新生大鼠海马神经元原代培养及钾离子通道特性研究

目的建立大鼠海马神经元原代培养方法,记录钾电流并观察其特性。方法无血清培养法进行海马神经元原代培养,从形态学和电生理学方面鉴定细胞活性;全细胞膜片钳技术记录钾电流,从药理学和动力学观察钾通道特性。结果经5～7d培养,获得胞膜完整、胞质均匀的海马神经元,并记录到典型的全细胞电压依赖性钾电流(IK)、延迟整流钾电流(IKDR),IK和IKDR均为外向电流,激活电压分别为-50mV和-40mV,随着去极化程度增加而增加,能被已知的钾通道的阻断剂4-AP和TEA-Cl阻断,IK和IKDR的半数最大激活膜电位(V1/2)分别为(22.1676±2.1778)mV(n=6)和(17.8457±1.7767)mV(n=6),斜率因子(κ)分别为(-6.1541±3.0541)mV(n=6)和(-6.5193±2.1894)mV(n=6)。结论在该实验条件下培养的海马神经元形态和生理特性良好,较好的表达了电压依赖性钾离子通道特性,适合电生理研究。     

胃动素对大鼠下丘脑PVN神经元细胞电压依赖性钾电流的影响

目的:研究胃动素对大鼠下丘脑PVN神经元细胞电压依赖性钾电流的影响。方法:采用急性分离新生Wistar大鼠下丘脑细胞和全细胞膜片钳技术的方法,观察胃动素对大鼠下丘脑PVN神经元细胞电压依赖性钾电流的影响。结果:胃动素可抑制大鼠下丘脑PVN神经元电压依赖性钾电流,使电流由(5.406±0.86)nA降至(3.621±0.78)nA,差异有统计学意义(P0.05)。步进电刺激下丘脑神经元,随着刺激电压强度的增强,钾外向电流增加,使电压-电流曲线(Ⅰ~Ⅴ曲线)右移,但不改变Ⅰ~Ⅴ曲线的形态。结论:胃动素可通过抑制大鼠下丘脑PVN神经元细胞电压依赖性钾电流,发挥其增强胃肠运动的作用。     

HEK293细胞内源性电压门控钾离子通道电生理学特性研究

目的探讨人胚胎肾细胞(HEK293细胞)内源性电压门控钾通道的电生理特性,避免HEK293细胞上内源性离子通道对外源性离子通道表达时的干扰。方法利用全细胞膜片钳技术分析了HEK293细胞内源性电压门控钾通道的电生理特性。结果在HEK293细胞上去极化电压从-80 mV开始可触发1个外向电流。在+100 mV时电流为(422.78±68.87)pA,电流密度为(21.91±3.20)pA/pF。钾通道阻断剂四乙胺(tetraethylammonium,TEA)、4-氨基吡啶(4-aminopyri-dine,4-AP),在将细胞外液钾浓度由4 mmol/L提高到40 mmol/L时,对外向电流有影响。结论正常培养的HEK293细胞本身有内源性的钾通道。该外向电流可能包括了IK、IK1、IKur和Ito。     

尾核神经元的原代培养及离子通道特性的研究

  目的 建立一种稳定的大鼠尾核神经元的分离和体外培养方法,用于中枢神经元离子通道特性的研究。方法 自新生24 h内的Wistar乳鼠大脑中分离出尾核,结合酶消化及机械吹打分离尾核神经元,进行体外原代神经元培养。采用全细胞膜片钳技术记录电压门控钠通道电流和电压门控钾通道（Kv）电流。结果 分离出的神经元形态正常,细胞膜光滑有弹性,保存了主要离子通道的活性。结论 本方法适合用于中枢神经系统神经元离子通道的研究。     

褪黑激素对新生大鼠海马神经元延迟整流钾电流的影响

目的 用膜片钳技术观察褪黑激素对电压门控性延迟整流钾电流(Ik)的影响,探讨褪黑激素在中枢神经系统的作用机制及其生物学意义.方法 选择7～12 d原代培养的新生Wistar大鼠海马锥体神经元,用膜片钳电压钳全细胞记录模式观察Ik的基本电生理特点,并观察不同浓度褪黑激素,包括1、10、100 nmol/L、1、10、100 μmol/L和1 mmol/L对Ik的幅度及动力学特性的影响.结果 利用海马锥体神经元的钾电流对4-AP、TEA的敏感性及电生理特性的不同可分离出激活、失活缓慢,具有强烈外向整流特性的延迟整流钾电流.褪黑激素对海马锥体神经元Ik的影响是快速、可逆、呈电压依赖性的,但对其激活曲线没有影响.褪黑激素对Ik的作用具有浓度依赖性.1～100nmoI/L的褪黑激素可逐渐递增地增加Ik幅度;1～100 μmol/L褪黑激素对Ik的增加程度随浓度增加而增大,而1 mmol/L褪黑激素的增加程度却减小.结论 褪黑激素可逆地增强体外培养新生大鼠海马神经元的Ik电流,这或许参与了神经元损伤和记忆损害的某些环节.     

无镁诱导培养大鼠海马神经元癫痫放电模型中延迟整流钾电流的变化

 摘要：目的 利用无镁细胞外液诱导原代培养大鼠海马神经元癫痫放电模型来检测延迟整流钾电流的变化。方法 采用新生24h内Wistar大鼠,分离海马神经元进行原代培养。体外培养至12-16d时,无镁细胞外液处理神经元3h并恢复正常细胞外液,应用全细胞膜片钳技术记录神经元的放电情况及延迟整流钾电流。结果 无镁处理后的神经元存在自发的“癫痫样”放电;无镁诱导可使神经元延迟整流钾电流增大。结论 延迟整流钾电流增大可能与无镁诱导体外培养大鼠海马神经元自发异常放电的基础病理机制相关。     

电压门控性钾通道与三叉神经痛

电压门控性钾通道维持神经元静息膜电位,参与细胞兴奋性的改变。在三叉神经痛发病过程中,三叉神经节神经元作为初级感觉神经元,在痛觉的传导和传递过程中起重要作用。电压门控性钾通道的多种类型在三叉神经节神经元中均有表达,激活时产生不同类型的钾电流。电压门控性钾通道功能的改变,及其与多种神经递质、炎性介质和受体间的相互作用,在三叉神经痛的发病过程中起到了重要作用。     

银杏内酯B诱导骨髓间充质干细胞分化为神经样细胞的功能

目的探讨银杏内酯B诱导的大鼠骨髓间充质干细胞(MSCs)的生理功能。方法取扩增5～10代的大鼠骨髓MSCs,40mg/L银杏内酯B诱导1周后,用膜片钳全细胞记录方式检测细胞内外的离子通道电流,步阶刺激从-70mV到 60mV,步阶10mV。结果6例银杏内酯B诱导后的神经元样MSCs的全细胞电流,除可见钾电流IK外,还可见外向整流IA,类似于神经元对照。结论银杏内酯B诱导的MSCs,不仅具有神经细胞的外形和免疫学特征,而且具有神经元的基本电生理功能。     

三叉神经节细胞电压门控通道研究中的钙电流振荡活动

目的 :探讨三叉神经节细胞电压门控性钙通道电流特性。方法 :在急性分离的三叉神经节细胞膜上 ,阻断电压门控性延迟整流钾通道和电压门控性钠通道 ,在 - 70mV的钳制电位下 ,给予 1 0mV步幅递增、80ms步宽的去极化脉冲刺激 ,进行全细胞膜片钳记录。结果 :在仅阻断电压门控性延迟整流钾通道时 ,- 1 0mV的去极化脉冲刺激激活了三叉神经节细胞膜上继快钠电流之后的慢内向电流 ,呈重复开闭的振荡特性 ;同时阻断电压门控性延迟整流钾通道和电压门控性钠通道 ,在 - 2 0mV的去极化脉冲刺下 ,也可记录到呈振荡特性的慢内向电流。振荡电流可被细胞外喷射的 1mmol·L-1 尼福地平所阻断。结论 :三叉神经节细胞膜上高电压激活的重复开闭慢内向电流可能为电压门控性钙电流 ,其振荡特性可能与感觉信息中枢传入的初级加工有关。     

2-花生四烯酸甘油对海人酸诱导损伤的大鼠尾状核神经元电压门控钠电流的调制作用

目的 探讨内源性大麻素2-花生四烯酸甘油（2-AG）对海人酸（KA）损伤的大鼠尾状核神经元电压门控钠通道电流（INa）的调制作用及其分子机制。方法 原代培养大鼠尾状核神经元,分为空白对照组、KA组、2-AG+KA组、RIM（CB1受体拮抗剂）+2-AG+KA组。培养7 d后,各组细胞于培养基中处理12 h;其中,2-AG+KA组和RIM+2-AG+KA组在添加2-AG、RIM 30 min后添加KA。应用全细胞膜片钳技术检测大鼠尾状核神经元电压门控钠通道电流：包括各组电流密度的变化、通道的电流-电压特性、通道的激活动力学特性和失活动力学特性。结果 在培养的大鼠尾状核神经元中,与对照组相比,KA显著增加神经元电压门控钠通道电流密度（P=0.009）;并使VGSCs的激活电压曲线向超极化方向偏移,半激活电压绝对值明显增大（P=0.008）。与KA组相比,直接给与2-AG提高2-AG水平可阻止KA诱导的钠电流密度增加（P=0.009）和钠电流激活曲线超极化方向移动（P=0.009）,且2-AG的这种作用是通过CB1受体依赖性途径介导的。2-AG本身对尾状核神经元电压门控钠通道电流密度、激活及失活等电流特性均不产生效应。结论 2-AG可通过CB1受体途径调控尾状核神经元VGSCs电流朋而起到神经保护作用。     

Role of vitamin K2 in the development of hepatocellular carcinoma in women with viral cirrhosis of the liver

Context  Previous findings indicate that vitamin K₂ (menaquinone) may play a role in controlling cell growth. Objective  To determine whether vitamin K₂has preventive effects on the development of hepatocellular carcinoma in women with viral cirrhosis of the liver. Design, Setting, and Participants  Forty women diagnosed as having viral liver cirrhosis were admitted to a university hospital between 1996 and 1998 and were randomly assigned to the treatment or control group. The original goal of the trial was to assess the long-term effects of vitamin K₂ on bone loss in women with viral liver cirrhosis. However, study participants also satisfied criteria required for examination of the effects of such treatment on the development of hepatocellular carcinoma. Interventions  The treatment group received 45 mg/d of vitamin K₂ (n = 21). Participants in the treatment and control groups received symptomatic therapy to treat ascites, if necessary, and dietary advice. Main Outcome Measure  Cumulative proportion of patients with hepatocellular carcinoma. Results  Hepatocellular carcinoma was detected in 2 of the 21 women given vitamin K₂ and 9 of the 19 women in the control group. The cumulative proportion of patients with hepatocellular carcinoma was smaller in the treatment group (log-rank test, P = .02). On univariate analysis, the risk ratio for the development of hepatocellular carcinoma in the treatment group compared with the control group was 0.20 (95% confidence interval [CI], 0.04-0.91; P = .04). On multivariate analysis with adjustment for age, alanine aminotransferase activity, serum albumin, total bilirubin, platelet count, -fetoprotein, and history of treatment with interferon alfa, the risk ratio for the development of hepatocellular carcinoma in patients given vitamin K₂ was 0.13 (95% CI, 0.02-0.99; P = .05). Conclusion  There is a possible role for vitamin K₂ in the prevention of hepatocellular carcinoma in women with viral cirrhosis.      

High extracellular potassium ion concentration attenuates the blockade action of ketanserin on Kv1.3 channels expressed in xenopus oocytes

Background Ketanserin （KT）, a selective serotonin （5-HT） 2-receptor antagonist, reduces peripheral blood pressure by blocking the activation of peripheral 5-HT receptors. In this study electrophysiological method was used to investigate the effect of KT and potassium ion on Kv1.3 potassium channels and explore the role of blocker KT in the alteration of channel kinetics contributing to the potassium ion imbalances. Methods Kv1.3 channels were expressed in xenopus oocytes, and currents were measured using the two-microelectrode voltage-clamp technique. Results KCI made a left shift of activation and an inactivation curve of Kv1.3 current and accelerated the activation and inactivation time constant. High extracellular [K^＋] attenuated the blockade effect of KT on Kv1.3 channels. In the presence of KT and KCI the activation and inactivation time constants were not influenced significantly no matter what was administered first. KT did not significantly inhibit Kv1.3 current induced by tetraethylammonium （TEA）. Conclusions KT is a weak blocker of Kv1.3 channels at different concentrations of extracellular potassium and binds to the intracellular side of the channel pore. The inhibitor KT of ion channels is not fully effective in clinical use because of high [K^＋]. and other electrolyte disorders.     

大鼠消化道平滑肌细胞K_(ATP)通道的牵张敏感性

目的探讨大鼠结肠平滑肌细胞上是否存在ATP敏感K+通道(ATP-sensitive potassium channel,KATP)及其牵张敏感性。方法用RT-PCR方法检测SD大鼠结肠平滑肌组织KATPmRNA的表达;联合应用单通道膜片钳技术和压力钳技术,采用inside-out模式记录大鼠结肠平滑肌细胞上KATP通道的电活动。结果在大鼠结肠平滑肌组织中可检测出较高水平的KATPmRNA的表达;用inside-out模式在大鼠结肠平滑肌上可记录到KATP通道的电活动,该通道在膜电位钳制电压为+60 mV时电导值为(44.5±1.5)pS。KATP通道特异性阻断剂——glibenclamide能抑制该通道的活动。且该KATP通道在负压刺激下开放概率增加。结论大鼠结肠平滑肌细胞上分布有KATP通道,该KATP通道对牵张刺激敏感。     

Intensity and Amount of Physical Activity in Relation to Insulin Sensitivity: The Insulin Resistance Atherosclerosis Study

Context.— Exercise training is associated with improved insulin sensitivity (S_I), but the potential impact of habitual, nonvigorous activity is uncertain. Objective.— To determine whether habitual, nonvigorous physical activity, as well as vigorous and overall activity, is associated with better S_I. Design.— A multicultural epidemiologic study. Setting.— The Insulin Resistance Atherosclerosis Study, conducted in Oakland, Calif; Los Angeles, Calif; the San Luis Valley, Colo; and San Antonio, Tex. Participants.— A total of 1467 men and women of African American, Hispanic, and non-Hispanic white ethnicity, aged 40 to 69 years, with glucose tolerance ranging from normal to mild non–insulin-dependent diabetes mellitus. Main Outcome Measure.— Insulin sensitivity as measured by an intravenous glucose tolerance test. Results.— The mean S_I for individuals who participated in vigorous activity 5 or more times per week was 1.59 min^-1·µU^-1·mL^-1·10^-4 (95% confidence interval [CI], 1.39-1.79) compared with 0.90 (95% CI, 0.83-0.97) for those who rarely or never participated in vigorous activity, after adjusting for potential confounders (P<.001). When habitual physical activity (estimated energy expenditure [EEE]) was assessed by 1-year recall of activities, the correlation coefficient between S_I and total EEE was 0.14 (P<.001). After adjustment for confounders, vigorous and nonvigorous levels of EEE (metabolic equivalent levels 6.0 and <6.0, respectively) were each positively and independently associated with S_I (P.01 for each). The association was attenuated after adjustment for the potential mediators, body mass index (a measure of weight in kilograms divided by the square of the height in meters), and waist-to-hip ratio. Results were similar for subgroups of sex, ethnicity, and diabetes. Conclusions.— Increased participation in nonvigorous as well as overall and vigorous physical activity was associated with significantly higher S_I. These findings lend further support to current public health recommendations for increased moderate-intensity physical activity on most days.      

Respiration during snow burial using an artificial air pocket

Context  Asphyxia is the most common cause of death after avalanche burial. A device that allows a person to breathe air contained in snow by diverting expired carbon dioxide (CO₂) away from a 500-cm³ artificial inspiratory air pocket may improve chances of survival in avalanche burial. Objective  To determine the duration of adequate oxygenation and ventilation during burial in dense snow while breathing with vs without the artificial air pocket device. Design  Field study of physiologic respiratory measures during snow burial with and without the device from December 1998 to March 1999. Study burials were terminated at the subject's request, when oxygen saturation as measured by pulse oximetry (SpO₂) dropped to less than 84%, or after 60 minutes elapsed. Setting  Mountainous outdoor site at 2385 m elevation, with an average barometric pressure of 573 mm Hg. Participants  Six male and 2 female volunteers (mean age, 34.6 years; range, 28-39 years). Main Outcome Measures  Burial time, SpO₂, partial pressure of end-tidal CO₂ (ETCO₂), partial pressure of inspiratory CO₂(PICO₂), respiratory rate, and heart rate at baseline (in open atmosphere) and during snow burial while breathing with the device and without the device but with a 500-cm³ air pocket in the snow. Results  Mean burial time was 58 minutes (range, 45-60 minutes) with the device and 10 minutes (range, 5-14 minutes) without it (P=.001). A mean baseline SpO₂ of 96% (range, 90%-99%) decreased to 90% (range, 77%-96%) in those buried with the device (P=.01) and to 84% (range, 79%-92%) in the control burials (P=.02). Only 1 subject buried with the device, but 6 control subjects buried without the device, decreased SpO₂ to less than 88% (P=.005). A mean baseline ETCO₂ of 32 mm Hg (range, 27-38 mm Hg) increased to 45 mm Hg (range, 32-53 mm Hg) in the burials with the device (P=.02) and to 54 mm Hg (range, 44-63 mm Hg) in the control burials (P=.02). A mean baseline PICO₂ of 2 mm Hg (range, 0-3 mm Hg) increased to 32 mm Hg (range, 20-44 mm Hg) in the burials with the device (P=.01) and to 44 mm Hg (range, 37-50 mm Hg) in the control burials (P=.02). Respiratory and heart rates did not change in burials with the device but significantly increased in control burials. Conclusions  In our study, although hypercapnia developed, breathing with the device during snow burial considerably extended duration of adequate oxygenation compared with breathing with an air pocket in the snow. Further study will be needed to determine whether the device improves survival during avalanche burial.      

Health Economic Benefits and Quality of Life During Improved Glycemic Control in Patients With Type 2 Diabetes Mellitus: A Randomized, Controlled, Double-Blind Trial

Context.— Although the long-term health benefits of good glycemic control in patients with diabetes are well documented, shorter-term quality of life (QOL) and economic savings generally have been reported to be minimal or absent. Objective.— To examine short-term outcomes of glycemic control in type 2 diabetes mellitus (DM). Design.— Double-blind, randomized, placebo-controlled, parallel trial. Setting.— Sixty-two sites in the United States. Participants.— A total of 569 male and female volunteers with type 2 DM. Intervention.— After a 3-week, single-blind placebo-washout period, participants were randomized to diet and titration with either 5 to 20 mg of glipizide gastrointestinal therapeutic system (GITS) (n=377) or placebo (n=192) for 12 weeks. Main Outcome Measures.— Change from baseline in glucose and hemoglobin A_1c (HbA_1c) levels and symptom distress, QOL, and health economic indicators by questionnaires and diaries. Results.— After 12 weeks, mean (±SE) HbA_1c and fasting blood glucose levels decreased with active therapy (glipizide GITS) vs placebo (7.5%±0.1% vs 9.3%±0.1% and 7.0±0.1 mmol/L [126±2 mg/dL] vs 9.3±0.2 mmol/L [168±4 mg/dL], respectively; P<.001). Quality-of-life treatment differences (SD units) for symptom distress (+0.59; P<.001), general perceived health (+0.36; P=.004), cognitive functioning (+0.34; P=.005), and the overall visual analog scale (VAS) (+0.24; P=.04) were significantly more favorable for active therapy. Subscales of acuity (+0.38; P=.002), VAS emotional health (+0.35; P =.003), general health (+0.27; P =.01), sleep (+0.26; P =.04), depression (+0.25; P =.05), disorientation and detachment (+0.23; P =.05), and vitality (+0.22; P =.04) were most affected. Favorable health economic outcomes for glipizide GITS included higher retained employment (97% vs 85%; P<.001), greater productive capacity (99% vs 87%; P<.001), less absenteeism (losses=$24 vs $115 per worker per month; P <.001), fewer bed-days (losses=$1539 vs $1843 per 1000 person-days; P=.05), and fewer restricted-activity days (losses=$2660 vs $4275 per 1000 person-days; P=.01). Conclusions.— Improved glycemic control of type 2 DM is associated with substantial short-term symptomatic, QOL, and health economic benefits.      

Surgical site infection and the routine use of perioperative hyperoxia in a general surgical population: a randomized controlled trial

Context  Surgical site infection (SSI) in the general surgical population is a significant public health issue. The use of a high fractional inspired concentration of oxygen (FIO₂) during the perioperative period has been reported to be of benefit in selected patients, but its role as a routine intervention has not been investigated. Objective  To determine whether the routine use of high FIO₂ during the perioperative period alters the incidence of SSI in a general surgical population. Design, Setting, and Patients  Double-blind, randomized controlled trial conducted between September 2001 and May 2003 at a large university hospital in metropolitan New York City of 165 patients undergoing major intra-abdominal surgical procedures under general anesthesia. Interventions  Patients were randomly assigned to receive either 80% oxygen (FIO₂ of 0.80) or 35% oxygen (FIO₂ of 0.35) during surgery and for the first 2 hours after surgery. Main Outcome Measures  Presence of clinically significant SSI in the first 14 days after surgery, as determined by clinical assessment, a management change, and at least 3 prospectively defined objective criteria. Results  The study groups were closely matched in a large number of clinical variables. The overall incidence of SSI was 18.1%. In an intention-to-treat analysis, the incidence of infection was significantly higher in the group receiving FIO₂ of 0.80 than in the group with FIO₂ of 0.35 (25.0% vs 11.3%; P = .02). FIO₂ remained a significant predictor of SSI (P = .03) in multivariate regression analysis. Patients who developed SSI had a significantly longer length of hospitalization after surgery (mean [SD], 13.3 [9.9] vs 6.0 [4.2] days; P<.001). Conclusions  The routine use of high perioperative FIO₂ in a general surgical population does not reduce the overall incidence of SSI and may have predominantly deleterious effects. General surgical patients should continue to receive oxygen with cardiorespiratory physiology as the principal determinant.      

Platelet activation in obese women: role of inflammation and oxidant stress

Context  Obesity, in particular abdominal adiposity, is associated with increased cardiovascular morbidity and mortality through mechanisms possibly linking the metabolic disorder to platelet and vascular abnormalities. Objective  To investigate the clinical and biochemical determinants of lipid peroxidation and platelet activation in obese women. Design, Setting, and Participants  Cross-sectional comparison, conducted between September 1999 and September 2001, of urinary 8-iso prostaglandin F₂ (8-iso PGF₂) and 11-dehydrothromboxane B₂ (11-dehyhdro-TxB₂) excretion levels in 93 women: 44 with a body mass index (BMI) higher than 28 and a waist-to-hip ratio (WHR) of 0.86 or higher, android obesity; 25 with a BMI higher than 28 and a WHR lower than 0.86, gynoid obesity; and 24 nonobese women with a BMI lower than 25. An additional study was conducted to determine the short-term effects of weight loss in 20 of the 44 women with android obesity. Intervention  During a 12-week period, 20 women with android obesity followed a weight loss program to reduce caloric intake to about 1200 kcal/d. Main Outcome Measures  Plasma C-reactive protein, insulin and leptin levels, and urinary 8-iso PGF₂ (marker of in vivo lipid peroxidation) and 11-dehyhdro-TxB₂ (marker of in vivo platelet activation) excretion. Weight loss was defined as successful when the initial body weight decreased by at least 5 kg after a 12-week period of caloric restriction. Results  Women with android obesity had higher levels of 8-iso PGF₂ (median [interquartile range {IQR}] 523 [393-685] vs 187 [140-225] pg/mg creatinine) and 11-dehyhdro-TxB₂ (median [IQR], 948 [729-1296] vs 215 [184-253] pg/mg creatinine) than nonobese women (P<.001). Both 8-iso PGF₂and 11-dehyhdro-TxB₂ were higher in women with android obesity than women with gynoid obesity (P<.001). Based on multiple regression analysis, C-reactive protein levels and WHRs of 0.86 or higher predicted the rate of 8-iso PGF₂ excretion independently of insulin and leptin levels. Of 20 women with android obesity, 11 achieved successful weight loss, which was associated with statistically significant reductions in C-reactive protein (median change, 23%; P<.05), 8-iso PGF₂ (median change, 32%; P = .04) and 11-dehydro-TxB₂ (median change, 54%; P = .005). Conclusions  Android obesity is associated with enhanced lipid peroxidation and persistent platelet activation. These abnormalities are driven by inflammatory triggers related to the degree of abdominal adiposity and are, at least in part, reversible with a successful weight-loss program.      

Effects of a 5-lipoxygenase-activating protein inhibitor on biomarkers associated with risk of myocardial infarction: a randomized trial

Context  Myocardial infarction (MI) is the leading cause of death in the world. Variants in the 5-lipoxygenase–activating protein (FLAP) gene are associated with risk of MI. Objective  To determine the effect of an inhibitor of FLAP on levels of biomarkers associated with MI risk. Design, Setting, and Patients  A randomized, prospective, placebo-controlled, crossover trial of an inhibitor of FLAP (DG-031) in MI patients who carry at-risk variants in the FLAP gene or in the leukotriene A₄ hydrolase gene. Of 268 patients screened, 191 were carriers of at-risk variants in FLAP (87%) or leukotriene A₄ hydrolase (13%). Individuals were enrolled in April 2004 and were followed up by designated cardiologists from a university hospital in Iceland until September 2004. Interventions  Patients were first randomized to receive 250 mg/d of DG-031, 500 mg/d of DG-031, 750 mg/d of DG-031, or placebo. After a 2-week washout period, patients received DG-031 if they had received placebo first or placebo if they had received DG-031 first. Treatment periods lasted for 4 weeks. Main Outcome Measures  Changes in levels of biomarkers associated with risk of MI. Results  In response to 750 mg/d of DG-031, production of leukotriene B₄ was significantly reduced by 26% (95% confidence interval [CI], 10%-39%; P = .003) and myeloperoxidase was significantly reduced by 12% (95% CI, 2%-21%; P = .02). The higher 2 doses of DG-031 produced a nonsignificant reduction in C-reactive protein (16%; 95% CI, –2% to 31%; P = .07) at 2 weeks. However, there was a more pronounced reduction (25%; 95% CI, 5%-40%; P = .02) in C-reactive protein at the end of the washout period that persisted for another 4 weeks thereafter. The FLAP inhibitor DG-031 was well tolerated and was not associated with any serious adverse events. Conclusion  In patients with specific at-risk variants of 2 genes in the leukotriene pathway, DG-031 led to significant and dose-dependent suppression of biomarkers that are associated with increased risk of MI events.