Objective To study the effect of ivabradine on hyperpolarization activated cation current in canine pulmonary vein(PY) sleeve cardiomyocytes with atrial fibrillation.Methods Dissociation of PVs yielded single cardiomy...Objective To study the effect of ivabradine on hyperpolarization activated cation current in canine pulmonary vein(PY) sleeve cardiomyocytes with atrial fibrillation.Methods Dissociation of PVs yielded single cardiomyocytes from a Landengorff column without or with pacemaker activity from long-term rapidly atrial pacing (RAP) canines.If current was measured with the whole-cell patch-clamp technique.Results Compared with the control group,the rapidly atrial pacing canine PV cardiomyocytes had spontaneous diastolic depolarization and had larger If densities.Ivabradine (Iva,1 μM),a selective inhibitor of the If current,markedly reduced If currents in the RAP from -2.66±0.4 pA/pF to -1.58±0.1 pA/pF at the test potential of-120 mV (P＜0.01,n=12).Inhibition effect of Iva of If current showed concentration-dependent range from 0.1 to 10.0μM,with IC50 of 2.2 μ M ( 1.8-2.9 μM,95% CL).Furthermore,V1/ of steady-state activated curve was shifted from -84.3±4.9 mV to -106.9±3.4 mV and k value of steady-state activated curve was changed from 12.1+2.6 mV to 9.9±3.4 mV by the application of.1.0 μM Iva ( P＜0.01,n=12).Conclusions Our study revealed that Ivarbadine may significantly decrease If of rapidly atrial pacing pulmonary vein sleeve ceUs with atrial fibdllation.(J Geriatr Cardiol 2008;5:39-42)展开更多
AIM:To assess the role of hyperpolarization-activated cyclic nucleotide-gated cation(HCN) channels in regulating the excitability of vagal and spinal gut afferents.METHODS:The mechanosensory response of mesenteric aff...AIM:To assess the role of hyperpolarization-activated cyclic nucleotide-gated cation(HCN) channels in regulating the excitability of vagal and spinal gut afferents.METHODS:The mechanosensory response of mesenteric afferent activity was measured in an ex vivo murine jejunum preparation.HCN channel activity was recorded through voltage and current clamp in acutely dissociated dorsal root ganglia(DRG) and nodose ganglia(NG) neurons retrogradely labeled from the small intestine through injection of a fluorescent marker(DiI).The isoforms of HCN channels expressed in DRG and NG neurons were examined by immunohistochemistry.RESULTS:Ramp distension of the small intestine evoked biphasic increases in the afferent nerve activity,reflecting the activation of low-and high-threshold fibers.HCN blocker CsCl(5 mmol/L) preferentially inhibited the responses of low-threshold fibers to distension and showed no significant effects on the high-threshold responses.The effect of CsCl was mimicked by the more selective HCN blocker ZD7288(10 μmol/L).In 71.4% of DiI labeled DRG neurons(n = 20) and 90.9% of DiI labeled NG neurons(n = 10),an inward current(I h current) was evoked by hyperpolarization pulses which was fully eliminated by extracellular CsCl.In neurons expressing I h current,a typical "sag" was observed upon injection of hyperpolarizing current pulses in current-clamp recordings.CsCl abolished the sag entirely.In some DiI labeled DRG neurons,the I h current was potentiated by 8-Br-cAMP,which had no effect on the I h current of DiI labeled NG neurons.Immunohistochemistry revealed differential expression of HCN isoforms in vagal and spinal afferents,and HCN 2 and HCN 3 seemed to be the dominant isoform in DRG and NG,respectively.CONCLUSION:HCNs differentially regulate the excitability of vagal and spinal afferent of murine small intestine.展开更多
Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels in the heart modulate cardiac automaticity via the hyperpolarization-activated cation current ( named Ⅰf, Ⅰh, or Ⅰq). Recent studies have unveiled ...Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels in the heart modulate cardiac automaticity via the hyperpolarization-activated cation current ( named Ⅰf, Ⅰh, or Ⅰq). Recent studies have unveiled the molecular identity of HCN (HCN1-4) channels. HCN isoforms are unevenly expressed in the heart, even in the sinoatrial node. Features of HCN currents have been characterized in cardiac and other types of cells or in cell lines transfected with the HCN isoforms. The factors modulating Ih and the physiological significance of HCN channels in the heart have been extensively investigated in recent years. The hypothesis for transplanting and/or creating biological pacemakers to replace diseased sinoatrial and/or atrioventricular nodes has been postulated and tested in animal models. Local overexpression of HCN2 channels in the left atrium or in the left conductive bundle branch of the left ventricle via gene delivery induced significant Ⅰh and escape rhythms during vagal stimulation in canines. In addition, implantation of human mesenchymal stem cells with overexpression of HCN2 channels to the canine left ventricular wall was associated with formation of spontaneous escape rhythms of left-sided origin during vagal-stimulation-induced sinus arrest. This preliminary data suggest that the use of HCN channels may hold great promise in,the development of biological pacemakers.展开更多
Abstract Hyperpolarization-activated cyclic-nucleotide-gated ( HCN) channels in the heart modulate cardiac automaticity via the hyperpolarization-activated cation current (named If, Ih, or Iq). Recent studies have unv...Abstract Hyperpolarization-activated cyclic-nucleotide-gated ( HCN) channels in the heart modulate cardiac automaticity via the hyperpolarization-activated cation current (named If, Ih, or Iq). Recent studies have unveiled the molecular identity of HCN (HCN 1-4) channels. HCN isoforms are unevenly expressed in the heart, even in the sinoatrial node. Features of HCN currents have been characterized in cardiac and other types of cells or in cell lines transfected with the HCN isoforms. The factors modulating Ih and the physiological significance of HCN channels in the heart have been extensively investigated in recent years. The hypothesis for transplanting and/or creating biological pacemakers to replace diseased sinoatrial and/or atrioventricular nodes has been postulated and tested in animal models. Local overexpression of HCN2 channels in the left atrium or in the left conductive bundle branch of the left ventricle via gene delivery induced significant Ih and escape rhythms during vagal stimulation in canines. In addition, implantation of human mesenchymal stem cells with overexpression of HCN2 channels to the canine left ventricular wall was associated with formation of spontaneous escape rhythms of left-sided origin during vagal-stimulation-induced sinus arrest. This preliminary data suggest that the use of HCN channels may hold great promise in the development of biological pacemakers.展开更多
The action potential （Na<sup>+</sup> spike） of neurons is often followed by a compound after hyperpolarization （AHP） which is mediated by Ca<sup>2+</sup>-dependent K<sup>+</sup>...The action potential （Na<sup>+</sup> spike） of neurons is often followed by a compound after hyperpolarization （AHP） which is mediated by Ca<sup>2+</sup>-dependent K<sup>+</sup> channels. Pyramidal cells in the cerebral cortex are known to have fast, medium and slow AHPs. It is commonly accepted that the fast AHP （fAHP） is mediated by a kind of C- or BK-K<sup>+</sup> channels. The fAHP is characterized by a short duration of about 20 ms, its remarkable voltage dependence and sensitivity to low concentration （【1 mmol/L） of Tetraethylammonium （TEA）.The mAHP results from activation of AHP- or SK-K<sup>+</sup> channels and has a long duration over 200 ms. It is poorly voltage-dependent and blocked by Apamin, but not by TEA.展开更多
The effects of rises in external K+(Kext) were examined on the hyperpolarization-activated cation current(Ih) in rat dorsal root ganglion neurons using the whole-cell patch clamp technique.The results showed that Kext...The effects of rises in external K+(Kext) were examined on the hyperpolarization-activated cation current(Ih) in rat dorsal root ganglion neurons using the whole-cell patch clamp technique.The results showed that Kext increased Ih in a certain concentration and voltage-dependent manner.At the basal Kext level(4 mmol/L),Ih had a maximal amplitude of 1085 ± 340 pA which was enhanced by ～45% and ～92% at 8 and 16 mmol/L Kext,respectively.The midpoint activation voltage was significantly shifted from -98 mV in the hyperpolarizing direction by 8 and 12 mV at 8 and 16 mmol/L Kext,respectively with alteration of the activation course of Ih.The short time constants of activation became longer with the increasing amplitude of the command potential upon rises in Kext.The long time constants became shorter.The reversal potentials were shifted in the positive direction without significant alterations upon rises in Kext.According to the functional role of Ih,Kext increased Ih,resulting in an enhanced neuronal excitability,which might produce activation potential abnormality and perhaps neuropathic pain involved.展开更多
The action potential of pacemaker cells in thesino-atrial node forms the automatic rhythm of theheart.The automatic depolarization in phase 4 is the basisof the automaticity in pacemaker cells.Many currents areinclude...The action potential of pacemaker cells in thesino-atrial node forms the automatic rhythm of theheart.The automatic depolarization in phase 4 is the basisof the automaticity in pacemaker cells.Many currents areincluded in phase 4,such as calcium current,TTX-sensitive sodium current,sustained inward current(I_(si)),decay of delayed rectifier potassium current,etc.Funny current(I_f)has long been recognized as展开更多
基金the National NaturalScience Foundation of China(No: 30570739)
文摘Objective To study the effect of ivabradine on hyperpolarization activated cation current in canine pulmonary vein(PY) sleeve cardiomyocytes with atrial fibrillation.Methods Dissociation of PVs yielded single cardiomyocytes from a Landengorff column without or with pacemaker activity from long-term rapidly atrial pacing (RAP) canines.If current was measured with the whole-cell patch-clamp technique.Results Compared with the control group,the rapidly atrial pacing canine PV cardiomyocytes had spontaneous diastolic depolarization and had larger If densities.Ivabradine (Iva,1 μM),a selective inhibitor of the If current,markedly reduced If currents in the RAP from -2.66±0.4 pA/pF to -1.58±0.1 pA/pF at the test potential of-120 mV (P＜0.01,n=12).Inhibition effect of Iva of If current showed concentration-dependent range from 0.1 to 10.0μM,with IC50 of 2.2 μ M ( 1.8-2.9 μM,95% CL).Furthermore,V1/ of steady-state activated curve was shifted from -84.3±4.9 mV to -106.9±3.4 mV and k value of steady-state activated curve was changed from 12.1+2.6 mV to 9.9±3.4 mV by the application of.1.0 μM Iva ( P＜0.01,n=12).Conclusions Our study revealed that Ivarbadine may significantly decrease If of rapidly atrial pacing pulmonary vein sleeve ceUs with atrial fibdllation.(J Geriatr Cardiol 2008;5:39-42)
基金the National Natural Science Foundation of China(No.30470559,30330230,30240059)the National Basic Research Development Program(973)of China(No.2007CB512501)Beijing Natural Science Foundation(No.7052039)
文摘Dorsal root ganglion(DRG)neurons have peripheral terminals in skin,muscle,and other peripheral tissues,andcentral
基金Supported by Science and Technology Commission of Shanghai Municipality,No. 10ZR1417300Educational Commission of Shanghai Municipality,No. 10ZZ69
文摘AIM:To assess the role of hyperpolarization-activated cyclic nucleotide-gated cation(HCN) channels in regulating the excitability of vagal and spinal gut afferents.METHODS:The mechanosensory response of mesenteric afferent activity was measured in an ex vivo murine jejunum preparation.HCN channel activity was recorded through voltage and current clamp in acutely dissociated dorsal root ganglia(DRG) and nodose ganglia(NG) neurons retrogradely labeled from the small intestine through injection of a fluorescent marker(DiI).The isoforms of HCN channels expressed in DRG and NG neurons were examined by immunohistochemistry.RESULTS:Ramp distension of the small intestine evoked biphasic increases in the afferent nerve activity,reflecting the activation of low-and high-threshold fibers.HCN blocker CsCl(5 mmol/L) preferentially inhibited the responses of low-threshold fibers to distension and showed no significant effects on the high-threshold responses.The effect of CsCl was mimicked by the more selective HCN blocker ZD7288(10 μmol/L).In 71.4% of DiI labeled DRG neurons(n = 20) and 90.9% of DiI labeled NG neurons(n = 10),an inward current(I h current) was evoked by hyperpolarization pulses which was fully eliminated by extracellular CsCl.In neurons expressing I h current,a typical "sag" was observed upon injection of hyperpolarizing current pulses in current-clamp recordings.CsCl abolished the sag entirely.In some DiI labeled DRG neurons,the I h current was potentiated by 8-Br-cAMP,which had no effect on the I h current of DiI labeled NG neurons.Immunohistochemistry revealed differential expression of HCN isoforms in vagal and spinal afferents,and HCN 2 and HCN 3 seemed to be the dominant isoform in DRG and NG,respectively.CONCLUSION:HCNs differentially regulate the excitability of vagal and spinal afferent of murine small intestine.
文摘Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels in the heart modulate cardiac automaticity via the hyperpolarization-activated cation current ( named Ⅰf, Ⅰh, or Ⅰq). Recent studies have unveiled the molecular identity of HCN (HCN1-4) channels. HCN isoforms are unevenly expressed in the heart, even in the sinoatrial node. Features of HCN currents have been characterized in cardiac and other types of cells or in cell lines transfected with the HCN isoforms. The factors modulating Ih and the physiological significance of HCN channels in the heart have been extensively investigated in recent years. The hypothesis for transplanting and/or creating biological pacemakers to replace diseased sinoatrial and/or atrioventricular nodes has been postulated and tested in animal models. Local overexpression of HCN2 channels in the left atrium or in the left conductive bundle branch of the left ventricle via gene delivery induced significant Ⅰh and escape rhythms during vagal stimulation in canines. In addition, implantation of human mesenchymal stem cells with overexpression of HCN2 channels to the canine left ventricular wall was associated with formation of spontaneous escape rhythms of left-sided origin during vagal-stimulation-induced sinus arrest. This preliminary data suggest that the use of HCN channels may hold great promise in,the development of biological pacemakers.
文摘Abstract Hyperpolarization-activated cyclic-nucleotide-gated ( HCN) channels in the heart modulate cardiac automaticity via the hyperpolarization-activated cation current (named If, Ih, or Iq). Recent studies have unveiled the molecular identity of HCN (HCN 1-4) channels. HCN isoforms are unevenly expressed in the heart, even in the sinoatrial node. Features of HCN currents have been characterized in cardiac and other types of cells or in cell lines transfected with the HCN isoforms. The factors modulating Ih and the physiological significance of HCN channels in the heart have been extensively investigated in recent years. The hypothesis for transplanting and/or creating biological pacemakers to replace diseased sinoatrial and/or atrioventricular nodes has been postulated and tested in animal models. Local overexpression of HCN2 channels in the left atrium or in the left conductive bundle branch of the left ventricle via gene delivery induced significant Ih and escape rhythms during vagal stimulation in canines. In addition, implantation of human mesenchymal stem cells with overexpression of HCN2 channels to the canine left ventricular wall was associated with formation of spontaneous escape rhythms of left-sided origin during vagal-stimulation-induced sinus arrest. This preliminary data suggest that the use of HCN channels may hold great promise in the development of biological pacemakers.
文摘The action potential （Na<sup>+</sup> spike） of neurons is often followed by a compound after hyperpolarization （AHP） which is mediated by Ca<sup>2+</sup>-dependent K<sup>+</sup> channels. Pyramidal cells in the cerebral cortex are known to have fast, medium and slow AHPs. It is commonly accepted that the fast AHP （fAHP） is mediated by a kind of C- or BK-K<sup>+</sup> channels. The fAHP is characterized by a short duration of about 20 ms, its remarkable voltage dependence and sensitivity to low concentration （【1 mmol/L） of Tetraethylammonium （TEA）.The mAHP results from activation of AHP- or SK-K<sup>+</sup> channels and has a long duration over 200 ms. It is poorly voltage-dependent and blocked by Apamin, but not by TEA.
基金Supported by the University of Science and Technology Foundation of Shanxi Province (Grant No. 200713010)
文摘The effects of rises in external K+(Kext) were examined on the hyperpolarization-activated cation current(Ih) in rat dorsal root ganglion neurons using the whole-cell patch clamp technique.The results showed that Kext increased Ih in a certain concentration and voltage-dependent manner.At the basal Kext level(4 mmol/L),Ih had a maximal amplitude of 1085 ± 340 pA which was enhanced by ～45% and ～92% at 8 and 16 mmol/L Kext,respectively.The midpoint activation voltage was significantly shifted from -98 mV in the hyperpolarizing direction by 8 and 12 mV at 8 and 16 mmol/L Kext,respectively with alteration of the activation course of Ih.The short time constants of activation became longer with the increasing amplitude of the command potential upon rises in Kext.The long time constants became shorter.The reversal potentials were shifted in the positive direction without significant alterations upon rises in Kext.According to the functional role of Ih,Kext increased Ih,resulting in an enhanced neuronal excitability,which might produce activation potential abnormality and perhaps neuropathic pain involved.
基金This study was supported by the grants from the National"863"Program(No.2001AA2160313)Beijing Important Program Fund of Science and Technology(No.H020220010490)Capital Medical Development Fund of Science and Technology(No.2003-3002)
文摘The action potential of pacemaker cells in thesino-atrial node forms the automatic rhythm of theheart.The automatic depolarization in phase 4 is the basisof the automaticity in pacemaker cells.Many currents areincluded in phase 4,such as calcium current,TTX-sensitive sodium current,sustained inward current(I_(si)),decay of delayed rectifier potassium current,etc.Funny current(I_f)has long been recognized as
