阿仑膦酸钠对绝经后骨质疏松症老年女性血清总碱性磷酸酶、骨特异性碱性磷酸酶的影响

摘 要 目的：研究阿仑膦酸钠对绝经后骨质疏松症老年女性血清AKP、骨特异性碱性磷酸酶（BAP）的影响,并进一步探讨两者的相关性。方法: 回顾性分析286例绝经后骨质疏松症老年女性患者,根据治疗前患者AKP值分为AKP正常组（245例）和非肝胆管源性AKP升高组（41例）,考察两组患者阿仑膦酸钠治疗前后AKP与BAP水平,并分析BAP与AKP、AKP变化（ΔAKP）与BAP变化（ΔBAP）在治疗前后的相关性。结果: AKP与BAP随患者年龄增大呈升高趋势。治疗前AKP升高组的BAP水平高于AKP正常组（P<0.05）,BAP与AKP呈显著正相关（P<0.05）;治疗后两组AKP与BAP水平均降低,BAP与AKP呈显著正相关（P<0.05）;治疗后ΔAKP与ΔBAP亦呈显著正相关（P<0.05）。结论: AKP与BAP水平随年龄呈升高趋势,非肝胆管源性AKP升高的绝经后骨质疏松症老年女性患者,阿仑膦酸钠治疗可显著降低AKP水平,其水平的降低与BAP水平的下降呈高度正相关。     

高强度聚焦超声与125I放射性粒子植入治疗中晚期胰腺癌疗效观察

摘 要 目的：观察高强度聚焦超声(HIFU)与¹²⁵I放射性粒子植入治疗中晚期胰腺癌的临床疗效和安全性。方法: 124例中晚期胰腺癌患者随机分为A组(29例)、B组(33例)、C组(32例)和D组(30例)。A组给予单纯化疗,B组采用HIFU治疗联合化疗,C组采用¹²⁵I放射性粒子植入治疗联合化疗,D组采用¹²⁵I放射性粒子植入治疗+HIFU治疗+化疗。比较各组患者临床受益情况、疗效、生存时间和不良反应。结果: A组、B组、C组和D组的临床受益率分别为27.59%,84.85%,78.13%和83.33%,联合治疗(B组、C组和D组)明显优于单纯化疗的A组（P<0.05),B组、C组和D组间差异无统计学意义(P>0.05);各组总有效率分别为17.24%,72.73%,43.75%和93.33%,联合治疗(B组、C组和D组)明显优于单纯化疗的A组(P<0.05),且D组明显优于B组,B组明显优于C组(P<0.05);A、B、C、D组的肿瘤体积缩小率分别为14.7%,54.3%,31.8%和65.5%,组间差异具统计学意义(P<0.05)。各组中位生存期比较,联合治疗(B组、C组和D组)生存率明显优于单纯化疗的A组(P<0.05),且D组明显优于B组,B组明显优于C组(P<0.05);各组不良反应无显著差别(P>0.05)。结论:HIFU、¹²⁵I放射性粒子植入和化疗均为治疗中晚期胰腺癌可选择的有效手段,联合治疗较单纯治疗更佳;HIFU和¹²⁵I放射性粒子植入联合治疗并辅助化疗的疗效明显,是一种安全、有效的治疗方法。     

11例阿德福韦酯致低血磷性骨软化症临床分析

摘 要 目的：对阿德福韦酯（ADV）致低血磷性骨软化症病例进行临床分析,提高对此病的认识。方法: 回顾性分析11例ADV致低血磷性骨软化症病例的病史资料及生化检查（转氨酶、白蛋白、肌酐、尿酸、血糖、血pH、BE）、骨代谢标志物检查（25OHD3、PTH、tP1NP、β-CTX、OC）、尿液检查（尿pH、24 h尿钙、24 h尿磷、24 h尿蛋白、尿肌酐）、X线双能骨密度值、骨扫描结果。并分别于停用ADV 1个月和2016年7月对11例患者症状、血磷及AKP水平、尿常规进行复查随访。结果: 11例患者服用ADV时间（5.7±1.2）年,骨痛时间（2.2±0.6）年,血磷水平（0.45±0.099）mmol·K^-1,24h尿磷水平（17.9±4.8）mmol,AKP（248±107）U·K^-1,肾磷酸根阈值（0.31±0.10）mmol·K^-1。停用ADV1个月后随访：患者骨痛缓解,在补磷情况下血磷上升。2016年7月随访：平均停用ADV（18.3±10.7）月;相较于入院时及停药1个月时血磷显著升高、AKP显著降低（P均＜0.05）;2例血磷恢复正常,血磷恢复率为20%（2/10）。回归分析显示：影响入院时血磷的因素是肾磷酸根阈值和tP1NP（P<0.05）;影响最后随访时血磷的因素是入院时的骨密度值（P<0.05）。结论:低血磷性骨软化症是用ADV潜在不良反应,所致肾损害并不完全可逆,在临床工作中应引起重视。     

99Tcm示踪血栓技术在家兔脑卒中模型的应用

目的 研究同位素⁹⁹Tc^m示踪血栓技术在家兔脑卒中模型上的应用,并动态示踪观察重组组织型纤溶酶原激活剂（rt-PA）对血栓的溶解效果。方法 将新鲜洗脱的放射性高锝酸钠（5 mCi/2 mL,92.5 MBq/mL）0.5 mL与5 mg/mL氯化亚锡30 μL充分混合成示踪标记液;分别向全血、红细胞、血浆中加入20 μL示踪标记液进行同位素标记,加入50 μL CaCl₂（0.5 mol/L）与牛凝血酶（50 IU/mL）混合物,迅速吸入聚乙烯塑料管（PE80）中,37℃固化2 h后取出血栓,分割成10 mm的示踪血栓,并计算标记率。采用经兔颈外动脉逆向颈内动脉插管方法,注射示踪血栓栓塞大脑中动脉,制备脑卒中模型,用γ计数仪在兔头部测定放射性强度即每分钟计数（Counts Per Minute,CPM）的动态变化,并观察临床等效剂量工具药rt-PA4.5 mg/kg的溶栓效果。结果 全血血栓标记率为53.5%,红细胞与血浆标记比率为4.5∶1,家兔大脑中动脉血栓栓塞后CPM明显增加,约为本底的5.1±1.3倍,表明模型制备成功,检测可靠。静脉给予工具药rt-PA能产生显著的渐进性溶栓效果。结论 锝标记主要以标记红细胞为主,对血浆及纤维蛋白原影响较小。⁹⁹Tc^m示踪血栓技术制备的脑卒中模型,分离区明显,模型制备成功、指标检测科学,模型对药物疗效应答能力的反应稳定、可靠。     

99TC-MDP联合131I治疗甲状腺眼病的疗效

目的 观察⁹⁹TC-MDP联合¹³¹I治疗甲状腺眼病的临床疗效。方法 选择2012年3月至 2014年4月皖北煤电集团总医院收治的72例甲状腺眼病患者,随机分为对照组和治疗组,每组36例。对照组采用单纯性的¹³¹I治疗,而治疗组在采用¹³¹I治疗的基础上进行联合⁹⁹TC-MDP治疗,分析两组患者的病情改善情况。结果 治疗组和对照组患者显效率分别为38.89%和13.89%,总体有效率分别为83.33%和38.89%,两组疗效差异显著（P<0.05）。⁹⁹TC-MDP联合¹³¹I治疗甲状腺眼病对改善轻、中度突眼总有效率分别为92.86%和84.62%,明显高于重度突眼。结论 ⁹⁹TC-MDP联合¹³¹I治疗甲状腺功能亢进伴甲状腺眼病有一定的临床应用价值,值得临床推广。     

分化型甲状腺癌术后131I清除残余甲状腺组织的疗效及其影响因素分析

目的 探讨分化型甲状腺癌（DTC）患者术后¹³¹I清除残余甲状腺组织（简称“清甲”）的疗效及¹³¹I清甲治疗效果的影响因素。方法 收集2013年3月至2015年1月安徽省立医院行¹³¹I 清甲治疗的DTC术后患者41例,其中乳头状癌37例、滤泡状癌4例,¹³¹I清甲治疗剂量为1 110～5 550 MBq。观察¹³¹I清甲成功率;采用logistic回归分析¹³¹I清甲治疗效果的影响因素。结果 41例DTC术后患者中,¹³¹I清甲成功率为60.98%（25/41）。单因素分析显示残余甲状腺质量（χ²=8.431,P=0.006）、24 h摄¹³¹I率（χ²=7.663,P=0.015）和¹³¹I剂量（χ²=12.751,P=0.001）是影响¹³¹I疗效的因素。多因素logistic回归分析表明残余甲状腺质量（Wald=4.326,P=0.018）和¹³¹I剂量（Wald=12.320,P=0.000）是影响¹³¹I清甲治疗效果的独立因素。结论 DTC患者术后¹³¹I清甲治疗的成功率较高,残余甲状腺质量和¹³¹I剂量是影响¹³¹I清甲治疗效果的主要因素。     

HLA-B*1502基因多态性与肾移植受者环孢素所致肝功能异常的相关性研究

摘 要 目的： 研究肾移植术后患者HLA-B^*     

参芪扶正注射液联合伊立替康和西妥昔单抗治疗晚期直肠癌的临床研究

目的 研究参芪扶正注射液联合伊立替康和西妥昔单抗治疗晚期直肠癌的临床疗效和安全性。方法 选取2013年1月-2015年5月武汉市第八医院收治的晚期直肠癌患者80例,随机分为对照组和治疗组,每组各40例。对照组患者在每个化疗周期的第1、8、15天静脉滴注盐酸伊立替康注射液,90 mg/m²,滴注时间30~90 min,同时静脉滴注西妥昔单抗注射液,首次剂量是400 mg/m²,滴注时间大于2 h,然后每周250 mg/m²,滴注时间大于1 h。治疗组在对照组化疗基础上静脉滴注参芪扶正注射液,250 mL/次,1次/d,化疗前3 d开始使用,连续使用14 d。每4周为1个化疗周期。连续治疗2个化疗周期后评定疗效。观察两组的临床疗效,同时比较两组治疗前后CD⁴⁺CD²⁵⁺调节性T细胞、肿瘤坏死因子α(TNF-α)、白介素12(IL-12)及生活质量评分的变化。结果 治疗后,对照组和治疗组的总有效率分别为37.5%、60.0%,两组比较差异具有统计学意义(P < 0.05)。治疗后,对照组CD⁴⁺CD²⁵⁺细胞、IL-12、TNF-α降低,治疗组CD⁴⁺CD²⁵⁺细胞显著降低,IL-12、TNF-α升高,同组治疗前后差异具有统计学意义(P < 0.05);且治疗后,治疗组这些观察指标的改善程度优于对照组,两组比较差异具有统计学意义(P < 0.05)。治疗后,两组心理评分、躯体评分、认知评分、社会评分、角色评分均显著升高,同组治疗前后差异具有统计学意义(P < 0.05);治疗后,治疗组心理评分、躯体评分、认知评分、社会评分均显著高于对照组,两组比较差异具有统计学意义(P < 0.05)。结论 参芪扶正注射液联合伊立替康和西妥昔单抗治疗晚期直肠癌具有较好的临床疗效,可调节患者的免疫功能,提高患者的生活质量,具有一定的临床推广应用价值。     

CD4+CD25+调节性T淋巴细胞在儿童传染性单核细胞增多症的变化及作用

目的 观察儿童传染性单核细胞增多症（IM）治疗前后外周血T淋巴细胞亚群和CD4⁺CD25⁺调节性T淋巴细胞（Treg细胞）比例变化,分析Treg对IM的影响。方法 选取2017年1月至2018年5月安徽医科大学第二附属医院儿科收治的IM患儿60例作为观察组,以同期于本院儿童保健门诊行体检的40例健康儿童作为对照组,采用流式细胞术检测观察组治疗前、后及对照组的外周血T细胞亚群（CD3⁺T细胞、CD3⁺CD4⁺T细胞、CD3⁺CD8⁺T细胞比例,CD4/CD8比值）、CD4⁺CD25⁺调节性T淋巴细胞比例,对比分析两组患者机体细胞免疫功能的变化。结果 观察组治疗前CD3⁺T细胞比例、CD3⁺CD8⁺T细胞比例显著高于对照组;CD3⁺CD4⁺T细胞比例、CD4/CD8比值低于对照组,差异均有统计学意义（P <0.05）。观察组治疗后CD3⁺T细胞比例、CD3⁺CD8⁺T细胞比例均低于观察组治疗前;CD3⁺CD4⁺T细胞比例、CD4/CD8比值高于治疗前,差异均有统计学意义（P <0.05）。观察组治疗前外周血Treg细胞比例低于正常对照组,差异有统计学意义（P <0.05）;而观察组治疗后外周血Treg细胞比例高于治疗前,差异有统计学意义（P <0.05）。结论 IM患儿存在T细胞亚群比例的变化,Treg细胞水平的降低,可能参与IM患儿疾病的发生发展过程。     

89SrCl2治疗恶性肿瘤骨转移的影响因素分析

目的 探讨⁸⁹SrCl₂治疗恶性肿瘤骨转移的疗效影响因素。方法 选择南充市川北医学院附属医院2013年2月至2016年9月行⁸⁹SrCl₂治疗的恶性肿瘤骨转移患者99例,分析患者的年龄、性别、肿瘤病理类型、⁸⁹SrCl₂治疗次数、手术切除原发灶、放疗、化疗、肿瘤骨转移的病灶数量、联合止痛药状况以及碱性磷酸酶（ALP）是否会影响⁸⁹SrCl₂的治疗效果。结果 ⁸⁹SrCl₂治疗的总有效率为63.6%。单因素分析结果显示不同肿瘤病理类型、不同治疗次数、是否联合放射治疗、是否手术切除原发灶、不同肿瘤骨转移病灶数量及是否联合止痛药患者的治疗效果进行比较,差异具有统计学意义（P<0.05）。logistics回归分析显示,患者的肿瘤病理类型、⁸⁹SrCl₂治疗次数、手术切除原发灶、肿瘤骨转移的病灶数量及联合止痛药是影响⁸⁹SrCl₂疗效的独立因素（P<0.05）。结论 肿瘤病理类型、⁸⁹SrCl₂治疗次数、手术切除原发灶、肿瘤骨转移病灶数量以及联合止痛药能影响⁸⁹SrCl₂治疗恶性肿瘤骨转移的疗效。     

Inhibition of Na+-pump enhances carbachol-induced influx of 45Ca2+ and secretion of catecholamines by elevation of cellular accumulation of 22Na+ in cultured bovine adrenal medullary cells

Summary In bovine adrenal medullary cells, we reported that ²²Na⁺ influx via nicotinic receptor-associated Na⁺ channels is involved in ⁴⁵Ca²⁺ influx, a requisite for initiating the secretion of catecholamines (Wada et al. 1984, 1985b).In the present study, we investigated whether the inhibition of Na⁺-pump modulates carbachol-induced ²²Na⁺ influx, ⁴⁵Ca²⁺ influx and catecholamine secretion in cultured bovine adrenal medullary cells. We also measured ⁸⁶Rb⁺ uptake by the cells to estimate the activity of Na⁺, K⁺-ATPase. (1) Ouabain and extracellular K⁺ deprivation remarkably potentiated carbachol-induced ²²Na⁺ influx, ⁴⁵Ca²⁺ influx and catecholamine secretion; this potentiation of carbachol-induced ⁴⁵Ca²⁺ influx and catecholamine secretion was not observed in Na⁺ free medium. (2) Carbachol increased the uptake of ⁸⁶Rb⁺; this increase was inhibited by hexamethonium and d-tubocurarine. In Na⁺ free medium, carbachol failed to increase ⁸⁶Rb⁺ uptake. (3) Ouabain inhibited carbachol-induced ⁸⁶Rb⁺ uptake in a concentration-dependent manner, as it increased the accumulation of cellular ²²Na⁺. These results suggest that Na⁺ influx via nicotinic receptor-associated Na⁺ channels increases the activity of Na⁺, K⁺-ATPase and the inhibition of Na⁺, K⁺-ATPase augmented carbachol-induced Ca²⁺ influx and catecholamine secretion by potentiating cellular accumulation of Na⁺. It seems that nicotinic receptor-associated Na⁺ channels and Na⁺, K⁺-ATPase, both modulate the influx of Ca²⁺ and secretion of catecholamines by accomodating cellular concentration of Na⁺.     

Radiopharmaceutical chemistry for positron emission tomography

Molecular imaging is an emerging technology that allows the visualization of interactions between molecular probes and biological targets. Molecules that either direct or are subject to homeostatic controls in biological systems could be labeled with the appropriate radioisotopes for the quantitative measurement of selected molecular interactions during normal tissue homeostasis and again after perturbations of the normal state. In particular, positron emission tomography (PET) offers picomolar sensitivity and is a fully translational technique that requires specific probes radiolabeled with a usually short-lived positron-emitting radionuclide. PET has provided the capability of measuring biological processes at the molecular and metabolic levels in vivo by the detection of the gamma rays formed as a result of the annihilation of the positrons emitted. Despite the great wealth of information that such probes can provide, the potential of PET strongly depends on the availability of suitable PET radiotracers. However, the development of new imaging probes for PET is far from trivial and radiochemistry is a major limiting factor for the field of PET. In this review, we provided an overview of the most common chemical approaches for the synthesis of PET-labeled molecules and highlighted the most recent developments and trends. The discussed PET radionuclides include ¹¹C (t_1/2 = 20.4 min), ¹³N (t_1/2 = 9.9 min), ¹⁵O (t_1/2 = 2 min), ⁶⁸Ga (t_1/2 = 68 min), ¹⁸F (t_1/2 = 109.8 min), ⁶⁴Cu (t_1/2 = 12.7 h), and ¹²⁴I (t_1/2 = 4.12 d).     

Some degree of overlap exists between the K+-channels opened by cromakalim and those opened by minoxidil sulphate in rat isolated aorta

Summary The effects of the K⁺ channel opening drugs minoxidil sulphate and cromakalim, on ⁴²K⁺ and ⁸⁶Rb⁺ efflux and on vasorelaxation in rat isolated aorta, were compared. In rat aortic rings precontracted with noradrenaline (100 nmol/l), minoxidil sulphate and cromakalim concentration-dependently inhibited induced tension by up to 90%, with pD₂ values of 7.35±0.1 and 7.17±0.1, respectively. Glibenclamide (300 nmol/l), produced 2200- and 19-fold rightward shifts in the concentration-relaxation curves to minoxidil sulphate and cromakalim, respectively, without an effect on the maximum relaxation.Both minoxidil sulphate and cromakalim increased the efflux of ⁴²K⁺ and ⁸⁶Rb⁺ from aorta in a concentration-dependent manner, with midpoints in the µmol/l range; the maximum efflux induced by minoxidil sulphate being approximately one tenth of that induced by cromakalim. The ratio of stimulated ⁸⁶Rb⁺/⁴²K⁺ efflux increased from 0.22 to 0.48 with increasing cromakalim concentrations, but was approximately constant (0.39) when the minoxidil sulphate concentration was varied. In the presence of minoxidil sulphate, the effects of cromakalim on ⁴²K⁺ and ⁸⁶Rb⁺ efflux were inhibited in a concentration-dependent manner, by up to 60%. In the continuing presence of cromakalim (300 nmol/l), minoxidil sulphate (10 µmol/l)-induced increases in ⁴²K⁺ and ⁸⁶Rb⁺ efflux were inhibited by 45%, whereas conditioning with cromakalim (1 µmol/l) inhibited the ⁸⁶Rb⁺ efflux stimulated by additional superfusion of cromakalim (1 µmol/l) by 85%. Glibenclamide inhibited minoxidil sulphate (10 µmol/l)- and cromakalim (1 µmol/l)-induced increases in ⁴²K⁺ and ⁸⁶Rb⁺ efflux in a concentration-dependent manner with IC₅₀ values of approximately 80 nmol/l.In conclusion, the efflux data suggest that considerable overlap exists between the channels opened by minoxidil sulphate and those opened by cromakalim in rat aorta. Minoxidil sulphate has a weak efficacy as a K⁺ channel opener, and may act to open a homogeneous population of K⁺ channels. In contrast, the actions of cromakalim (1 µmol/l) are associated with large increases in tracer efflux, which are probably mediated via a heterogeneous population of K⁺ channels. However, only a small proprtion of this induced efflux appears to be required for relaxation. The differential inhibition by glibenclamide of the vasorelaxant effects of minoxidil sulphate and cromakalim may result from (a) the partial agonist properties of minoxidil sulphate in opening K⁺ channels and/or (b) additional mechanisms of vasorelaxation, which differ in their sensitivity to glibenclamide. Send offprint requests to U. Quasi at the above address     

Role of Na+ and protein kinase C in angiotensin desensitization and tachyphylaxis in the guinea-pig ileum

Summary Simultaneous recordings of the tension and intracellular Ca²⁺ concentration of guinea-pig ileum longitudinal smooth muscle strips, as well as ²⁴Na⁺ and ⁴⁵Ca²⁺ influx measurements in cultured myocytes from the same tissue, were used to investigate the mechanisms underlying angiotensin-induced desensitization and tachyphylaxis. Angiotensin II and [2-lysine]-angiotensin II (Lys²All), incubated for prolonged periods (10 min) with muscle strips, induced fading of the contractile response (desensitization) and reappearance of the intracellular Ca²⁺ concentration oscillations, which were inhibited during the initial increase in cytosolic Ca²⁺. The desensitization was paralleled, in cultured myocytes, by inhibition of the ⁴⁵Ca²⁺ but not of the ²⁴Na⁺ influxes which were initially stimulated by the peptides. On the other hand, repeated administrations of angiotensin II (but not of Lys²All) caused gradual reduction of the contractile response and of the ²⁴Na⁺ influx stimulation evoked by the agonist (tachyphylaxis). Treatment with phorbol 12–13 dibutyrate accelerated the desensitization induced by both angiotensin II and by Lys²All and aggravated the tachyphylaxis to angiotensin II. The results support the hypothesis that activation of protein kinase C is responsible for the desensitization and that tachyphylaxis is due to the slow dissociation of angiotensin II from a postulated Na⁺-dependent regulatory site on the receptor.Correspondence to S.I. Shimuta at the above address     

Distribution of 2, 21,4,41, 5,51-hexaehlorobiphenyl in mice and Chinese Hamsters

The distribution of 2,2¹,4,4¹,5,5¹-hexachlorobiphenyl-¹⁴C was studied in mice and Chinese Hamsters using whole body autoradiography and liquid scintillation counting. The mice exhibited a strong and persistent accumulation of radioactivity in the bronchial mucosa, and this accumulation was not fully developed until about 24 hrs after an intravenous injection. The labelled substance passed to the fetuses of pregnant mice and was also concentrated in the fetal bronchi. Mice pretreated with a large dose of unlabelled PCB per os in peanut oil showed a completely different distribution pattern in the lungs — only traces of label being taken up by the bronchi. Quantitative measurements revealed a concomitant reduction of the total radioactivity retained by the lungs. Except for the lungs, however, no major differences in the distribution pattern were found at the various dose levels. The distribution in the Chinese hamsters equaled approximately that of the mice, but a very weak accumulation of label was observed in the hamster bronchi. The radioactivity in the mouse bronchi was considered as perhaps representing metabolized PCB.     

Decontamination of rat and human skin experimentally contaminated with 99mTc, 201Tl and 131I radionuclides using “Dermadecon” – a skin decontamination kit: an efficacy study

Radioactive skin contamination is one of the most likely risks which occurs after accidental or occupational radiological accidents apart from internal contamination. In such cases where the radioactive contamination has occurred, the person who is contaminated should be decontaminated as early as possible to reduce the damaging health effects of radiation. In the present study, the decontamination efficiency of a developed skin decontamination kit “dermadecon” has been evaluated in animal models and human subjects using gamma scintigraphy. Decontamination efficiency (percentage of the radioactive contaminant removed) was calculated for each radioactive isotope of the study and compared with control where general washing procedure was followed using liquid and soap. The effectiveness of the kit was calculated in animal model with respect to ^99mTc-sodium-pertechnetate (^99mTcO^4?), ²⁰¹TlCl and ¹³¹I and was found 92.84?±?4.9%, 91.18?±?3.23% and 94.67?±?2.92%, respectively. Whereas, in case of human skin, the decontamination efficiency for ^99mTcO^4? was observed to be 95.00?±?3.21%. On the basis of findings from the study, it can be concluded that the decontamination agents of the used skin decontamination kit are effective for removal of localized radioactive contaminants from skin, as compared with normal decontamination using soap and water.     

Effects of propylthiouracil and methylthiouracil on cyclic AMP and ion movements in rat pancreatic islets

Summary Propylthiouracil and methylthiouracil have been shown to potentiate glucose-induced insulin secretion from rat pancreatic islets: the effect of methylthiouracil being less pronounced than that of propylthiouracil. In this study the effects of these substances on cAMP levels, ⁸⁶Rb⁺ efflux, ⁴⁵Ca²⁺ net uptake, and ⁴⁵Ca²⁺ efflux were tested in isolated rat islets in order to obtain information on their possible mechanism of action. Propylthiouracil and to a lesser extent methylthiouracil increased islet cyclic AMP in a concentration-related manner. Maximum increases at the highest concentrations tested were 261% and 190% respectively. In the presence of 3 mM glucose propylthiouracil and methylthiouracil led to a decrease in the ⁸⁶Rb efflux rate. With 5.6 mM glucose, both thiourea derivatives produced an increase in the ⁸⁶Rb⁺ efflux rate which was independent of the presence or absence of calcium in the medium. Propylthiouracil and methylthiouracil augmented the ⁴⁵Ca²⁺ efflux rate in the presence as well as in the absence of external calcium at various glucose concentrations. Propylthiouracil did not change, and methylthiouracil only slightly augmented, ⁴⁵Ca²⁺ net uptake into the isolated islets. It is suggested that the synergistic effect of propylthiouracil and methylthiouracil on glucose-induced insulin release is at least in part due to an increase in islet cAMP levels. Whether the two substances have additional direct effects on ionic fluxes which contribute to their insulinotropic action or whether the observed changes in ion movements are secondary to the elevation of cAMP levels remains to be unclear and needs further investigation. Send offprint requests to H. P. T. Ammon at the above address     

Comparison of the effluxes of 42K+ and 86Rb+ elicited by cromakalim (BRL 34915) in tonic and phasic vascular tissue

Summary The cromakalim-induced effluxes of ⁴²K⁺ and ⁸⁶Rb⁺ were compared in rat aortic segments and in guinea-pig portal vein. In both vessels, low concentrations of cromakalim (0.1 M) increased the permeability to ⁸⁶Rb⁺ 3–4 times less than that to ⁴²K⁺; at 10 M the difference was about a factor of 1.3–2. In rat aorta, the threshold concentration of cromakalim for ⁴²K⁺ efflux was 0.03 M; with ⁸⁶Rb⁺ as the tracer ion it was 0.1 M. At similar concentrations, cromakalim relaxed the tension of aortic segments precontracted with 23 mM KCl (IC₅₀ = 0.06 ± 0.01 M). However, no concomitant increase in ⁴²K⁺ or ⁸⁶Rb⁺ efflux could be detected from this stimulated preparation at these concentrations. In guinea-pig portal vein, ⁴²K⁺ efflux measurements were performed in the presence and absence of the dihydropyridine Ca²⁺ entry blocker PN 200-110 (isradipine) yielding comparable results. In the presence of PN 200-110, where spontaneous activity and the K⁺ efflux associated with it were abolished, the threshold concentration of cromakalim for ⁴²K⁺ efflux was 0.02 M as compared to 0.06 M for ⁸⁶Rb⁺ efflux. In the absence of PN 200-110, spontaneous activity of the portal vein was inhibited by 70% and 90% at these concentrations. In double isotope experiments, the K⁺ channel inhibitor tetraethylammonium did not discriminate between the effluxes of ⁴²K⁺ and ⁸⁶Rb⁺ stimulated by cromakalim.It is concluded that in the two vascular tissues examined, cromakalim increased the permeability to ⁴²K⁺ more than to ⁸⁶Rb⁺, the difference being more marked at low cromakalim concentrations. The use of ⁴²K⁺ as the tracer ion narrows the apparent gap between the concentrations of cromakalim which elicit vasorelaxant effects and those which induce an observable increase in K⁺ permeability; however a significant difference persists.Part of the data was presented at the Winter Meeting of the British Pharmacological Society London 1988 [Br J Pharmacol 93 (1988) p 19] Send offprint requests to U. Quasi at the above address     

On the mechanism of action of phenylephrine in rat atrial heart muscle

Both in rat left atrial heart and in aortic smooth muscle preparations, phenylephrine (PE) caused a concentration-dependent increase in force of contraction (F_c) in the presence of atenolol (10 mol/l), which was antagonized by phentolamine, prazosin and WB 4101 in a competitive manner. The pA₂ values of the antagonists in the cardiac tissue were 10–20fold lower than those in the rat thoracic aorta. In the spontaneously beating right atrium, PE exerted a positive chronotropic action, which was not significantly antagonized by phentolamine or prazosin. It is therefore assumed that the effects of phenylephrine in the left atrium and in the aorta are mediated by different subtypes of ₁-adrenoceptors, whereas the effects in the sino-atrial node are probably unrelated to ₁-adrenoceptors. To further elucidate the mechanisms of the positive inotropic effect of PE, action potential configuration and ⁴⁵Ca²⁺ fluxes were monitored in the rat left atrium. The increase in F_c by PE was associated with an increase in action potential duration (APD) and a reduction in resting membrane potential (RP). In the presence of (–)-devapamil (13888), the effects of PE on APD and RP persisted, whereas the increase in F_c was antagonized in a non-competitive manner. Forskolin (300 nmol/l) enhanced the positive inotropic effect of PE. PE exerted a significant increase in ⁴⁵CA²⁺ uptake in beating preparations, which was abolished in the presence of (–)13888 (1 mol/l). In addition to the PE-induced increase in ⁴⁵Ca²⁺ uptake, a decrease in ⁴⁵Ca²⁺ efflux was observed. Similarly, depolarization of the membrane by raising [K⁺]_o to 85 mmol/l revealed an increase in ⁴⁵Ca²⁺ uptake and a decrease in ⁴⁵Ca²⁺ efflux. The latter observations support the view that the membrane potential strongly determines the movement of ⁴⁵Ca²⁺ across the membrane. It is assumed that the ₁-adrenoceptor-mediated changes in APD and RP may enhance F_c, first, by increasing net Ca²⁺ entry from the extracellular space through voltage-dependent Ca²⁺ channels and, second, by decreasing Ca²⁺ efflux possibly via the Na ⁺/Ca²⁺ exchange mechanism.     

Molecular and functional characterization of the human platelet Na(+) /Ca(2+) exchangers

BACKGROUND AND PURPOSE The Na(+) /Ca(2+) exchanger is a bi-directional transporter that plays an important role in maintaining the concentration of cytosolic Ca(2+) ([Ca(2+) ](i) ) of quiescent platelets and increasing it during activation with some, but not all, agonists. There are two classes of Na(+) /Ca(2+) exchangers: K(+) -independent Na(+) /Ca(2+) exchanger (NCX) and K(+) -dependent Na(+) /Ca(2+) exchanger (NCKX). Platelets have previously been shown to express NCKX1. However, initial studies from our laboratory suggest that NCX may also play a role in platelet activation. The objective of this study was to determine if the human platelet expresses functional NCXs. EXPERIMENTAL APPROACH RT-PCR, DNA sequencing and Western blot analysis were utilized to characterize the human platelet Na(+) /Ca(2+) exchangers. Their function during quiescence and collagen-induced activation was determined by measuring [Ca(2+) ](i) with calcium-green/fura-red in response to: changes in the Na(+) and K(+) gradient, NCX pharmacological inhibitors (CBDMB, KB-R7943 and SEA0400) and antibodies specific to extracellular epitopes of the exchangers. KEY RESULTS Human platelets express NCX1.3, NCX3.2 and NCX3.4. The NCXs operate in the Ca(2+) efflux mode in resting platelets and also during their activation with thrombin but not collagen. Collagen-induced increase in [Ca(2+) ](i) was reduced with the pharmacological inhibitors of NCX (CBDMB, KB-R7943 or SEA0400), anti-NCX1 and anti-NCX3. In contrast, anti-NCKX1 enhanced the collagen-induced increase in [Ca(2+) ](i) . CONCLUSIONS AND IMPLICATIONS Human platelets express K(+) -independent Na(+) /Ca(2+) exchangers NCX1.3, NCX3.2 and NCX3.4. During collagen activation, NCX1 and NCX3 transiently reverse to promote Ca(2+) influx, whereas NCKX1 continues to operate in the Ca(2+) efflux mode to reduce [Ca(2+) ](i) .