To determine the effects of HOE 694, a new and potent Na＋- H＋ exchanger blocker, on transient inward current (Iti) and Na＋- Ca2＋ exchange during hypoxia- reoxygenation in guinea pig cardiomyocytes. Methods. Cardio...To determine the effects of HOE 694, a new and potent Na＋- H＋ exchanger blocker, on transient inward current (Iti) and Na＋- Ca2＋ exchange during hypoxia- reoxygenation in guinea pig cardiomyocytes. Methods. Cardiomyocytes were isolated from adult guinea pig ventricle. Experiment was performed in an experimental chamber that allowed the cells to be exposed to a sufficiently low O2 pressure. The cells were subjected to hypoxia and reoxygenation. The ionic currents were studied with patch clamp technique. Results. In the absence of HOE 694, hypoxia- reoxygenation induced Iti in 12 of 15 experiments; but in cardiomyocytes pretreated with HOE 694 (10～ 50μ mol/L), the incidence of Iti observed during reoxygenation was reduced to 5 of 11 experiments and 3 of 10 experiments, P Conclusions. Blockade of the Na＋- H＋ exchange by HOE 694 could reduce Ca2＋ overload upon hypoxia- reoxygenation, and inhibition of Na＋- H＋ exchange may also indirectly decrease Na＋- Ca2＋ exchange activity during hypoxia.展开更多
Powered by the mitochondrial membrane potential,Ca2+ permeates the mitochondria via a Ca2+ channel termed Ca2+ uniporter and is pumped out by a Na+/Ca2+ exchanger,both of which are located on the inner mitochondrial m...Powered by the mitochondrial membrane potential,Ca2+ permeates the mitochondria via a Ca2+ channel termed Ca2+ uniporter and is pumped out by a Na+/Ca2+ exchanger,both of which are located on the inner mitochondrial membrane.Mitochondrial Ca2+ transients are critical for metabolic activity and regulating global Ca2+ responses.On the other hand,failure to control mitochondrial Ca2+ is a hallmark of ischemic and neurodegenerative diseases.Despite their importance,identifying the uniporter and exchanger remains elusive and their inhibitors are non-specific.This review will focus on the mitochondrial exchanger,initially describing how it was molecularly identified and linked to a novel member of the Na+/Ca2+ exchanger superfamily termed NCLX.Molecular control of NCLX expression provides a selective tool to determine its physiological role in a variety of cell types.In lymphocytes,NCLX is essential for refilling the endoplasmic reticulum Ca2+ stores required for antigen-dependent signaling.Communication of NCLX with the store-operated channel in astroglia controls Ca2+ influx and thereby neuro-transmitter release and cell proliferation.The refilling of the Ca2+ stores in the sarcoplasmic reticulum,which is controlled by NCLX,determines the frequency of action potential and Ca2+ transients in cardiomyocytes.NCLX is emerging as a hub for integrating glucose-dependent Na+ and Ca2+ signaling in pancreatic β cells,and the specific molecular control of NCLX expression resolved the controversy regarding its role in neurons and β cells.Future studies on an NCLX knockdown mouse model and identification of human NCLX mutations are expected to determine the role of mitochondrial Ca2+ efflux in organ activity and whether NCLX inactivation is linked to ischemic and/or neurodegenerative syndromes.Structure-function analysis and protein analysis will identify the NCLX mode of regulation and its partners in the inner membrane of the mitochondria.展开更多
目的:探讨绝对不应期电刺激(ARPES)对正常豚鼠和慢性心力衰竭(衰竭)豚鼠心窀肌细胞动作电位(AP)及钠离子—钙离子(Na^+-Ca^(2+))交换的影响。方法:应用膜片钳技术中电流钳记录 ARPES 对 AP 时程的影响,再以不同的 AP 电压钳记录细胞膜 N...目的:探讨绝对不应期电刺激(ARPES)对正常豚鼠和慢性心力衰竭(衰竭)豚鼠心窀肌细胞动作电位(AP)及钠离子—钙离子(Na^+-Ca^(2+))交换的影响。方法:应用膜片钳技术中电流钳记录 ARPES 对 AP 时程的影响,再以不同的 AP 电压钳记录细胞膜 Na^+-Ca^(2+)交换电结果:①ARPES 延长 AP 时程,以 APD_(30)最为显著(P<0.01),差异有统计学意义。②与正常豚鼠心室肌细胞比较,衰竭豚鼠心室肌细胞 AP 的平台期明显不同,表现在 APD_(90)变化(P<0.05)及 APD_(50)变化(P<0.01),差异有统计学意义。③分别以基础刺激(S_t)下的 AP(AP_(S1))和 ARPES 下的 AP(AP_(ARPES))为测试电压,记录 AP 电压钳下的细胞膜 Na^+-Ca^(2+)交换电流,在正常豚鼠心空肌细胞,AP_(ARPES)电压钳记录的单位膜电容下的外向电流强度的帑合值高于 AP_(S1)电压钳记录的相应值,而单位膜电容下的内向电流强度的整合值无显著变化。在衰竭豚鼠心室肌细胞,AP_(ARPES)电压钳记录的单位膜电容下的外向电流强度的整合值明显高于 AP_(S1)电压钳记录的相应值,而单位膜电容下的内向电流强度的整合值无显著变化。外向电流峰值的增加更为明显。结论:ARPES 延长正常豚鼠和衰竭豚鼠心室肌细胞 AP 时程,对心室肌细胞膜 Na^+-Ca^(2+)交换电流的影响可能是其增强整体心脏收缩功能的机制之一。展开更多
基金This work was supported by Leading Specialty Funding of Shanghai, Grant No.94- III- 001.
文摘To determine the effects of HOE 694, a new and potent Na＋- H＋ exchanger blocker, on transient inward current (Iti) and Na＋- Ca2＋ exchange during hypoxia- reoxygenation in guinea pig cardiomyocytes. Methods. Cardiomyocytes were isolated from adult guinea pig ventricle. Experiment was performed in an experimental chamber that allowed the cells to be exposed to a sufficiently low O2 pressure. The cells were subjected to hypoxia and reoxygenation. The ionic currents were studied with patch clamp technique. Results. In the absence of HOE 694, hypoxia- reoxygenation induced Iti in 12 of 15 experiments; but in cardiomyocytes pretreated with HOE 694 (10～ 50μ mol/L), the incidence of Iti observed during reoxygenation was reduced to 5 of 11 experiments and 3 of 10 experiments, P Conclusions. Blockade of the Na＋- H＋ exchange by HOE 694 could reduce Ca2＋ overload upon hypoxia- reoxygenation, and inhibition of Na＋- H＋ exchange may also indirectly decrease Na＋- Ca2＋ exchange activity during hypoxia.
文摘Powered by the mitochondrial membrane potential,Ca2+ permeates the mitochondria via a Ca2+ channel termed Ca2+ uniporter and is pumped out by a Na+/Ca2+ exchanger,both of which are located on the inner mitochondrial membrane.Mitochondrial Ca2+ transients are critical for metabolic activity and regulating global Ca2+ responses.On the other hand,failure to control mitochondrial Ca2+ is a hallmark of ischemic and neurodegenerative diseases.Despite their importance,identifying the uniporter and exchanger remains elusive and their inhibitors are non-specific.This review will focus on the mitochondrial exchanger,initially describing how it was molecularly identified and linked to a novel member of the Na+/Ca2+ exchanger superfamily termed NCLX.Molecular control of NCLX expression provides a selective tool to determine its physiological role in a variety of cell types.In lymphocytes,NCLX is essential for refilling the endoplasmic reticulum Ca2+ stores required for antigen-dependent signaling.Communication of NCLX with the store-operated channel in astroglia controls Ca2+ influx and thereby neuro-transmitter release and cell proliferation.The refilling of the Ca2+ stores in the sarcoplasmic reticulum,which is controlled by NCLX,determines the frequency of action potential and Ca2+ transients in cardiomyocytes.NCLX is emerging as a hub for integrating glucose-dependent Na+ and Ca2+ signaling in pancreatic β cells,and the specific molecular control of NCLX expression resolved the controversy regarding its role in neurons and β cells.Future studies on an NCLX knockdown mouse model and identification of human NCLX mutations are expected to determine the role of mitochondrial Ca2+ efflux in organ activity and whether NCLX inactivation is linked to ischemic and/or neurodegenerative syndromes.Structure-function analysis and protein analysis will identify the NCLX mode of regulation and its partners in the inner membrane of the mitochondria.
文摘目的:探讨绝对不应期电刺激(ARPES)对正常豚鼠和慢性心力衰竭(衰竭)豚鼠心窀肌细胞动作电位(AP)及钠离子—钙离子(Na^+-Ca^(2+))交换的影响。方法:应用膜片钳技术中电流钳记录 ARPES 对 AP 时程的影响,再以不同的 AP 电压钳记录细胞膜 Na^+-Ca^(2+)交换电结果:①ARPES 延长 AP 时程,以 APD_(30)最为显著(P<0.01),差异有统计学意义。②与正常豚鼠心室肌细胞比较,衰竭豚鼠心室肌细胞 AP 的平台期明显不同,表现在 APD_(90)变化(P<0.05)及 APD_(50)变化(P<0.01),差异有统计学意义。③分别以基础刺激(S_t)下的 AP(AP_(S1))和 ARPES 下的 AP(AP_(ARPES))为测试电压,记录 AP 电压钳下的细胞膜 Na^+-Ca^(2+)交换电流,在正常豚鼠心空肌细胞,AP_(ARPES)电压钳记录的单位膜电容下的外向电流强度的帑合值高于 AP_(S1)电压钳记录的相应值,而单位膜电容下的内向电流强度的整合值无显著变化。在衰竭豚鼠心室肌细胞,AP_(ARPES)电压钳记录的单位膜电容下的外向电流强度的整合值明显高于 AP_(S1)电压钳记录的相应值,而单位膜电容下的内向电流强度的整合值无显著变化。外向电流峰值的增加更为明显。结论:ARPES 延长正常豚鼠和衰竭豚鼠心室肌细胞 AP 时程,对心室肌细胞膜 Na^+-Ca^(2+)交换电流的影响可能是其增强整体心脏收缩功能的机制之一。
