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Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive brain stimulation technique that has been paid attention to with increasing interests as a therapeutic neural rehabilitative tool. Studies confirmed that high-frequency rTMS could improve the cognitive performance in behavioral test as well as the excitability of the neuron in animals. This study aimes to investigate the effects of rTMS on the cognition and neuronal excitability of Kunming mice during the natural aging. Twelve young mice, 12 adult mice, and 12 aged mice were used, and each age group were randomly divided into rTMS group and control group. rTMS-treated groups were subjected to high-frequency rTMS treatment for 15 days, and control groups were treated with sham stimulation for 15 days. Then, novel object recognition and step-down tests were performed to examine cognition of learning and memory. Whole-cell patch clamp technique was used to record and analyze resting membrane potential, action potential (AP), and related electrical properties of AP of hippocampal dentate gyrus (DG) granule neurons. Data analysis showed that cognition of mice and neuronal excitability of DG granule neurons were degenerated significantly as the age increased. Cognitive damage and degeneration of some electrical properties were alleviated under the condition of high-frequency rTMS. It may be one of the mechanisms of rTMS to alleviate cognitive damage and improve cognitive ability by changing the electrophysiological properties of DG granule neurons and increasing neuronal excitability.
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AIM: To investigate the effect of zacopride, an inward rectifier potassium channel agonist, on ouabain-induced arrhythmias in adult rats, and to explore the underlying electrophysiological mechanism.METHODS: Using ouabain to establish in vitro and in vivo arrhythmic rat models, the effects of zacopride on ouabain-induced arrhythmias were observed.The technique of whole-cell patch clamp was used to observe the effects of zacopride on inward rectifier potassium current (IK1), resting membrane potential (RMP) and delayed afterdepolarizations (DADs) in single rat ventricular myocyte.RESULTS: Zacopride at 1 μmol/L significantly reduced total number of premature ventricular beats, and the duration and incidence of ventricular tachycardia and ventricular fibrillation induced by ouabain in rat hearts in vitro (P<0.05).In anesthetized rats, zacopride at 15 μg/kg significantly reduced total number of premature ventricular beats, and the duration and incidence of ventricular tachycardia and ventricular fibrillation induced by ouabain (P<0.05).IK1 was significantly inhibited by ouabain (P<0.05), which was partially and even completely reversed by zacopride at 0.1~10 μmol/L.RMP value was significantly reduced by ouabain (P<0.05), and then increased to different levels after treatment with zacopride (0.1~10 μmol/L).Zacopride at 1 μmol/L showed its maximal effect and RMP was restored to normal level.Moreover, zacopride at 1 μmol/L markedly suppressed ouabain-induced DADs in single rat ventricular myocyte.The incidence of DADs decreased from 91.67% to 12.50% after zacopride was applied (P<0.05), and this effect was abolished by 1 μmol/L BaCl2.CONCLUSION: Inward rectifier potassium channel agonist zacopride significantly inhibits ouabain-induced ventricular arrhythmias in adult rats.The mechanism is related to increased RMP level and inhibition of DADs by activation of IK1 channel.
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Aim To investigate the effect of zacopride ( Zac) on cardiac arrhythmia in isoproterenol ( ISO)-in-duced myocardial hypertrophic rats and the underlying electrophysiological mechanisms .Methods ① Fifty-one rats were randomly divided into control group ( n=17 ) , ISO group ( n=17 ) and ISO +Zac group ( n =17 ) .Rat model with cardiac arrhythmia and hypertro-phy was established by intraperitoneal ISO ( 5 mg?kg -1 ) injection.②ECGs were recorded to observe the effects of Zac on arrhythmia in model rats .③ Whole-cell patch clamp was applied to record inwardly rectifi-er potassium current(IK1), resting membrane potential ( RMP ) and amplicated delayed afterdepolarizations (DADs).Results ① Echocardiographic examination showed that , left ventricular end-diastolic dimension (LVEDD) and left ventricular end-systolic dimension (LVESD) significantly decreased in rats in ISO group compared with control group , whereas left ventricular posterior wall end-diastolic thickness ( LVPWd) and in-terventricular septum end-diastolic thickness ( IVSd ) increased ( P<0.05 ) , suggesting rat model of isoprot-erenol-induced myocardial hypertrophy was successfully established .② ECGs showed that 88.89% of rats in ISO group had ventricular premature beats ( VPBs ) , which significantly decreased to 11.11% after the ap-plication of Zac ( P <0.05 ) .③ Values of RMP de-creased from ( -71.05 ±1.27 ) mV in control group to (-69.38 ±1.21 ) mV in ISO group ( P<0.05 ) . After Zac administration , RMP significantly increased to ( -73.86 ±1.33 ) mV compared with control and ISO group(P<0.05).④DADs and TA incidence sig-nificantly decreased from 88.24% in ISO group to 11.76%in ISO+Zac group ( P<0.05 ) .⑤ Compared with control group , IK1 density was markedly reduced in ISO group, whereas Zac could effectively rescue IK1 suppression to normal level .Conclusions Zac, as a selective IK1 channel agonist , can significantly inhibit cardiac arrhythmia in isoproterenol-induced myocardial hypertrophic rats , which is mainly attributed to in-creased RMP by enhancing IK1 and subsequent suppres-sion of DADs.
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Aim To investigate the inhibitory effects of zacopride(Zac) on arrhythmia induced by isoproterenol ( ISO) and the underlying mechanisms in rats. Meth-ods ①ECGs were recorded in anesthetized rats in vi-vo to observe the effects of zacopride on arrhythmia in-duced by ISO. ② Intracellular microelectrode tech-nique was used to investigate the effects of zacopride on resting membrane potential, delayed afterdepolariza-tions ( DADs) and triggered activity ( TA) induced by ISO combined with 3. 6 mmol·L-1 CaCl2 in right ven-tricular papillary muscle of rats. Results ① In ISO group rats, ventricular premature beats ( VPB ) oc-curred frequently with ST-segment depression. Com-pared with ISO group, the incidence of VPB in ISO+Zac group decreased from 100% to 50% ( n=6 , P<0. 05 ) and the total number of VPB recorded in 1 hour significantly reduced from 1 574 ± 521 to 33 ± 40 ( n=6,P<0. 05). ② Zacopride at 1 μmol·L-1 could hy-perpolarize the resting membrane potential of right ven-tricular papillary muscle in normal rat from ( -74. 42 ± 1. 95 ) mV to ( -78. 50 ± 2. 07 ) mV ( n =6 , P <0. 05). ③ Zacopride at 1 μmol·L-1 significantly de-pressed the DADs and TA induced by ISO combined with 3. 6 mmol·L-1 CaCl2 in right ventricular papilla-ry muscle. The incidence of DADs decreased from 93. 75% in rats in ISO group to 25% in ISO +Zac group ( n =16 , P <0. 05 ) , and this antiarrhythmic effect could be reversed by 1 μmol·L-1 BaCl2 . Conclusions Zacopride, a selective IK1 channel ago-nist , can significantly inhibit cardiac arrthymia induced by ISO in rats, the mechanism of which is mainly at-tributed to zacopride-induced hyperpolarization of the resting membrane potential and subsequent suppression of DADs and TA via enhancing IK1 . These results pro-vide further evidence that to enhance IK1 moderately may be a feasible pathway for antiarrthymic therapy.
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Aim To investigate the effects of 5-HT_4 receptor agonist and 5-HT_3 receptor antagonist 2-[1-(4-piperonyl)piperazinyl]benzothiazole on rat heart rhythm and the involved ionic mechanisms.Methods Langendorff-perfused rat hearts were subjected to 0.1～10 μmol·L~(-1) 2-[1-(4-piperonyl)-piperazinyl]benzothiazole for 15 minutes with simultaneous ECGs recording.The whole-cell patch-clamp electrophysiology was used to record effects of 2-[1-(4-piperonyl)piperazinyl]benzothiazole on inward rectifier K~+ current(I_(K1)),transient outward K~+ current(I_(to)),resting membrane potential(RMP)and action potential(AP)in enzymatic dissociated rat ventricular myocytes.Results In ex vivo Langendorff-perfused hearts,0.1～10 μmol·L~(-1) 2-[1-(4-piperonyl)piperazinyl]benzothiazole elicited singnificant rhythm disturbances.In the presence of 10 μmol·L~(-1) agent,the total of PVB were 236±37,87.5%(7/8)hearts exhibited VT,and 62.5%(5/8)hearts exhibited VF(P<0.01).At the concentration of 0.1～10 μmol·L~(-1),2-[1-(4-piperonyl)piperazinyl]benzothiazole could inhibit I_(K1)(EC50=0.74 μmol·L~(-1))and I_(to)(EC50=2.16 μmol·L~(-1)),decrease RMP and prolong action potential duration(APD)in concentration-dependent manners(n=6,P<0.01).Conclusion Inhibition of IK1,Ito and resultant prolongation of APD,depolarization of RMP might be the critical causes for induction of arrhythmias by 2-[1-(4-piperonyl)piperazinyl]benzothiazole in rat.
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The aim of the present study is to investigate the contribution of Ca2+-activated K+ (KCa) channels and delayed rectifier K+ (KV) channels to the resting membrane potential (RMP) in rabbit middle cerebral arterial smooth muscle cells. The RMP and membrane currents were recorded using the whole-cell patch configuration and single KCa channel was recorded using the outside-out patch configuration. Using the pipette solution containing 0.05 mM EGTA, the RMP was -25.76+/-5.08 mV (n=12) and showed spontaneous transient hyperpolarizations (STHPs). The membrane currents showed time- and voltage-dependent outward currents with spontaneous transient outward currents (STOCs). When we recorded the membrane potential using the pipette solution containing 10 mM EGTA, the RMP was depolarized and did not show STHPs. The membrane currents showed no STOCs but only showed slowly inactivating outward currents. External TEA (1 mM) reversibly inhibited the STHPs, depolarized the RMP, reduced the membrane currents, abolished STOCs, and decreased the open probability of single KCa channel. When KV currents were isolated, the application of 4-AP (5 mM) depolarized the RMP. The important aspect of our results is that KCa channel is responsible for the generation of the STHPs in the membrane potential and plays an important role in the regulation of the RMP and KV channel is also responsible for the regulation of the RMP in rabbit middle cerebral arterial smooth muscle cells.