AIM:To investigate the effect of hydrogen sulfide(H2S)on smooth muscle motility in the gastric fundus.METHODS:The expression of cystathionineβ-synthase(CBS)and cystathionineγ-lyase(CSE)in cultured smooth muscle cell...AIM:To investigate the effect of hydrogen sulfide(H2S)on smooth muscle motility in the gastric fundus.METHODS:The expression of cystathionineβ-synthase(CBS)and cystathionineγ-lyase(CSE)in cultured smooth muscle cells from the gastric fundus was examined by the immunocytochemistry technique.The tension of the gastric fundus smooth muscle was recorded by an isometric force transducer under the condition of isometric contraction with each end of the smooth muscle strip tied with a silk thread.Intracellular recording was used to identify whether hydrogen sulfide affects the resting membrane potential of the gastric fundus in vitro.Cells were freshly separated from the gastric fundus of mice using a variety of enzyme digestion methods and whole-cell patch-clamp technique was used to find the effects of hydrogen sulfide on voltage-dependent potassium channel and calcium channel.Calcium imaging with fura-3AM loading was used to investigate the mechanism by which hydrogen sulfide regulates gastric fundus motility in cultured smooth muscle cells.RESULTS:We found that both CBS and CSE were expressed in the cul tured smooth muscle cel ls from the gastric fundus and that H2S increased the smooth muscle tension of the gastric fundus in mice at low concentrations.In addition,nicardipine and aminooxyacetic acid(AOAA),a CBS inhibitor,reduced the tension,whereas Nω-nitro-L-arginine methyl ester,a nonspecific nitric oxide synthase,increased the tension.The AOAA-induced relaxation was significantly recovered by H2S,and the Na HS-induced increase in tonic contraction was blocked by 5 mmol/L4-aminopyridine and 1μmol/L nicardipine.Na HS significantly depolarized the membrane potential and inhibited the voltage-dependent potassium currents.Moreover,Na HS increased L-type Ca2+currents and caused an elevation in intracellular calcium([Ca2+]i).CONCLUSION:These findings suggest that H2S may be an excitatory modulator in the gastric fundus in mice.The excitatory effect is mediated by voltagedependent potassium and L-type calcium channels.展开更多
Ion channels modulate cellular excitability by regulating ionic fluxes across biological membranes.Pathogenic mutations in ion channel genes give rise to epileptic disorders that are among the most frequent neurologic...Ion channels modulate cellular excitability by regulating ionic fluxes across biological membranes.Pathogenic mutations in ion channel genes give rise to epileptic disorders that are among the most frequent neurological diseases affecting millions of individuals worldwide.Epilepsies are trigge red by an imbalance between excitatory and inhibitory conductances.However,pathogenic mutations in the same allele can give rise to loss-of-function and/or gain-of-function va riants,all able to trigger epilepsy.Furthermore,certain alleles are associated with brain malformations even in the absence of a clear electrical phenotype.This body of evidence argues that the underlying epileptogenic mechanisms of ion channels are more diverse than originally thought.Studies focusing on ion channels in prenatal cortical development have shed light on this apparent paradox.The picture that emerges is that ion channels play crucial roles in landmark neurodevelopmental processes,including neuronal migration,neurite outgrowth,and synapse formation.Thus,pathogenic channel mutants can not only cause epileptic disorders by alte ring excitability,but further,by inducing morphological and synaptic abnormalities that are initiated during neocortex formation and may persist into the adult brain.展开更多
The influence of hypoxia on the activity of voltage-gated potassium channel in pulmonary artery smooth muscle cells(PASMCs) of rats and its roles in the pathogenesis of chronic pulmonary heart disease were investigate...The influence of hypoxia on the activity of voltage-gated potassium channel in pulmonary artery smooth muscle cells(PASMCs) of rats and its roles in the pathogenesis of chronic pulmonary heart disease were investigated. Eighty male Sprague-Dawley rats were randomly allocated into control group(n=10), acute hypoxic group(n=10), and chronic hypoxic groups(n=60). The chronic hypoxic groups were randomly divided into 6 subgroups(n=10 each) according to the chronic hypoxic periods.The rats in the control group were kept in room air and those in acute hypoxic group in hypoxia environmental chamber for 8 h. The rats in chronic hypoxic subgroups were kept in hypoxia environmental chamber for 8 h per day for 5, 10, 15, 20, 25, and 30 days, respectively. The mean pulmonary arterial pressure(mPAP), right ventricular hypertrophy index(RVHI), and the current of voltage-gated potassium channel(IK) in PASMCs were measured. Results showed that both acute and chronic hypoxia could decrease the IK in PASMCs of rats and the I-V relationship downward shifted to the right. And the peak IK density at +60mV decreased with prolongation of hypoxia exposure. No significant difference was noted in the density of IK(at +60 mV) and I-V relationship between control group and chronic hypoxic subgroup exposed to hypoxia for 5 days(P>0.05), but there was a significant difference between control group and chronic hypoxic subgroup exposed to hypoxia for 10 days(P<0.05). Significant differences were noted in the IK density(at +60 mV) and I-V relationships between control group and chronic hypoxic subgroups exposed to hypoxia for 20 days and 30 days(P<0.01). Compared with control rats, the mPAP and RVHI were significantly increased after chronic exposure to hypoxia for 10 days(P<0.05), which were further increased with prolongation of hypoxia exposure, and there were significant differences between control group and chronic hypoxic subgroups exposed to hypoxia for 20 days and 30 days(P<0.01). Both the mPAP and the RVHI were negatively correlated with the density of IK(r=–0.89769 and –0.94476, respectively, both P<0.01). It is concluded that exposure to hypoxia may cause decreased activity of voltage-gated potassium channel, leading to hypoxia pulmonary vasoconstriction(HPV). Sustained HPV may result in chronic pulmonary hypertension, even chronic pulmonary heart disease, contributing to the pathogenesis of chronic pulmonary heart disease.展开更多
Catilan extracted from Leiurus quinquestriatus is a specific ion channel blocker.It can specifically bind chloride channels of glioma cells and kill these tumor cells.The questions remain as to whether antigliomatin,t...Catilan extracted from Leiurus quinquestriatus is a specific ion channel blocker.It can specifically bind chloride channels of glioma cells and kill these tumor cells.The questions remain as to whether antigliomatin,the extract from scorpion venom of Buthus martensii Karsch in China,can inhibit glioma growth,and whether this inhibition is correlated with ion channels of tumor cells.The present study treated rat C6 glioma cells with 0.8,1.2,and 1.6 μg/mL antigliomatin for 20 hours.Whole-cell patch clamp technique showed that antigliomatin delayed rectifier potassium channels of C6 glioma cells.Antigliomatin inhibited tumor growth,which could potentially involve potassium channels of tumor cells.展开更多
The effects of levobunolol hydrochlorid (Bun) on the type L calciumchannel currents (Ica) and delayed rectifier potassium channel currents (Ik) in isolated ventricular myocytes of guinea pig were studied by using patc...The effects of levobunolol hydrochlorid (Bun) on the type L calciumchannel currents (Ica) and delayed rectifier potassium channel currents (Ik) in isolated ventricular myocytes of guinea pig were studied by using patch clamp wholecell recording techniques. The results were showed that: 1) Bun caused a dosedependent decrease in Ica and a dose-dependent increase in Ik of the ventricular myocytes.The threshold concentrations of Bun for Ica and Ik were 10-8 mol/L and10-7 mol/L respectively. The maximum effective concentration of Bun for both Ica and Ik was 3 × 10-5 mol/L, and half-maximal concentration was 3 × 10-6 mol/L;2 ) Ik was blocked by 2× 10-6mol/L tetraethylammonium (TEA). A concentration of 3 × 10-6 mol/L Bun showed a decreasing effect on the Ica as revealed by the current-voltage relationship curve, i. e., Bun caused an elevation of the curve; 3)When Ica was blocked by 2 × 10-6 mol/L Isoptin (Verapamil), at a concentrationof 3 × 106- mol/L Bun showed an increasing effect on Ik and the effect could be blocked by TEA. The above-mentioned results indicated that Bun had an inhibito-ry effect on Ica and a fascilitatory effect on Ik The results suggested that themolecular mechanisms of antihypertensive, heart rate slowing and β-receptorblocking effects of Bun might be due to decrease of Ica and increase of Ik.展开更多
There is accumulating evidence that the subfamily of large-conductance potassium (“big”, “BK”) channels are involved in diverse, and perhaps coordinated, protective or counteractive responses to local or generaliz...There is accumulating evidence that the subfamily of large-conductance potassium (“big”, “BK”) channels are involved in diverse, and perhaps coordinated, protective or counteractive responses to local or generalized ischemia and hypoxia. Although widely distributed, the physiological differences among BK channels which results from posttranslational modification (alternative splicing) and co-assembly with auxiliary modulatory subunits (<em>β</em><sub>1-4</sub> and <em>γ</em><sub>1-4</sub>), bestows localized differences in subunit composition, distribution, 2<sup>nd</sup>-messenger coupling, and pharmacologic properties. Due to the ubiquitous nature of BK channels and the multiplicity of subtypes, they have many potential therapeutic applications in the maintenance of oxygen homeostasis, cerebro- and cardio-protection, and stimulation of respiration in response to drug-induced respiratory depression. BK channels may also offer other potentially broad and underrecognized promising targets for novel pharmaceutical development.展开更多
Objectives To investigate the effect of Gαq/11 signaling pathway and ATP-sensitive potassium channel ( KATP channel ) on ischemic preconditioning (IPC) protection in rat hearts. Methods Two series of experiments were...Objectives To investigate the effect of Gαq/11 signaling pathway and ATP-sensitive potassium channel ( KATP channel ) on ischemic preconditioning (IPC) protection in rat hearts. Methods Two series of experiments were performed in Wistar rat hearts. In the first series of experiment, ischemic preconditioning was induced by left anterior descending occlusion (three, 5 min episodes separated by 5 min of reperfusion), ischemia-reperfusion injury was induced by 30 min coronary artery occlusion followed by 90 min reperfusion. Hemodynamics, infarct size and scores of ventricular arrhythmias were measured. The expression of Gαq/11 protein in the heart was measured by Western blot analysis in the second series. Results Ischemic preconditioning rats showed decreased infarct size and scores of ventricular arrhythmia vs non-IP control rats. The effect of IPC was significantly attenuated by glibenclamide (1 mg/kg, ip), a nonselective KATP channel inhibitor. IPC caused a significant increase in the expression of Gαq/11 protein. Conclusions Activations of Gαq/11 signal pathway and KATP channel played significant roles in the classical cardioprotection of ischemic precon-ditioning rat heart and might be an important mechanism of signal transduction pathway during the ischemic preconditioning.展开更多
This study investigated the effects of ATP-sensitive potassium channels on the expression of P21, P27 and leptin. The expression of receptor of ATP-sensitive potassium channels (sulphony- lurea receptor, SUR) mRNA in ...This study investigated the effects of ATP-sensitive potassium channels on the expression of P21, P27 and leptin. The expression of receptor of ATP-sensitive potassium channels (sulphony- lurea receptor, SUR) mRNA in the preadipocytes and leptin mRNA was detected by PCR after rat preadipocytes were treated with the opener (diazoxide) or inhibitor (glibenclamide) of ATP-sensitive potassium channels during the process of inducing differentiation. The expression of P21 and P27 in preadipocytes treated with diazoxide or glibenclamide was assayed by Western blot. The results showed that the expression of SUR2, not SUR1 was detected in adipose tissue, preadipocytes and adipocytes. After treatment of preadipocytes with diazoxide, the expression levels of P21 and P27 were obviously higher than those in control group, but the expression levels of P21 and P27 in glibenclamide-treated group were lower than those in control group. During the process of inducing differentiation, the expression of leptin mRNA in preadipocytes treated with diazoxide was increased greatly, but the expression of leptin mRNA in glibenclamide-treated group decreased obviously. It was concluded that ATP-sensitive potassium channels might be involved in the proliferation and dif- ferentiation of rat preadipocytes by changing the expression of P21, P27 and leptin.展开更多
Objectives Ischemia induced arrhythmia(ventricular tachycardia/ventricular fibrillation) is one of the major causes of death.Potassium channels change are likely to be responsible for the ischemia-related arrhythmias....Objectives Ischemia induced arrhythmia(ventricular tachycardia/ventricular fibrillation) is one of the major causes of death.Potassium channels change are likely to be responsible for the ischemia-related arrhythmias.Cardiac potassium current is the major outward current involved in cardiac repolarization.The properties of potassium channels have been intensively studied.Here,we investigated the association between ischemia induced arrhythmia and potassium channels genetic variations.Methods 23 patients with ventricular tachycardia/ventricular fibrillation induced by ischemia were selected as objects.5ML peripheral blood were taken from each person,from which DNA was extracted us- ing a standard enzymatic phenol-chloroform method.Candidate genes(HERG、KCNJ2、KCNQ1、Mink、Mirp1、Kir2.1、KV4.3、Kir3.1、KV1.5、Kir6.1、Kir6.2、Kir2.1) Were screened for potassium channels gene mutations with direct sequencing methods.Results Here 4 potassium channels gene mutations have been discovered.In the gene coding for the ATP-sensitive K^+ channels subunit Kir6.2,there is a change from valine to isoleucine at the position of 326(V326I).At the position 448,arginine substitutes proline(P448R) in the KC-NQ1 gene.In the gene KCNJ2 two mutations have been found(P156L,Q193H).Conclusions This study implicated that there is a high relationship between ischemia induced arrhythmia and the mutation of potassium channels.In order to identify the precisely relationship there is need functional analysis.展开更多
Objective: To investigate the role of large Ca2+-activated, delayed-rectifier and ATP-sensitive potassium channel in regulating the relaxation induced by nitric oxide (NO) in normal and passively sensitized human airw...Objective: To investigate the role of large Ca2+-activated, delayed-rectifier and ATP-sensitive potassium channel in regulating the relaxation induced by nitric oxide (NO) in normal and passively sensitized human airway smooth muscle (HASM) with serum from asthmatic patients. Methods: The effects of NO or/and potassium channel blockers on the tensions of normal and passively sensitized HASM were measured by using nitric oxide donor and potassium blockers, with the isometric tension recording technique. Results: Showed that(1)In the control group and passively sensitized group, Kv blocker(4-AP) cause concentration-dependent augmentation in the contraction induced by histamine(1×10-4 mol/L),(P﹤0.05),but Glib (1×10-2 mol/L) and TEA(1×10-3 mol/L) have no significant effects on the contraction induced by histamine(1×10-4 mol/L). The maximum tension induced by histamine in passively sensitized group is higher than that in the control group (P﹤0.05). (2) NO-donor Sodium Nitroprusside (SNP) bring about significant relaxation in normal and passively sensitized HASM rings (P﹤0.05). Relaxations of passively sensitized airway rings [(29.4 ± 3.3)%] were significant less than those of normal HASM rings[(44.1 ± 10.2)%],(P﹤0.05).(3) Glib(1×10-2 mol/L)have no significant effect on the relaxations induced by SNP(1×10-4 mol/L). 4-AP(1×10-2 mol/L) inhibited relaxation induced by SNP(1×10-4 mol/L),(P﹤0.01). TEA(1×10-3 mol/L) inhibited relaxation induced by SNP(1×10-4 mol/L)(P﹤0.05), and the inhibiting effect in passively sensitized HASM rings were significant less than in normal HASM,(P﹤0.05). Conclusion: It was concluded that SNP(NO-donor) relaxed the contraction of HASM partly via BKca channel opening. In passively sensitized HASM in vitro, the relaxation of SNP decreased compared with control group, which might be associated with the down-regulating activity of BKca in passively sensitized HASM. .展开更多
Objective: To investigate changes of Ca2+ activated potassium channels (KCa) in autogenous vein grafts. Methods: Contraction of venous ring was measured by means of perfusion in vitro. The intimal rabbits proliferatio...Objective: To investigate changes of Ca2+ activated potassium channels (KCa) in autogenous vein grafts. Methods: Contraction of venous ring was measured by means of perfusion in vitro. The intimal rabbits proliferation of vascular and proliferation of cultured smooth muscle cells(vascular smooth muscle cells, VSMCs)were observed by the means of computerised image analysis and MTT method respectively. Furthermore, whole cell mode of patch clamp was used to record KCa of VSMCs isolated from autogenous vein grafts. Results: One week after transplantation there were no significant differences of contraction and intimal relative thickness between autogenous vein grafts and control. Contraction and intimal relative thickness of autogenous vein graft were significantly increased 2 weeks after transplantation (P<0.05, n=8 vs control), and they was more enhanced 4 weeks after vein transplantation (P<0.01, n=8 vs control).TEA(blocker of Ca2+ activated potassium channels)increased MTT A490 nm value of VSMCs from femoral vein in a dose dependent manner(P<0.05, n=8). KCa current density was significantly attenuated in VSMCs from autogenous vein grafts (1-4) week after transplantation(P<0.05, n=5).Conclusion: KCa is inhibited in autogenous vein graft, which account for vasospasm and intimal proliferation.展开更多
In this study, we treated PC12 cells with 0-20 μM amyloid-β peptide (25-35) for 24 hours to induce cytotoxicity, and found that 5-20 μM amyloid-β peptide (25-35) decreased PC12 cell viability, but adenosine tripho...In this study, we treated PC12 cells with 0-20 μM amyloid-β peptide (25-35) for 24 hours to induce cytotoxicity, and found that 5-20 μM amyloid-β peptide (25-35) decreased PC12 cell viability, but adenosine triphosphate-sensitive potassium channel activator diazoxide suppressed the decrease in PC12 cell viability induced by amyloid-β peptide (25-35). Diazoxide protected PC12 cells against amyloid-β peptide (25-35)-induced increases in mitochondrial membrane potential and intracellular reactive oxygen species levels. These protective effects were reversed by the selective mitochondrial adenosine triphosphate-sensitive potassium channel blocker 5-hydroxydecanoate. An inducible nitric oxide synthase inhibitor, Nω-nitro-L-arginine, also protected PC12 cells from amyloid-β peptide (25-35)-induced increases in both mitochondrial membrane potential and intracellular reactive oxygen species levels. However, the H2O2-degrading enzyme catalase could not reverse the amyloid-β peptide (25-35)-induced increase in intracellular reactive oxygen species. A 24-hour exposure to amyloid-β peptide (25-35) did not result in apoptosis or necrosis, suggesting that the increases in both mitochondrial membrane potential and reactive oxygen species levels preceded cell death. The data suggest that amyloid-β peptide (25-35) cytotoxicity is associated with adenosine triphosphate-sensitive potassium channels and nitric oxide. Regulation of adenosine triphosphate-sensitive potassium channels suppresses PC12 cell cytotoxicity induced by amyloid-β peptide (25-35).展开更多
Uging diet control method to feed the weaning male Wistar rats with selenium and iodine deficiency Keshan endemic area food for 8 weeks to set up animal model. Singal channel recortling in cell attached model was used...Uging diet control method to feed the weaning male Wistar rats with selenium and iodine deficiency Keshan endemic area food for 8 weeks to set up animal model. Singal channel recortling in cell attached model was used to measure cardiac cell membrane potassium channel conductances. which coincide with the cardiac cell membrane potassium channel conductances in normal Wistar rats.The potassium channel conductance on selenlum and lodine cleficiency rat cardiac cell membrane is showing current-voltage increasing lineally in the range of clamping volatge 0±30 mV with channel conductance of 43.4 pS. The channel current does not increase depending on the clamping voltage that is showing the rectifying characteristic and the channel current amplitude can be augmented by added KIOa 5 mmol/L in bath solution. A kind of inward rectiyfing potassium channel activity was recorded, but this channel activity disappeared affer lasting 6～ 10 minutes only. Then an inward rectifying potassium channel with the conductance of 11. 2 PS was activated by KIOa 5 mmol/L, introduced to bath solution. Both conductances are less than that of normal Wistar rats.展开更多
Diabetes mellitus affects the heart through various mechanisms such as microvascular defects,metabolic abnormalities,autonomic dysfunction and incompatible immune response.Furthermore,it can also cause functional and ...Diabetes mellitus affects the heart through various mechanisms such as microvascular defects,metabolic abnormalities,autonomic dysfunction and incompatible immune response.Furthermore,it can also cause functional and structural changes in the myocardium by a disease known as diabetic cardiomyopathy(DCM)in the absence of coronary artery disease.As DCM progresses it causes electrical remodeling of the heart,left ventricular dysfunction and heart failure.Electrophysiological changes in the diabetic heart contribute significantly to the incidence of arrhythmias and sudden cardiac death in diabetes mellitus patients.In recent studies,significant changes in repolarizing K+currents,Na+currents and L-type Ca^(2+)currents along with impaired Ca^(2+ )homeostasis and defective contractile function have been identified in the diabetic heart.In addition,insulin levels and other trophic factors change significantly to maintain the ionic channel expression in diabetic patients.There are many diagnostic tools and management options for DCM,but it is difficult to detect its development and to effectively prevent its progress.In this review,diabetes-associated alterations in voltage-sensitive cardiac ion channels are comprehensively assessed to understand their potential role in the pathophysiology and pathogenesis of DCM.展开更多
Although it has been more than 165 years since the first introduction of modern anesthesia to the clinic, there is surprisingly little understanding about the exact mechanisms by which general anesthetics induce uncon...Although it has been more than 165 years since the first introduction of modern anesthesia to the clinic, there is surprisingly little understanding about the exact mechanisms by which general anesthetics induce unconsciousness. As a result, we do not know how general anesthetics produce anesthesia at different levels. The main handicap to understanding the mechanisms of general anesthesia is the diversity of chemically unrelated compounds including diethyl ether and halogenated hydrocarbons, gases nitrous oxide, ketamine, propofol, benzodiazepines and etomidate, as well as alcohols and barbiturates. Does this imply that general anesthesia is caused by many different mechanisms? Until now, many receptors, molecular targets and neuronal transmission pathways have been shown to contribute to mechanisms of general anesthesia. Among these molecular targets, ion channels are the most likely candidates for general anesthesia, in particular γ-aminobutyric acid type A, potassium and sodium channels, as well as ion channels mediated by various neuronal transmitters like acetylcholine, amino acids amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid or N-methyl-D-aspartate. In addition, recent studies have demonstrated the involvement in general anesthesia of other ion channels with distinct gating properties suchas hyperpolarization-activated, cyclic- nucleotide-gated channels. The main aim of the present review is to summarize some aspects of current knowledge of the effects of general anesthetics on various ion channels.展开更多
Hypoxic pulmonary hypertension(HPH) is a syndrome characterized by the increase of pulmonary vascular tone and the structural remodeling of peripheral pulmonary arteries.The aim of specific therapies for hypoxic pulmo...Hypoxic pulmonary hypertension(HPH) is a syndrome characterized by the increase of pulmonary vascular tone and the structural remodeling of peripheral pulmonary arteries.The aim of specific therapies for hypoxic pulmonary hypertension is to reduce pulmonary vascular resistance,reverse pulmonary vascular remodeling,and thereby improving right ventricular function.Iptakalim,a lipophilic para-amino compound with a low molecular weight,has been demonstrated to be a new selective ATP-sensitive potassium(K ATP) channel opener via pharmacological,electrophysiological,biochemical studies,and receptor binding tests.In hypoxia-induced animal models,iptakalim decreases the elevated mean pressure in pulmonary arteries,and attenuates remodeling in the right ventricle,pulmonary arteries and airways.Furthermore,iptakalim has selective antihypertensive effects,selective vasorelaxation effects on smaller arteries,and protective effects on endothelial cells,but no effects on the central nervous,respiratory,digestive or endocrine systems at therapeutic dose.Our previous studies demonstrated that iptakalim inhibited the effects of endothelin-1,reduced the intracellular calcium concentration and inhibited the proliferation of pulmonary artery smooth muscle cells.Since iptakalim has been shown safe and effective in both experimental animal models and phase I clinical trials,it can be a potential candidate of HPH in the future.展开更多
Remodeling of ion channels is an important mechanism of arrhythmia induced by heart failure (HF).We investigated the expression of potassium channel encoding genes in the ventricles of rabbit established by volumeover...Remodeling of ion channels is an important mechanism of arrhythmia induced by heart failure (HF).We investigated the expression of potassium channel encoding genes in the ventricles of rabbit established by volumeoverload operation followed with pressure-overload.The reversible effect of these changes with bisoprolol was also evaluated.The HF group exhibited left ventricular enlargement,systolic dysfunction,prolongation of corrected QT interval (QTc),and increased plasma brain natriuretic peptide levels in the HF rabbits.Several potassium channel subunit encoding genes were consistently down-regulated in the HF rabbits.After bisoprolol treatment,heart function was improved significantly and QTc was shortened.Additionally,the mRNA expression of potassium channel subunit genes could be partially reversed.The down-regulated expression of potassium channel subunits Kv4.3,Kv1.4,KvLQT1,minK and Kir 2.1 may contribute to the prolongation of action potential duration in the heart of rabbits induced by volume combined with pressure overload HF.Bisoprolol could partially reverse these down-regulations and improve heart function.展开更多
基金Supported by National Natural Science Foundation of China,No.31171107,No.31071011 and No.31271236
文摘AIM:To investigate the effect of hydrogen sulfide(H2S)on smooth muscle motility in the gastric fundus.METHODS:The expression of cystathionineβ-synthase(CBS)and cystathionineγ-lyase(CSE)in cultured smooth muscle cells from the gastric fundus was examined by the immunocytochemistry technique.The tension of the gastric fundus smooth muscle was recorded by an isometric force transducer under the condition of isometric contraction with each end of the smooth muscle strip tied with a silk thread.Intracellular recording was used to identify whether hydrogen sulfide affects the resting membrane potential of the gastric fundus in vitro.Cells were freshly separated from the gastric fundus of mice using a variety of enzyme digestion methods and whole-cell patch-clamp technique was used to find the effects of hydrogen sulfide on voltage-dependent potassium channel and calcium channel.Calcium imaging with fura-3AM loading was used to investigate the mechanism by which hydrogen sulfide regulates gastric fundus motility in cultured smooth muscle cells.RESULTS:We found that both CBS and CSE were expressed in the cul tured smooth muscle cel ls from the gastric fundus and that H2S increased the smooth muscle tension of the gastric fundus in mice at low concentrations.In addition,nicardipine and aminooxyacetic acid(AOAA),a CBS inhibitor,reduced the tension,whereas Nω-nitro-L-arginine methyl ester,a nonspecific nitric oxide synthase,increased the tension.The AOAA-induced relaxation was significantly recovered by H2S,and the Na HS-induced increase in tonic contraction was blocked by 5 mmol/L4-aminopyridine and 1μmol/L nicardipine.Na HS significantly depolarized the membrane potential and inhibited the voltage-dependent potassium currents.Moreover,Na HS increased L-type Ca2+currents and caused an elevation in intracellular calcium([Ca2+]i).CONCLUSION:These findings suggest that H2S may be an excitatory modulator in the gastric fundus in mice.The excitatory effect is mediated by voltagedependent potassium and L-type calcium channels.
基金NJ Governor’s Council for Medical Research and Treatment of Autism predoctoral fellowship (CAUT23AFP015) to ABNational Science Foundation grant (2030348) to FS。
文摘Ion channels modulate cellular excitability by regulating ionic fluxes across biological membranes.Pathogenic mutations in ion channel genes give rise to epileptic disorders that are among the most frequent neurological diseases affecting millions of individuals worldwide.Epilepsies are trigge red by an imbalance between excitatory and inhibitory conductances.However,pathogenic mutations in the same allele can give rise to loss-of-function and/or gain-of-function va riants,all able to trigger epilepsy.Furthermore,certain alleles are associated with brain malformations even in the absence of a clear electrical phenotype.This body of evidence argues that the underlying epileptogenic mechanisms of ion channels are more diverse than originally thought.Studies focusing on ion channels in prenatal cortical development have shed light on this apparent paradox.The picture that emerges is that ion channels play crucial roles in landmark neurodevelopmental processes,including neuronal migration,neurite outgrowth,and synapse formation.Thus,pathogenic channel mutants can not only cause epileptic disorders by alte ring excitability,but further,by inducing morphological and synaptic abnormalities that are initiated during neocortex formation and may persist into the adult brain.
文摘The influence of hypoxia on the activity of voltage-gated potassium channel in pulmonary artery smooth muscle cells(PASMCs) of rats and its roles in the pathogenesis of chronic pulmonary heart disease were investigated. Eighty male Sprague-Dawley rats were randomly allocated into control group(n=10), acute hypoxic group(n=10), and chronic hypoxic groups(n=60). The chronic hypoxic groups were randomly divided into 6 subgroups(n=10 each) according to the chronic hypoxic periods.The rats in the control group were kept in room air and those in acute hypoxic group in hypoxia environmental chamber for 8 h. The rats in chronic hypoxic subgroups were kept in hypoxia environmental chamber for 8 h per day for 5, 10, 15, 20, 25, and 30 days, respectively. The mean pulmonary arterial pressure(mPAP), right ventricular hypertrophy index(RVHI), and the current of voltage-gated potassium channel(IK) in PASMCs were measured. Results showed that both acute and chronic hypoxia could decrease the IK in PASMCs of rats and the I-V relationship downward shifted to the right. And the peak IK density at +60mV decreased with prolongation of hypoxia exposure. No significant difference was noted in the density of IK(at +60 mV) and I-V relationship between control group and chronic hypoxic subgroup exposed to hypoxia for 5 days(P>0.05), but there was a significant difference between control group and chronic hypoxic subgroup exposed to hypoxia for 10 days(P<0.05). Significant differences were noted in the IK density(at +60 mV) and I-V relationships between control group and chronic hypoxic subgroups exposed to hypoxia for 20 days and 30 days(P<0.01). Compared with control rats, the mPAP and RVHI were significantly increased after chronic exposure to hypoxia for 10 days(P<0.05), which were further increased with prolongation of hypoxia exposure, and there were significant differences between control group and chronic hypoxic subgroups exposed to hypoxia for 20 days and 30 days(P<0.01). Both the mPAP and the RVHI were negatively correlated with the density of IK(r=–0.89769 and –0.94476, respectively, both P<0.01). It is concluded that exposure to hypoxia may cause decreased activity of voltage-gated potassium channel, leading to hypoxia pulmonary vasoconstriction(HPV). Sustained HPV may result in chronic pulmonary hypertension, even chronic pulmonary heart disease, contributing to the pathogenesis of chronic pulmonary heart disease.
基金the Science and Technology Development Program of Jilin Province, No. 20050407-6
文摘Catilan extracted from Leiurus quinquestriatus is a specific ion channel blocker.It can specifically bind chloride channels of glioma cells and kill these tumor cells.The questions remain as to whether antigliomatin,the extract from scorpion venom of Buthus martensii Karsch in China,can inhibit glioma growth,and whether this inhibition is correlated with ion channels of tumor cells.The present study treated rat C6 glioma cells with 0.8,1.2,and 1.6 μg/mL antigliomatin for 20 hours.Whole-cell patch clamp technique showed that antigliomatin delayed rectifier potassium channels of C6 glioma cells.Antigliomatin inhibited tumor growth,which could potentially involve potassium channels of tumor cells.
文摘The effects of levobunolol hydrochlorid (Bun) on the type L calciumchannel currents (Ica) and delayed rectifier potassium channel currents (Ik) in isolated ventricular myocytes of guinea pig were studied by using patch clamp wholecell recording techniques. The results were showed that: 1) Bun caused a dosedependent decrease in Ica and a dose-dependent increase in Ik of the ventricular myocytes.The threshold concentrations of Bun for Ica and Ik were 10-8 mol/L and10-7 mol/L respectively. The maximum effective concentration of Bun for both Ica and Ik was 3 × 10-5 mol/L, and half-maximal concentration was 3 × 10-6 mol/L;2 ) Ik was blocked by 2× 10-6mol/L tetraethylammonium (TEA). A concentration of 3 × 10-6 mol/L Bun showed a decreasing effect on the Ica as revealed by the current-voltage relationship curve, i. e., Bun caused an elevation of the curve; 3)When Ica was blocked by 2 × 10-6 mol/L Isoptin (Verapamil), at a concentrationof 3 × 106- mol/L Bun showed an increasing effect on Ik and the effect could be blocked by TEA. The above-mentioned results indicated that Bun had an inhibito-ry effect on Ica and a fascilitatory effect on Ik The results suggested that themolecular mechanisms of antihypertensive, heart rate slowing and β-receptorblocking effects of Bun might be due to decrease of Ica and increase of Ik.
文摘There is accumulating evidence that the subfamily of large-conductance potassium (“big”, “BK”) channels are involved in diverse, and perhaps coordinated, protective or counteractive responses to local or generalized ischemia and hypoxia. Although widely distributed, the physiological differences among BK channels which results from posttranslational modification (alternative splicing) and co-assembly with auxiliary modulatory subunits (<em>β</em><sub>1-4</sub> and <em>γ</em><sub>1-4</sub>), bestows localized differences in subunit composition, distribution, 2<sup>nd</sup>-messenger coupling, and pharmacologic properties. Due to the ubiquitous nature of BK channels and the multiplicity of subtypes, they have many potential therapeutic applications in the maintenance of oxygen homeostasis, cerebro- and cardio-protection, and stimulation of respiration in response to drug-induced respiratory depression. BK channels may also offer other potentially broad and underrecognized promising targets for novel pharmaceutical development.
文摘Objectives To investigate the effect of Gαq/11 signaling pathway and ATP-sensitive potassium channel ( KATP channel ) on ischemic preconditioning (IPC) protection in rat hearts. Methods Two series of experiments were performed in Wistar rat hearts. In the first series of experiment, ischemic preconditioning was induced by left anterior descending occlusion (three, 5 min episodes separated by 5 min of reperfusion), ischemia-reperfusion injury was induced by 30 min coronary artery occlusion followed by 90 min reperfusion. Hemodynamics, infarct size and scores of ventricular arrhythmias were measured. The expression of Gαq/11 protein in the heart was measured by Western blot analysis in the second series. Results Ischemic preconditioning rats showed decreased infarct size and scores of ventricular arrhythmia vs non-IP control rats. The effect of IPC was significantly attenuated by glibenclamide (1 mg/kg, ip), a nonselective KATP channel inhibitor. IPC caused a significant increase in the expression of Gαq/11 protein. Conclusions Activations of Gαq/11 signal pathway and KATP channel played significant roles in the classical cardioprotection of ischemic precon-ditioning rat heart and might be an important mechanism of signal transduction pathway during the ischemic preconditioning.
文摘This study investigated the effects of ATP-sensitive potassium channels on the expression of P21, P27 and leptin. The expression of receptor of ATP-sensitive potassium channels (sulphony- lurea receptor, SUR) mRNA in the preadipocytes and leptin mRNA was detected by PCR after rat preadipocytes were treated with the opener (diazoxide) or inhibitor (glibenclamide) of ATP-sensitive potassium channels during the process of inducing differentiation. The expression of P21 and P27 in preadipocytes treated with diazoxide or glibenclamide was assayed by Western blot. The results showed that the expression of SUR2, not SUR1 was detected in adipose tissue, preadipocytes and adipocytes. After treatment of preadipocytes with diazoxide, the expression levels of P21 and P27 were obviously higher than those in control group, but the expression levels of P21 and P27 in glibenclamide-treated group were lower than those in control group. During the process of inducing differentiation, the expression of leptin mRNA in preadipocytes treated with diazoxide was increased greatly, but the expression of leptin mRNA in glibenclamide-treated group decreased obviously. It was concluded that ATP-sensitive potassium channels might be involved in the proliferation and dif- ferentiation of rat preadipocytes by changing the expression of P21, P27 and leptin.
文摘Objectives Ischemia induced arrhythmia(ventricular tachycardia/ventricular fibrillation) is one of the major causes of death.Potassium channels change are likely to be responsible for the ischemia-related arrhythmias.Cardiac potassium current is the major outward current involved in cardiac repolarization.The properties of potassium channels have been intensively studied.Here,we investigated the association between ischemia induced arrhythmia and potassium channels genetic variations.Methods 23 patients with ventricular tachycardia/ventricular fibrillation induced by ischemia were selected as objects.5ML peripheral blood were taken from each person,from which DNA was extracted us- ing a standard enzymatic phenol-chloroform method.Candidate genes(HERG、KCNJ2、KCNQ1、Mink、Mirp1、Kir2.1、KV4.3、Kir3.1、KV1.5、Kir6.1、Kir6.2、Kir2.1) Were screened for potassium channels gene mutations with direct sequencing methods.Results Here 4 potassium channels gene mutations have been discovered.In the gene coding for the ATP-sensitive K^+ channels subunit Kir6.2,there is a change from valine to isoleucine at the position of 326(V326I).At the position 448,arginine substitutes proline(P448R) in the KC-NQ1 gene.In the gene KCNJ2 two mutations have been found(P156L,Q193H).Conclusions This study implicated that there is a high relationship between ischemia induced arrhythmia and the mutation of potassium channels.In order to identify the precisely relationship there is need functional analysis.
文摘Objective: To investigate the role of large Ca2+-activated, delayed-rectifier and ATP-sensitive potassium channel in regulating the relaxation induced by nitric oxide (NO) in normal and passively sensitized human airway smooth muscle (HASM) with serum from asthmatic patients. Methods: The effects of NO or/and potassium channel blockers on the tensions of normal and passively sensitized HASM were measured by using nitric oxide donor and potassium blockers, with the isometric tension recording technique. Results: Showed that(1)In the control group and passively sensitized group, Kv blocker(4-AP) cause concentration-dependent augmentation in the contraction induced by histamine(1×10-4 mol/L),(P﹤0.05),but Glib (1×10-2 mol/L) and TEA(1×10-3 mol/L) have no significant effects on the contraction induced by histamine(1×10-4 mol/L). The maximum tension induced by histamine in passively sensitized group is higher than that in the control group (P﹤0.05). (2) NO-donor Sodium Nitroprusside (SNP) bring about significant relaxation in normal and passively sensitized HASM rings (P﹤0.05). Relaxations of passively sensitized airway rings [(29.4 ± 3.3)%] were significant less than those of normal HASM rings[(44.1 ± 10.2)%],(P﹤0.05).(3) Glib(1×10-2 mol/L)have no significant effect on the relaxations induced by SNP(1×10-4 mol/L). 4-AP(1×10-2 mol/L) inhibited relaxation induced by SNP(1×10-4 mol/L),(P﹤0.01). TEA(1×10-3 mol/L) inhibited relaxation induced by SNP(1×10-4 mol/L)(P﹤0.05), and the inhibiting effect in passively sensitized HASM rings were significant less than in normal HASM,(P﹤0.05). Conclusion: It was concluded that SNP(NO-donor) relaxed the contraction of HASM partly via BKca channel opening. In passively sensitized HASM in vitro, the relaxation of SNP decreased compared with control group, which might be associated with the down-regulating activity of BKca in passively sensitized HASM. .
文摘Objective: To investigate changes of Ca2+ activated potassium channels (KCa) in autogenous vein grafts. Methods: Contraction of venous ring was measured by means of perfusion in vitro. The intimal rabbits proliferation of vascular and proliferation of cultured smooth muscle cells(vascular smooth muscle cells, VSMCs)were observed by the means of computerised image analysis and MTT method respectively. Furthermore, whole cell mode of patch clamp was used to record KCa of VSMCs isolated from autogenous vein grafts. Results: One week after transplantation there were no significant differences of contraction and intimal relative thickness between autogenous vein grafts and control. Contraction and intimal relative thickness of autogenous vein graft were significantly increased 2 weeks after transplantation (P<0.05, n=8 vs control), and they was more enhanced 4 weeks after vein transplantation (P<0.01, n=8 vs control).TEA(blocker of Ca2+ activated potassium channels)increased MTT A490 nm value of VSMCs from femoral vein in a dose dependent manner(P<0.05, n=8). KCa current density was significantly attenuated in VSMCs from autogenous vein grafts (1-4) week after transplantation(P<0.05, n=5).Conclusion: KCa is inhibited in autogenous vein graft, which account for vasospasm and intimal proliferation.
基金supported by the Project Sponsored by Yantai Science and Technology Bureau,China,No.2010232
文摘In this study, we treated PC12 cells with 0-20 μM amyloid-β peptide (25-35) for 24 hours to induce cytotoxicity, and found that 5-20 μM amyloid-β peptide (25-35) decreased PC12 cell viability, but adenosine triphosphate-sensitive potassium channel activator diazoxide suppressed the decrease in PC12 cell viability induced by amyloid-β peptide (25-35). Diazoxide protected PC12 cells against amyloid-β peptide (25-35)-induced increases in mitochondrial membrane potential and intracellular reactive oxygen species levels. These protective effects were reversed by the selective mitochondrial adenosine triphosphate-sensitive potassium channel blocker 5-hydroxydecanoate. An inducible nitric oxide synthase inhibitor, Nω-nitro-L-arginine, also protected PC12 cells from amyloid-β peptide (25-35)-induced increases in both mitochondrial membrane potential and intracellular reactive oxygen species levels. However, the H2O2-degrading enzyme catalase could not reverse the amyloid-β peptide (25-35)-induced increase in intracellular reactive oxygen species. A 24-hour exposure to amyloid-β peptide (25-35) did not result in apoptosis or necrosis, suggesting that the increases in both mitochondrial membrane potential and reactive oxygen species levels preceded cell death. The data suggest that amyloid-β peptide (25-35) cytotoxicity is associated with adenosine triphosphate-sensitive potassium channels and nitric oxide. Regulation of adenosine triphosphate-sensitive potassium channels suppresses PC12 cell cytotoxicity induced by amyloid-β peptide (25-35).
文摘Uging diet control method to feed the weaning male Wistar rats with selenium and iodine deficiency Keshan endemic area food for 8 weeks to set up animal model. Singal channel recortling in cell attached model was used to measure cardiac cell membrane potassium channel conductances. which coincide with the cardiac cell membrane potassium channel conductances in normal Wistar rats.The potassium channel conductance on selenlum and lodine cleficiency rat cardiac cell membrane is showing current-voltage increasing lineally in the range of clamping volatge 0±30 mV with channel conductance of 43.4 pS. The channel current does not increase depending on the clamping voltage that is showing the rectifying characteristic and the channel current amplitude can be augmented by added KIOa 5 mmol/L in bath solution. A kind of inward rectiyfing potassium channel activity was recorded, but this channel activity disappeared affer lasting 6～ 10 minutes only. Then an inward rectifying potassium channel with the conductance of 11. 2 PS was activated by KIOa 5 mmol/L, introduced to bath solution. Both conductances are less than that of normal Wistar rats.
文摘Diabetes mellitus affects the heart through various mechanisms such as microvascular defects,metabolic abnormalities,autonomic dysfunction and incompatible immune response.Furthermore,it can also cause functional and structural changes in the myocardium by a disease known as diabetic cardiomyopathy(DCM)in the absence of coronary artery disease.As DCM progresses it causes electrical remodeling of the heart,left ventricular dysfunction and heart failure.Electrophysiological changes in the diabetic heart contribute significantly to the incidence of arrhythmias and sudden cardiac death in diabetes mellitus patients.In recent studies,significant changes in repolarizing K+currents,Na+currents and L-type Ca^(2+)currents along with impaired Ca^(2+ )homeostasis and defective contractile function have been identified in the diabetic heart.In addition,insulin levels and other trophic factors change significantly to maintain the ionic channel expression in diabetic patients.There are many diagnostic tools and management options for DCM,but it is difficult to detect its development and to effectively prevent its progress.In this review,diabetes-associated alterations in voltage-sensitive cardiac ion channels are comprehensively assessed to understand their potential role in the pathophysiology and pathogenesis of DCM.
文摘Although it has been more than 165 years since the first introduction of modern anesthesia to the clinic, there is surprisingly little understanding about the exact mechanisms by which general anesthetics induce unconsciousness. As a result, we do not know how general anesthetics produce anesthesia at different levels. The main handicap to understanding the mechanisms of general anesthesia is the diversity of chemically unrelated compounds including diethyl ether and halogenated hydrocarbons, gases nitrous oxide, ketamine, propofol, benzodiazepines and etomidate, as well as alcohols and barbiturates. Does this imply that general anesthesia is caused by many different mechanisms? Until now, many receptors, molecular targets and neuronal transmission pathways have been shown to contribute to mechanisms of general anesthesia. Among these molecular targets, ion channels are the most likely candidates for general anesthesia, in particular γ-aminobutyric acid type A, potassium and sodium channels, as well as ion channels mediated by various neuronal transmitters like acetylcholine, amino acids amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid or N-methyl-D-aspartate. In addition, recent studies have demonstrated the involvement in general anesthesia of other ion channels with distinct gating properties suchas hyperpolarization-activated, cyclic- nucleotide-gated channels. The main aim of the present review is to summarize some aspects of current knowledge of the effects of general anesthetics on various ion channels.
基金Acknowledgments We thank Dr Emily Liman （University of Southern California, USA） for providing the pGEMHE vector for the Xenopus oocyte experiments. We also thank Dr Richer Gaber （Northwestern Uni- versity, USA） for providing the yeast mutant strain with K＋ transport deficiency. We are grateful to Dr Rainer Hedrich （University of Wurzburg, Germany） for critical discussion. This work was supported by the National Natural Science Foundation of China （grant no. 30830013 to WHW）, the Beijing Municipal Education Commission （grant no. YB20081001901 to WHW） and the Program of Introducing Talents of Discipline to Universities （grant no. B06003 to WHW）.
基金supported by National Major Scientific and Technological Special Project for"Significant New Drugs Development"(2011ZX09302-003-02)
文摘Hypoxic pulmonary hypertension(HPH) is a syndrome characterized by the increase of pulmonary vascular tone and the structural remodeling of peripheral pulmonary arteries.The aim of specific therapies for hypoxic pulmonary hypertension is to reduce pulmonary vascular resistance,reverse pulmonary vascular remodeling,and thereby improving right ventricular function.Iptakalim,a lipophilic para-amino compound with a low molecular weight,has been demonstrated to be a new selective ATP-sensitive potassium(K ATP) channel opener via pharmacological,electrophysiological,biochemical studies,and receptor binding tests.In hypoxia-induced animal models,iptakalim decreases the elevated mean pressure in pulmonary arteries,and attenuates remodeling in the right ventricle,pulmonary arteries and airways.Furthermore,iptakalim has selective antihypertensive effects,selective vasorelaxation effects on smaller arteries,and protective effects on endothelial cells,but no effects on the central nervous,respiratory,digestive or endocrine systems at therapeutic dose.Our previous studies demonstrated that iptakalim inhibited the effects of endothelin-1,reduced the intracellular calcium concentration and inhibited the proliferation of pulmonary artery smooth muscle cells.Since iptakalim has been shown safe and effective in both experimental animal models and phase I clinical trials,it can be a potential candidate of HPH in the future.
基金supported by the State Key Program of the National Natural Science Foundation of China (No. 30830051)
文摘Remodeling of ion channels is an important mechanism of arrhythmia induced by heart failure (HF).We investigated the expression of potassium channel encoding genes in the ventricles of rabbit established by volumeoverload operation followed with pressure-overload.The reversible effect of these changes with bisoprolol was also evaluated.The HF group exhibited left ventricular enlargement,systolic dysfunction,prolongation of corrected QT interval (QTc),and increased plasma brain natriuretic peptide levels in the HF rabbits.Several potassium channel subunit encoding genes were consistently down-regulated in the HF rabbits.After bisoprolol treatment,heart function was improved significantly and QTc was shortened.Additionally,the mRNA expression of potassium channel subunit genes could be partially reversed.The down-regulated expression of potassium channel subunits Kv4.3,Kv1.4,KvLQT1,minK and Kir 2.1 may contribute to the prolongation of action potential duration in the heart of rabbits induced by volume combined with pressure overload HF.Bisoprolol could partially reverse these down-regulations and improve heart function.
