5-Hydroxytryptamine transporter wasinvolved in monocrotaline-induced pulmonary hypertension in the rat

AIM: To compare the expression of 5-hydroxytryptamine transporter (5-HTF) gene in PAs from normal and chronic “inflammatory“ PHT rats. METHODS: MCT-treated rats were used as a model for chronic PHT. Arterial pressure and pulmonary arterial pressure were measured with a pressure transducer connected to a polygraph and recorded with a thermal recorder. The right ventricle (RV), septum and the left ventricle (S LV) were dissected and the ratio of RV weight to S LV weight was calculated     

难治性癫痫患者的苯妥英钠血药浓度监测及用药分析

本文对38例服用苯妥英钠的难治性癫痫患者进行血药浓度监测和用药分析.结果38例中,中毒人数为21例,用药不足人数7例.提示难治性癫痫患者与苯妥英钠的用药水平有关,临床应用苯妥英钠应个体化,每位患者的治疗剂量不能只凭经验用药,必须进行血药浓度监测.     

Hypoxic pulmonary vasoconstriction: redox regulation of O2-sensitive K+ channels by a mitochondrial O2-sensor in resistance artery smooth muscle cells

Hypoxic pulmonary vasoconstriction (HPV) is a widely-conserved mechanism for matching ventilation and perfusion that optimizes systemic PO(2). HPV is elicited by moderate alveolar hypoxia through a mechanism that is intrinsic to the pulmonary circulation, particularly the resistance pulmonary arteries (PA), and is robust even in isolated perfused lungs. Although modulated by the endothelium, HPV persists in denuded PA rings and PA smooth muscle cells (PASMC). Beginning within seconds of hypoxia, HPV plateaus in minutes and persists for hours. During focal hypoxia (e.g. atelectasis), HPV is restricted to the vascular segments serving hypoxic lobes, and diverts blood to better-ventilated segments without causing pulmonary hypertension (PHT). However, with global hypoxia, as occurs at high altitude or in the fetal lung, HPV increases pulmonary vascular resistance (PVR) and may contribute to PHT. This review focuses on a comprehensive Redox Theory of HPV but considers relevant modulatory factors (endothelin), triggering stimuli (cyclic ADP-ribose-induced release of sarcoplasmic reticulum (SR) Ca(2+)) and sustaining pathways (Rho kinase-modulated Ca(2+) sensitization of the contractile apparatus). The Redox Theory proposes that an O(2)-sensor in resistance PASMC (complexes I and III of the mitochondrial electron transport chain (ETC)) generates reactive O(2) species (ROS) in proportion to PO(2). During normoxia, a redox mediator, like hydrogen peroxide (H(2)O(2)), maintains voltage-gated O(2)-sensitive K(+) channels (Kv) in an oxidized open state. Hypoxic withdrawal of ROS inhibits Kv channels, thereby depolarizing PASMCs, activating L-type voltage-gated Ca(2+) channels, enhancing Ca(2+) influx and promoting vasoconstriction. The role of O(2)-sensitive K(+) channels is conserved in most specialized O(2)-sensitive tissues, including the ductus arteriosus and carotid body. The unique occurrence of hypoxic vasoconstriction in the pulmonary circulation relates to the colocalization of an O(2)-sensor and O(2)-sensitive Kv channels in resistance PAs. HPV has relevance to human physiology, pathophysiology (high altitude pulmonary edema (HAPE) and PHT) and therapy (single lung anesthesia).     

贲门周围血管离断术治疗晚期血吸虫病门静脉高压症的近远期疗效

目的评估贲门周围血管离断术(PCDV)治疗晚期血吸虫病门静脉高压症近远期疗效。方法总结1980年1月～2010年1月采用PCDV治疗晚期血吸虫病门静脉高压症患者的资料,统计相关数据,分析近远期疗效。结果治疗性手术493例(急诊手术264例,择期治疗性手术229例),预防性手术1 380例。近期止血率98.1%,手术死亡率1.87%,急诊手术死亡率10.2%,择期治疗性手术死亡率2.6%,预防性手术死亡率0.14%。随访1 629例,总出血率为11.2%,其中治疗性手术后再出血率30.8%,其5、10、20和30年再出血率分别为5.2%、10.1%、1.5%和0.6%。预防性手术后出血率2.3%。5、10、20和30年生存率分别为90.9%、87.6%、80.3%和79.6%,5、10、20和30年肝性脑病发生率分别为1.29%、3.2%、4.5%和4.8%。肝功能好转79.8%,腹水好转87.3%,脾功能亢进症消失81.0%,好转12.3%,食管静脉曲张好转79.8%。结论 PCDV是治疗晚期血吸虫病门静脉高压症的最佳术式;保护已经建立的不碍生命安全的侧支循环,常规联合大网膜包肾术,保留胃冠状静脉的完整性,是保证疗效的关键要点。     

(4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone inhibits tubulin polymerization,induces G2/M arrest,and triggers apoptosis in human leukemia HL-60 cells

(4-Methoxyphenyl)(3,4,5-trimethoxyphenyl)methanone (PHT) is a known cytotoxic compound belonging to the phenstatin family. However, the exact mechanism of action of PHT-induced cell death remains to be determined. The aim of this study was to investigate the mechanisms underlying PHT-induced cytotoxicity. We found that PHT displayed potent cytotoxicity in different tumor cell lines, showing IC₅₀ values in the nanomolar range. Cell cycle arrest in G₂/M phase along with the augmented metaphase cells was found. Cells treated with PHT also showed typical hallmarks of apoptosis such as cell shrinkage, chromatin condensation, phosphatidylserine exposure, increase of the caspase 3/7 and 8 activation, loss of mitochondrial membrane potential, and internucleosomal DNA fragmentation without affecting membrane integrity. Studies conducted with isolated tubulin and docking models confirmed that PHT binds to the colchicine site and interferes in the polymerization of microtubules. These results demonstrated that PHT inhibits tubulin polymerization, arrests cancer cells in G₂/M phase of the cell cycle, and induces their apoptosis, exhibiting promising anticancer therapeutic potential.     

Relative contribution of different l-arginine sources to the substrate supply of endothelial nitric oxide synthase

In certain cases of endothelial dysfunction l-arginine becomes rate-limiting for NO synthesis in spite of sufficiently high plasma concentrations of the amino acid. To better understand this phenomenon, we investigated routes of substrate supply to endothelial nitric oxide synthase (eNOS). Our previous data with human umbilical vein (HUVEC) and EA.hy.926 endothelial cells demonstrated that eNOS can obtain its substrate from the conversion of l-citrulline to l-arginine and from protein breakdown. In the present study, we determined the quantitative contribution of proteasomal and lysosomal protein degradation and investigated to what extent extracellular peptides and l-citrulline can provide substrate to eNOS. The RFL-6 reporter cell assay was used to measure eNOS activity in human EA.hy926 endothelial cells. Individual proteasome and lysosome inhibition reduced eNOS activity in EA.hy926 cells only slightly. However, the combined inhibition had a pronounced reducing effect. eNOS activity was fully restored by supplementing either l-citrulline or l-arginine-containing dipeptides. Histidine prevented the restoration of eNOS activity by the dipeptide, suggesting that a transporter accepting both, peptides and histidine, mediates the uptake of the extracellular peptide. In fact, the peptide and histidine transporter PHT1 was expressed in EA.hy926 cells and HUVECs (qRT/PCR). Our study thus demonstrates that l-citrulline and l-arginine-containing peptides derived from either intracellular protein breakdown or from the extracellular space seem to be good substrate sources for eNOS.     

Effects of WIN 55,212-2 mesylate (a synthetic cannabinoid) on the protective action of clonazepam, ethosuximide, phenobarbital and valproate against pentylenetetrazole-induced clonic seizures in mice

The aim of this study was to determine the effect of WIN 55,212-2 mesylate (WIN — a non-selective cannabinoid CB1 and CB2 receptor agonist) on the protective action of four classical antiepileptic drugs (AEDs: clonazepam [CZP], ethosuximide [ETS], phenobarbital [PB], and valproate [VPA]) in the mouse pentylenetetrazole (PTZ)-induced clonic seizure model.WIN (15 mg/kg, i.p.) significantly enhanced the anticonvulsant action of ETS, PB and VPA, but not that of CZP against PTZ-induced clonic seizures. The ED₅₀ values of ETS, PB and VPA were reduced from 148.0, 13.9 and 137.1 mg/kg to 104.0, 8.3 and 85.6 mg/kg, respectively (P < 0.05). WIN (5 and 10 mg/kg, i.p.) had no impact on the anticonvulsant action of all studied AEDs against PTZ-induced clonic seizures. WIN (15 mg/kg, i.p.) significantly elevated total brain concentrations of ETS and VPA, but not those of CZP and PB in mice. Moreover, WIN combined with CZP, ETS, PB and VPA significantly impaired motor performance, long-term memory and muscular strength in mice subjected to the chimney, passive avoidance and grip-strength tests, respectively.Pharmacodynamic enhancement of the anticonvulsant action of PB by WIN against PTZ-induced clonic seizures is favorable from a preclinical viewpoint. Advantageous effects of WIN in combination with ETS and VPA against PTZ-induced seizures were pharmacokinetic in nature. However, WIN combined with CZP, ETS, PB and VPA impaired motor coordination and long-term memory as well as reduced skeletal muscular strength in the experimental animals.