole-cell patch clamps.
Results:The lengthening of the APD was more notable after NGF infusion than that of the HMI and control cardiomyocytes. Current amplitudes of Ito in HMI+NGF cardiomyocytes were markedly smaller than that in HMI and control cardiomyocytes. Current calcium amplitudes (ICa, L) in HMI+NGF cardiomyocytes were significantly increased than other groups. Current amplitudes of IKr in the HMI cardiomyocytes with NGF treatment were smaller than those of the HMI and control cardiomyocytes. Compared with the HMI group, the current amplitudes of IKs from NGF treated HMI cardiomyocytes were significantly smaller.
Conclusion:After infusion of NGF, APD in a rabbit model of healed Myocardial Infarction would be prolonged. This due to that Ito,IKr and IKs were decreased, and that Ica, L were significantly increased.
第一部分神经生长因子对陈旧性心梗兔交感神经分布及室颤阈值的影响
方法
日本大耳兔按体重随机分为四组,每组10只：陈旧性心梗(HMI)组、给予NGF刺激p75NTR作为p75NTR激活组、给予p75NTR受体单克隆抗体抑制p75NTR作为p75NTR抑制组、假手术(sham)组。实验组兔结扎冠状动脉左回旋支。10w后测各组兔的室颤阈值(VFT)。用免疫组织化学技术标记,检测S-100蛋白阳性和TH阳性的神经纤维的分布及其密度。
结果
HMI组的VFT与Sham组比较显著降低；p75 NTR激活组的VFT与HMI组和Sham组比较明显降低；p75 NTR抑制组VFT与p75 NTR激活组相比有显著性差异。HMI组的神经纤维密度与Sham组比较增加明显；p75 NTR激活组的神经纤维密度较Sham组和HMI组显著增加。
结论
1.陈旧性心梗兔VFT降低,交感神经纤维密度增加。
2.NGF可能通过与p75NTR结合后促进心梗后交感神经增生,降低VFT,增加发生恶性心律失常的风险。
3. p75NTR抑制剂可部分逆转NGF的上述作用,提高陈旧性心梗兔的VFT,抑制非梗死区交感神经增生。
第二部分神经生长因子对陈旧性心梗兔心肌细胞动作电位时程和复极电流的影响
方法
日本大耳兔按体重随机分为3组：HMI组,HMI+NGF组,Sham组。8w后,从非梗死区的心肌壁分离出心肌细胞,并应用全细胞膜片钳技术检测这些细胞的动作电位和Ito、ICa,L、IKr、及IKs等电流的情况。
结果
HMI组和HMI+NGF组的APD与对照组比较显著延长。HMI+NGF组及HMI组的Ito电流密度明显降低,HMI+NGF组激活曲线右移,失活后通道恢复减慢。HMI+NGF组ICa,L电流较HMI组及Sham组明显增大。HMI+NGF的ICa,L半激活电压左移,通道失活后恢复加速。HMI+NGF组IKr,tail电流密度降低显著,稳态失活曲线向负电位移动,失活后恢复时间常数延长。HMI+NGF组心肌细胞的IKs,tail幅值明显变小,电流在各个电位下均显著降低,且随着电位增加电流密度降低幅度相对更大,NGF使通道失活曲线向更负的方向移动,从而加速通道失活,NGF使灭活时间常数降低。
结论
1.陈旧性心梗兔模型非梗死区心肌细胞的APD延长,NGF使APD延长更加明显,而APA和RMP基本不变。
2.NGF使陈旧性心梗兔非梗死区心肌细胞的Ito明显降低,其门控机制可能与激活曲线右移,通道开放减少,关闭态失活增加有关。
3.NGF使陈旧性心梗兔非梗死区心肌细胞钙通道的失活减慢,恢复加快,进而导致ICa,L电流增大。
4. NGF可降低陈旧性心梗兔非梗死区心肌细胞的IKr,tail电流,主要通过加速通道失活,减慢通道恢复所致。
5.NGF使陈旧性心梗兔非梗死区心肌细胞的IKs.tail降低,机制可能为加快通道失活和灭活动力学所致。
Sympathetic hyperinnervation in healed-infarction is an important factor for triggering ventricular arrhythmias by binding to p75NTR, which is thought to be due to sudden cardiac death during the post-infarction period. We examined the effect of NGF and p75NTR on the action potential in cardiomyocytes.
The first part Effects of Nerve Growth Factor on the Ventricular Fibrillation Threshold and the Distribution of Sympathetic Nerve in a Rabbit Model of Healed Myocardial Infarction
Methods:Forty rabbits were divided into four groups as HMI group, p75 NTR activation group, p75 NTR inhibition group and the sham group. Rabbits with occlusion of the left circumflex coronary artery were prepared and allowed to recover for ten weeks. The VFTs in rabbit heart with HMI and sham group were studied. The distribution and densities of S-100 protein and tyrosine hydroxylase(TH) in ventricle were detected with immunohistochemical technique.
Results:The VFT of p75 NTR activation group were lower significantly than those of HMI and sham groups. Comparing with those in sham and HMI groups, the distribution of sympathetic nerve fibers in p75 NTR activation group increased significantly (P<0.05). The distributions of nerve fibers in p75 NTR inhibition group were significantly reduced than those of p75 NTR activation and HMI groups.
Conclusions:The VFT decreased and the densities of sympathetic nerve increased in the noninfarcted myocardium in a rabbit model of healed Myocardial Infarction. NGF is essential for enhanced sympathetic hyperinnervation and decreased VFT that may be mediated by binding to p75NTR in a rabbit model of healed Myocardial Infarction. These changes were partly reversed by p75 NTR inhibition.
The second part Effects of Nerve Growth Factor on the Action Potential Duration and Repolarizing Currents in a Rabbit Model of Healed Myocardial Infarction
Methods:Rabbits with occlusion of the left anterior descending coronary artery were prepared and allowed to recover for eight weeks (HMI group). During ligation surgery of the left coronary artery, a polyethylene pipe was placed near the left stellate ganglion in the subcutis of the neck for the purpose of administering NGF 400 U/day for eight weeks (HMI+NGF group). Cardiomyocytes were isolated from regions of the noninfarcted left ventricular wall and the action potentials and ion currents in these cells were recorded using whole-cell patch clamps.
Results:The lengthening of the APD was more notable after NGF infusion than that of the HMI and control cardiomyocytes. Current amplitudes of Ito in HMI+NGF cardiomyocytes were markedly smaller than that in HMI and control cardiomyocytes. Current calcium amplitudes (ICa, L) in HMI+NGF cardiomyocytes were significantly increased than other groups. Current amplitudes of IKr in the HMI cardiomyocytes with NGF treatment were smaller than those of the HMI and control cardiomyocytes. Compared with the HMI group, the current amplitudes of IKs from NGF treated HMI cardiomyocytes were significantly smaller.
Conclusion:After infusion of NGF, APD in a rabbit model of healed Myocardial Infarction would be prolonged. This due to that Ito,IKr and IKs were decreased, and that Ica, L were significantly increased.
引文
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