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Wang S.-Y.,Tianjin Institute of Health and Environmental Medicine | Cui W.-Y.,Thadweik Academy of Medicine | Wang H.,Tianjin Institute of Health and Environmental Medicine
Acta Pharmacologica Sinica | Year: 2015

Aim: To investigate the mechanisms underlying the activation of ATP-sensitive potassium channels (KATP) by iptakalim in cultured rat mesenteric microvascular endothelial cells (MVECs). Methods: Whole-cell KATP currents were recorded in MVECs using automated patch clamp devices. Nucleotides (ATP, ADP and UDP) were added to the internal perfusion system, whereas other drugs were added to the cell suspension on NPC-1 borosilicate glass chips. Results: Application of iptakalim (10 and 100 μmol/L) significantly increased the whole-cell KATP currents, which were prevented by the specific KATP blocker glibenclamide (1.0 μmol/L). The opening of KATP channels by iptakalim depended upon the intracellular concentrations of ATP or NDPs: iptakalim activated KATP channels when the intracellular ATP or NDPs were at 100 or 1000 μmol/L, and was ineffective when the non-hydrolysable ATP analogue ATPγS (1000 μmol/L) was infused into the cells. In contrast, the KATP opener pinacidil activated KATP channels when the intracellular concentrations of ATP or NDPs ranged from 10 to 5000 μmol/L, and even ATPγS (1000 μmol/L) was infused into the cells. Conclusion: Iptakalim activates KATP channels in the endothelial cells of resistance blood vessels with a low metabolic status, and this activation is dependent on both ATP hydrolysis and ATP ligands. © 2015 CPS and SIMM All rights reserved.


Shi Y.P.,Thadweik Academy of Medicine
Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi = Chinese journal of applied physiology | Year: 2013

To investigate the protective effects of Shengui tablet (Chinese Traditional Medicine) on experimental cerebral ischemia by acute cerebral ischemia hypoxia in mice and bilateral ligation of the carotid artery in rats. In the acute cerebral ischemia hypoxia model, the mice were randomly divided into control group, low-, middle- and high-dose (0.16, 0.33 and 1.00 g/kg) groups of Shengui tablet, after oral treatment for 30 d, gasping time of isolated heads of mice were observed. In bilateral ligation of the carotid artery cerebral ischemia model, the rats were randomly divided into control group, model group and low-, middle-, high-dose (0.072, 0.149 and 0.450 g/kg) groups of Shengui tablet. After oral treatment for 7 d, the cerebral index, superoxide dismutase (SOD) activity and the content of malondialdehyde (MDA) were measured. Compared with the control model, Shengui tablet middle- and high-dose could significantly prolong gasping time of isolate heads of mice. Compared with model group, Shengui tablet low-, middle- and high-dose could significantly decrease the cerebral index and enhance SOD activity in brain tissue; only high-dose could reduce the content of MDA. Shengui tablet has significant protective effect on the cerebral ischemia.


Zhao R.-J.,Academy of Military Medical science | Wang H.,Academy of Military Medical science | Wang H.,Thadweik Academy of Medicine
Acta Pharmacologica Sinica | Year: 2011

Aim: To elucidate the modulation of the chemerin/ChemR23 axis by iptakalim-induced opening of KATP channels and to determine the role of the chemerin/ChemR23 axis in the iptakalim-mediated endothelial protection. Methods: Cultured rat aortic endothelial cells (RAECs) were used. Chemerin secretion and ChemR23 protein expression were investigated using Western blot analysis. The gene expression level of ChemR23 was examined with RT-PCR. In addition, the release of nitric oxide (NO) was measured with a nitric oxide assay. Results: Homocysteine, uric acid, high glucose, or oxidized low-density lipoprotein (ox-LDL) down-regulated the chemerin secretion and ChemR23 gene/protein expression in RAECs as a function of concentration and time, which was reversed by pretreatment with iptakalim (1-10 μmol/L). Moreover, these effects of iptakalim were abolished in the presence of the KATP channel antagonist glibenclamide (1 μmol/L). Both iptakalim and recombinant chemerin restored the impaired NO production in RAECs induced by uric acid, and the effects were abolished by anti-ChemR23 antibodies. Conclusion: Iptakalim via opening KATP channels enhanced the endothelial chemerin/ChemR23 axis and NO production, thus improving endothelial function. © 2011 CPS and SIMM All rights reserved.


Ran Y.-H.,Academy of Military Medical science | Wang H.,Academy of Military Medical science | Wang H.,Thadweik Academy of Medicine
Journal of Zhejiang University: Science B | Year: 2011

Objective: To investigate the role of iptakalim, an ATP-sensitive potassium channel opener, in transient cerebral ischemia/reperfusion (I/R) injury and its involved mechanisms. Methods: Intraluminal occlusion of middle cerebral artery (MCAO) in a rat model was used to investigate the effect of iptakalim at different time points. Infarct volume was measured by staining with 2,3,5-triphenyltetrazolium chloride, and immunohistochemistry was used to evaluate the expressions of Bcl-2 and Bax. In vitro, neurovascular unit (NVU) cells, including rat primary cortical neurons, astrocytes, and cerebral microvascular endothelial cells, were cultured and underwent oxygen-glucose deprivation (OGD). The protective effect of iptakalim on NVU cells was investigated by cell viability and injury assessments, which were measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and release of lactate dehydrogenase. Caspase-3, Bcl-2 and Bax mRNA expressions were evaluated by real-time polymerase chain reaction (PCR). Results: Administration of iptakalim 0 or 1 h after reperfusion significantly reduced infarct volumes, improved neurological scores, and attenuated brain edema after cerebral I/R injury. Iptakalim treatment (0 h after reperfusion) also reduced caspase-3 expression and increased the ratio of Bcl-2 to Bax by immunohistochemistry. Iptakalim inhibited OGD-induced cell death in cultured neurons and astrocytes, and lactate dehydrogenase release from cerebral microvascular endothelial cells. Iptakalim reduced mRNA expression of caspase-3 and increased the ratio of Bcl-2 to Bax in NVU cells. Conclusions: Iptakalim confers neuroprotection against cerebral I/R injury by protecting NVU cells via inhibiting of apoptosis. © 2011 Zhejiang University and Springer-Verlag Berlin Heidelberg.


Duan R.-F.,Academy of Military Medical science | Cui W.-Y.,Academy of Military Medical science | Wang H.,Academy of Military Medical science | Wang H.,Thadweik Academy of Medicine
Acta Pharmacologica Sinica | Year: 2011

Aim: To study the relationship between the antihypertensive response of iptakalim and KCNJ11 polymorphisms in Chinese Han hypertensive patients. Methods: One hundred sixty two Chinese Han hypertensive patients were administered iptakalim (5 or 10 mg/d, po) for 8 weeks. Before the treatment and 24 h after completing the treatment blood pressure (BP) was measured. Genotyping was performed using direct sequencing. Results: Four common A190A, E23K, I337V and 3′UTR +62 G/A polymorphisms were found in KCNJ11. The E23K, I337V and 3′UTR +62 G/A polymorphisms were in complete linkage disequilibrium, and I337V was used as a representative. There were no significant differences in age, body mass index, sex, baseline systolic BP (SBP) and diastolic BP (DBP) among the 3 genotypes for the four polymorphisms. Significant association was found between SBP response and the polymorphisms (adjusted regression coefficient: 3.5 [1.2] mmHg; P=0.003 for the A190A polymorphism; adjusted regression coefficient: 3.1 [1.2] mmHg; P=0.012 for the I337V polymorphism). The patients with TT genotype for A190A polymorphism had higher clinical efficacy than those with CC genotype. Conclusion: The results suggest the KCNJ11 polymorphisms are associated with the SBP-lowering response of short-term iptakalim therapy in Chinese Han hypertensive patients. © 2011 CPS and SIMM All rights reserved.


Li C.-G.,Academy of Military Medical science | Cui W.-Y.,Thadweik Academy of Medicine | Wang H.,Academy of Military Medical science | Wang H.,Thadweik Academy of Medicine
Acta Pharmacologica Sinica | Year: 2016

Aim:ATP-sensitive potassium (K ATP) channels formed by a combination of SUR/Kir6.x subunits play a crucial role in protection against hypoxic or ischemic injuries resulting from cell metabolic disorders. In this study we investigated the effects of Na-azide, a metabolic inhibitor, on K ATP channels expressed in Xenopus oocytes, and explored the structure basis for their sensitivity to cell metabolic disorders.Methods:Six subtypes of K ATP channels (wild SUR1/Kir6.2, SUR2B/Kir6.2, SUR1/Kir6.1, SUR2B/Kir6.1, SUR2A/Kir6.2 and SUR2A/Kir6.1), as well as eleven subtypes of K ATP channels with mutant subunits were expressed in Xenopus oocytes. K ATP currents were recorded using a two-electrode voltage clamp recording technique. The drugs were applied through bath.Results:Except SUR2A/Kir6.1, five subtypes of K ATP channels were activated by Na-azide (3 mmol/L) with an order of the responses: SUR1/Kir6.2>SUR2B/Kir6.2>SUR1/Kir6.1>SUR2B/Kir6.1>SUR2A/Kir6.2, and the opening rate (t 1/2) was SUR1/Kir6.x>SUR2B/Kir6.x>SUR2A/Kir6.2. Furthermore, Kir6.2, rather than Kir6.1, had intrinsic sensitivity to Na-azide, and the residues involved in ATP-binding (R50 and K185) or pH-sensing (H175) were associated with the sensitivity of the Kir6.2 subunit to Na-azide. Moreover, the residues (K707 and K1348) within the Walker A (WA) motifs of two nucleotide-binding domains (NBDs) were essential for SUR2B/Kir6.x (especially SUR2B/Kir6.1) channel activation by Na-azide, suggesting a key role for Mg-adenine nucleotide binding and/or hydrolysis in the SUR2B subunit.Conclusion:Among the six subtypes of K ATP channels, SUR1/Kir6.2 is the most sensitive, whereas SUR2A/Kir6.1 is insensitive, to cell metabolic disorders. The Kir6.2 subunit, rather than the Kir6.1 subunit, has intrinsic sensitivity to cell metabolic disorders. The residues (K707 and K1348) within the WA motifs of SUR2B are important for the sensitivity of SUR2B/Kir6.x channels to cell metabolic disorders. © 2016 CPS and SIMM All rights reserved.


Pan Z.-Y.,Academy of Military Medical science | Wang H.,Academy of Military Medical science | Wang H.,Thadweik Academy of Medicine
International Immunopharmacology | Year: 2014

The simultaneous use of drugs with different mechanisms of anti-inflammatory action is a strategy for achieving effective control of inflammation while minimizing dose-related side effects. Choline was described to potentiate the antinociceptive action of aspirin at small doses in several inflammatory pain models. However, these findings are only limited to alleviating pain, more associated data are required to confirm the effectiveness of the combined choline and aspirin therapy against inflammatory disorders. Moreover, no report is available regarding the mechanism responsible for their synergism. Here, we first investigated the anti-inflammatory activity and pharmacological mechanisms of co-administration of choline and aspirin in 2 commonly studied inflammation models, carrageenan-induced paw edema and lipopolysaccharide (LPS)-induced sepsis in mice. Isobolographic analysis revealed that combined choline and aspirin administration exhibited a strong synergistic interaction in reducing carrageenan-mediated edema, and the estimated combination index values at 50%, 75%, and 90% effective dose (ED 50, ED75, and ED90) were 0.25, 0.32, and 0.44. Drug co-administration also afforded synergistic protection against LPS-induced sepsis and mortality, since aspirin or choline alone was inadequate to improve survival. The effects of choline-aspirin co-administration were blocked by methyllycaconitine, suggesting that activation of alpha 7 nicotinic acetylcholine receptor participates in the interaction between choline and aspirin. Furthermore, co-administration of choline and aspirin was more likely to inhibit the production of pro-inflammatory mediators induced by LPS. Our results indicated that combined choline and aspirin therapy represented a significant synergistic interaction in attenuating acute inflammatory response. This preclinical relevant evidence provides a promising approach to treat inflammation-based diseases such as arthritis and sepsis. © 2014 Elsevier B.V.


Li J.,Academy of Military Medical science | Li J.,Chinese People's Liberation Army | Long C.,Academy of Military Medical science | Cui W.,Academy of Military Medical science | And 2 more authors.
Journal of Cardiovascular Pharmacology and Therapeutics | Year: 2013

Objectives: We sought to investigate the experimental therapeutic effects and mechanisms of iptakalim, a new adenosine triphosphate (ATP)-sensitive potassium channel (KATP) opener, on monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and right heart ventricle remodeling in rats. Methods: Rats were injected with a single dose (50 mg/kg, ip) of MCT and given iptakalim (1, 3, and 9 mg/kg per d, orally [po]) or saline for 28 days. The hemodynamic andmorphometric parameters were assessed. Tissue and plasma sampleswere collected for histological andmolecular analysis.Results: Treatmentwith iptakalim at daily oral doses of 1, 3, and 9 mg/kg fromthe day ofMCT injection attenuated the high right ventricle systolic pressure (RVSP) and the increased weight ratio of right ventricle (RV) to left ventricle (LV) plus septum(S) (RV/(LVS)), decreased heart rate (HR) and decreased mean arterial pressure (MAP), inhibited the RV myocardial tissue cell apoptosis, and the RV myocardial cell B-type natriuretic peptide (BNP) protein expression. Iptakalimalso decreased the serumlevels of nitric oxide (NO), endothelin 1 (ET-1), BNP, and the levels ofNO, ET-1, and tumor necrosis factor-alpha (TNF-α) in the lung tissue.Conclusion: These results indicate that iptakalimpreventsMCT-induced PAH and RV remodeling and its mechanisms are related to inhibiting the pathological increases inNO, ET-1, BNP, and TNF-α, and Iptakalim may be a promising candidate for the treatment of PAH. © 2013 The Author(s).


PubMed | Thadweik Academy of Medicine and Academy of Military Medical science
Type: Journal Article | Journal: Acta pharmacologica Sinica | Year: 2016

Both iptakalim (Ipt) and natakalim (Nat) activate the SUR2B/Kir6.1 channel, an ATP-sensitive potassium channel (KATP) subtype, with high selectivity. In this study we investigated the therapeutic effects of Ipt and Nat against isoproterenol-induced chronic heart failure (ISO-CHF) in rats, and demonstrated a new therapeutic approach to the treatment of CHF through activation of the SUR2B/Kir6.1 channel in endothelial cells. In ISO-CHF rats, oral administration of Nat (1, 3, 9 mgkg


PubMed | Thadweik Academy of Medicine and Academy of Military Medical science
Type: Journal Article | Journal: Acta pharmacologica Sinica | Year: 2016

ATP-sensitive potassium (KATP) channels formed by a combination of SUR/Kir6.x subunits play a crucial role in protection against hypoxic or ischemic injuries resulting from cell metabolic disorders. In this study we investigated the effects of Na-azide, a metabolic inhibitor, on KATP channels expressed in Xenopus oocytes, and explored the structure basis for their sensitivity to cell metabolic disorders.Six subtypes of KATP channels (wild SUR1/Kir6.2, SUR2B/Kir6.2, SUR1/Kir6.1, SUR2B/Kir6.1, SUR2A/Kir6.2 and SUR2A/Kir6.1), as well as eleven subtypes of KATP channels with mutant subunits were expressed in Xenopus oocytes. KATP currents were recorded using a two-electrode voltage clamp recording technique. The drugs were applied through bath.Except SUR2A/Kir6.1, five subtypes of KATP channels were activated by Na-azide (3 mmol/L) with an order of the responses: SUR1/Kir6.2>SUR2B/Kir6.2>SUR1/Kir6.1>SUR2B/Kir6.1>SUR2A/Kir6.2, and the opening rate (t1/2) was SUR1/Kir6.x>SUR2B/Kir6.x>SUR2A/Kir6.2. Furthermore, Kir6.2, rather than Kir6.1, had intrinsic sensitivity to Na-azide, and the residues involved in ATP-binding (R50 and K185) or pH-sensing (H175) were associated with the sensitivity of the Kir6.2 subunit to Na-azide. Moreover, the residues (K707 and K1348) within the Walker A (WA) motifs of two nucleotide-binding domains (NBDs) were essential for SUR2B/Kir6.x (especially SUR2B/Kir6.1) channel activation by Na-azide, suggesting a key role for Mg-adenine nucleotide binding and/or hydrolysis in the SUR2B subunit.Among the six subtypes of KATP channels, SUR1/Kir6.2 is the most sensitive, whereas SUR2A/Kir6.1 is insensitive, to cell metabolic disorders. The Kir6.2 subunit, rather than the Kir6.1 subunit, has intrinsic sensitivity to cell metabolic disorders. The residues (K707 and K1348) within the WA motifs of SUR2B are important for the sensitivity of SUR2B/Kir6.x channels to cell metabolic disorders.

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