Effect of Zhenwu Decoction on electrical remodeling of cardiomyocytes in heart failure via I_(to)/Kv channels / 中国中药杂志

This study aimed to investigate the underlying mechanism of Zhenwu Decoction in the treatment of heart failure by regulating electrical remodeling through the transient outward potassium current(I_(to))/voltage-gated potassium(Kv) channels. Five normal SD rats were intragastrically administered with Zhenwu Decoction granules to prepare drug-containing serum, and another seven normal SD rats received an equal amount of distilled water to prepare blank serum. H9c2 cardiomyocytes underwent conventional passage and were treated with angiotensin Ⅱ(AngⅡ) for 24 h. Subsequently, 2%, 4%, and 8% drug-containing serum, simvastatin(SIM), and BaCl_2 were used to interfere in H9c2 cardiomyocytes for 24 h. The cells were divided into a control group [N, 10% blank serum + 90% high-glucose DMEM(DMEM-H)], a model group(M, AngⅡ + 10% blank serum + 90% DMEM-H), a low-dose Zhenwu Decoction-containing serum group(Z1, AngⅡ + 2% drug-containing serum of Zhenwu Decoction + 8% blank serum + 90% DMEM-H), a medium-dose Zhenwu Decoction-containing serum group(Z2, AngⅡ + 4% drug-containing serum of Zhenwu Decoc-tion + 6% blank serum + 90% DMEM-H), a high-dose Zhenwu Decoction-containing serum group(Z3, AngⅡ + 8% drug-containing serum of Zhenwu Decoction + 2% blank serum + 90% DMEM-H), an inducer group(YD, AngⅡ + SIM + 10% blank serum + 90% DMEM-H), and an inhibitor group(YZ, AngⅡ + BaCl_2 + 10% blank serum + 90% DMEM-H). The content of ANP in cell extracts of each group was detected by ELISA. The relative mRNA expression levels of ANP, Kv1.4, Kv4.2, Kv4.3, DPP6, and KChIP2 were detected by real-time quantitative PCR. The protein expression of Kv1.4, Kv4.2, Kv4.3, DPP6, and KChIP2 was detected by Western blot. I_(to) was detected by the whole cell patch-clamp technique. The results showed that Zhenwu Decoction at low, medium, and high doses could effectively reduce the surface area of cardiomyocytes. Compared with the M group, the Z1, Z2, Z3, and YD groups showed decreased ANP content and mRNA level, increased protein and mRNA expression of Kv4.2, Kv4.3, DPP6, and KChIP2, and decreased protein and mRNA expression of Kv1.4, and the aforementioned changes were the most notable in the Z3 group. Compared with the N group, the Z1, Z2, and Z3 groups showed significantly increased peak current and current density of I_(to). The results indicate that Zhenwu Decoction can regulate myocardial remodeling and electrical remodeling by improving the expression trend of Kv1.4, Kv4.2, Kv4.3, KChIP2, and DPP6 proteins and inducing I_(to) to regulate Kv channels, which may be one of the mechanisms of Zhenwu Decoction in treating heart failure and related arrhythmias.

The insulinotropic effects and its relevant mechanism of telmisartan in rats / 中国药理学通报

Aim To investigate the insulinotropic effect of telmisartan anrl the underlying electrophysiological mechanism.Methods Islets and cells were isolated from Wistar rats.Islets were incubated with drugs un¬der different conditions, then supernatant liquid was collected for insulin secretion.Intracellular Ca" + ( Ca'+ j) levels of (3-cells were measured by calcium imaging technology.Patch-clamp technology was ap¬plied to detect effects on voltage-gated potassium chan¬nel ( Kv ) , and voltage-gated calcium channel ( VGCC ).Results Not affecting insulin secretion un¬der low glucose condition, telmisartan dose-dependent- ly stimulated insulin secretion under high glucose con¬ dition, and stimulation was enhanced with increasing glucose concentration.Acute increases of Ca' + concentration were elicited by telmisartan under high glucose condition.Telmisartan decreased current den¬sity of Kv channel, and increased VGCC current densi¬ty.Conclusions Telmisartan enhanced Ca~+ ; lev¬els of p-cells through its action on Kv channel and VGCC, thereby amplifying glucose-stimulated insulin secretion.

Expression of KCNA2 in the dorsal root ganglia of rats with osteoarthritis pain induced by monoiodoacetate / 南方医科大学学报

OBJECTIVE@#To investigate the changes in the expression of voltage-gated potassium channel subunit KCNA2 in the dorsal root ganglion (DRG) neurons of rats with osteoarthritis (OA) pain induced by sodium monoiodoacetate and explore the mechanism.@*METHODS@#A total of 156 adult male Sprague-Dawley rats were randomly divided into blank control group, saline group and intra-articular monoiodoacetate injection-induced OA group. The paw withdrawal mechanical threshold (PWMT) was measured before and at 1, 2, 4, and 6 weeks after monoiodoacetate injection. At 4 weeks after the injection, the pathological changes in the knee joints were analyzed using HE staining and Safranin O-Fast Green staining, and the expression of activating transcription factor 3 (ATF-3) and inducible nitric oxide synthase (iNOS) in the DRG neurons were detected by immunofluorescence staining. The expression of mRNA in the DRG neurons was detected by RT-qPCR at 1, 2, 4 and 6 weeks after the injection. The expression of KCNA2 in the DRG was measured by Western blotting, and the methylation level of promoter region was measured by MSPCR at 4 weeks after the injection.@*RESULTS@#The PWMT of the rats in OA group was significantly decreased at 2, 4, and 6 weeks after the injection as compared with the baseline ( < 0.05 or < 0.001) as well as the control group ( < 0.05 or < 0.001). Four weeks after the intra-articular injection, fractures and defects on the surface of the articular cartilage, bone hyperplasia, and blurred tidal line were observed in the rats in OA group, but no obvious pathological changes were detected in the control or saline groups. Compared with those in the control group, the expressions of ATF-3 and iNOS were significantly increased ( < 0.01) at 4 weeks after injection; the expression of mRNA at 2, 4 and 6 weeks and the expression of KCNA2 protein at 4 weeks were all significantly decreased ( < 0.05 or < 0.01), and the methylation level of gene was significantly increased at 4 weeks after the injection in OA group ( < 0.01).@*CONCLUSIONS@#The expression of KCNA2 is decreased in the DRG neurons of rats with OA pain likely as a result of enhanced methylation of promoter region.

Expression of Potassium Channels in Peripheral Monocyte from Patients with Coronary Artery Disease and the Regulation of Simvastatin / 中国药房

OBJECTIVE:To discuss the expression of voltage-gated potassium channel(KV1.3)and calcium activated potassi-um channel(KCa3.1)in peripheral monocyte from patients with coronary artery disease(CAD)and the regulatory effect of simvas-tatin. METHODS:20 patients with CAD and 8 control patients without CAD diagnosed by percutaneous coronary intervention but correlated to risk factor of CAD were enrolled. The expression of KV1.3 mRNA and KCa3.1 mRNA were measured by RT-PCR in 2 groups,and those of CAD group were measured by RT-PCR after 1 month of simvastatin treatment. RESULTS:Compared with control group,mRNA expression of KV1.3 [(1.54±0.08)vs.(0.77±0.06),P<0.01] and KCa3.1 [(1.32±0.08)vs.(1.06±0.06), P<0.05] were significantly increased in CAD group. mRNA expression of KV1.3 was significantly correlated to the concentration of C reactive protein (CRP)(P=0.003)and was decreased by simvastatin for one month [(1.54 ± 0.08)vs.(1.14 ± 0.05),P<0.01]. However,mRNA expression of KCa3.1 was not correlated to the concentration of CRP and simvastatin didn’t affect it’s expression. CONCLUSIONS:KV1.3 and KCa3.1 in peripheral monocytes may be two new markers of CAD. Regulating KV1.3 may be one of mechanisms of statin’s pleiotrophic effect.

Voltage-gated potassium channels in cognitive dysfunction / 医学研究生学报

The growing number of cognitive dysfunction patients is bringing heavy mental and financial burdens to the society and families.Voltage-gated potassium channels (Kv), which consist of delayed rectifier potassium channels and transient outward po -tassium channels , are involved in the incidence of cognitive dysfunction .This review summarized the role of Kv channels in cognitive dysfunction and their relationship with N-methyl-D-aspartic acid receptors ( NMDARs) that play an important role in the process of learning and memory .

Anti-LGI1 Antibody Autoimmune Encephalitis Which Manifests Faciobrachial Dystonic Seizure

Anti-LGI1 (leucine-rich glioma inactivated-1) antibody encephalitis is one of autoimmune encephalitis. We report a 66-year-old man who presented with frequent, brief dystonic seizures which involve predominantly ipsilateral face and arm without cognitive impairment. Brain MRI showed normal finding. Serum and CSF tests revealed anti-LGI1 antibody. His symptom was not relieved by antiepileptic drugs, but completely controlled after immunotherapy. This case indicates that recognition of the brief, dystonic seizures should do tests for anti-LGI1 antibodies.

Rapid effect of ATP on transient outward potassium current (IA) in rat trigeminal ganglion neurons / 第二军医大学学报

Objective To observe the effect of ATP on transient outward potassium current (Ia) and the underlying mechanism in the cultured trigeminal ganglion (TG) neurons by using whole-cell patch clamp technique. Methods The TG neurons were acutely separately from male SD rats and were cultured in vitro, and then were subjected to whole-cell patch clamp 4 h later. Results The results showed that the ATP-activated currents in rat TG neurons could be classified into three types (T, S and B type). ATP significantly inhibited Ia on T type neurons (P<0. 05), and TNP-ATP, an antagonist of P2X3 receptors, could block the inhibitory effect of ATP against IA. ATP did not inhibit IA in S type neurons. Meanwhile, ATP could inhibit IA in TG neurons in which ATP could not induce any inward currents. Suramin, an antagonist of P2Y receptors, could block the inhibitory effect of ATP against IA. Conclusion ATP can inhibit IAin cultured TG neurons, probably through P2X3 or P2Y receptors. Further studies are required to clarify the underlying mechanisms by which ATP affect IA, which will cast lights on the mechanism of neuropathic pain and provide evidence for the clinical therapy.

Potassium channels in health, disease & development of channel modulators.

Ion channels present in the plasma membrane and intracellular organelles of all cells, play an important role in maintaining cellular integrity, smooth muscle contraction, secretion of hormones and neurotransmitters. Among the ion channels, potassium channels (K+) are the most abundant having important role in cardiac repolarization, smooth muscle relaxation and insulin release. These are also involved in the regulation of physiological functions like gastrointestinal peristalsis. These channels are the most diverse of all ion channels and are coded by at least 75 genes. Moreover, these have different subunits which co-assemble to form diverse functional channels. Abnormalities in K+ channels are associated with diseases like long QT syndrome, Anderson Tawil syndrome, epilepsy, type 2 diabetes mellitus, etc. A number of naturally occurring as well as synthetic compounds have been identified that modulate the opening and closure of KATP Channels. Some of the currently available K+ channel modulators like sulphonylureas, minoxidil, amiodarone, etc. lack tissue selectivity and have adverse effects. Hence, the success of KATP channel modulators depend on their tissue selectivity. Molecular level studies are needed to understand the type of K+ channels as this can lead to the development of newer drugs with tissue selectivity for various diseases.

A Case of Voltage Gated Potassium Channel Antibodies-associated Nonparaneoplastic Limbic Encephalitis

Limbic encephalitis has been reported usually as an autoimmune complication related to onconeuronal antigen of underlying cancer with poor prognosis. Antibodies reactive with neuronal voltage-gated potassium channels (VGKCs) are recently recognized as a pathogenic cause in nonparaneoplastic limbic encephalitis, which is responsive to immunotherapy. We report a patient who had subacute encephalopathy with clinical and radiographic evidences of limbic encephalitis. The patient was seropositive for VGKC antibodies and resulted in a good prognosis with steroids. This has not yet been reported in Korea.