Glucose uptake and binding of digoxin to skeletal muscle

Summary. Physical exercise induces increased uptake of both digoxin and glucose in exercising skeletal muscle. Glucose uptake could be a regulatory factor for the digoxin binding to skeletal muscle, since in dogs, insulin and glucose infusion have been reported to increase the uptake of digoxin in muscle. In the present study on eight healthy digitalized subjects (0·5 mg digoxin daily) the uptake of glucose in skeletal muscle was achieved by infusion of 6 mg/kg body weight/min glucose, 0·004 IE/kg body weight/min insulin and 300 μg/h somatostatin. Serum and skeletal muscle digoxin levels were analysed before and during the infusion. We found no changes in the digoxin levels in serum and skeletal muscle in spite of an increased uptake of glucose in the muscle. Thus, glucose uptake in skeletal muscle is probably not an important regulatory factor for the change in muscle digoxin binding induced by exercise.     

Comparison between endogenous digoxin-like immunoreactivity and 86Rb uptake by erythrocytes in extracts of human plasma

1. To investigate endogenous cardiac glycoside-like compounds in plasma and their ability to inhibit the sodium pump, digoxin-like immunoreactivity [digoxin-like immunoreactive substance(s), DLIS] and 86Rb uptake by erythrocytes were measured in plasma extracts from normal adults, hypertensive adults and neonates. 2. DLIS levels in neonate plasma extracts were significantly higher than those found for normotensive or hypertensive adults. No difference was observed between normotensive and hypertensive subjects. DLIS was significantly increased when boiled plasma was extracted. 3. Extracts of boiled neonate and adult plasma inhibited 86Rb uptake. Instead, when boiling was omitted, no detectable inhibition was found in extracts of plasma from normotensive or hypertensive adult subjects. When present, the inhibition resulted from a depression of the ouabain-sensitive (sodium-pump-mediated) component, and, for the boiled neonate plasma only, also of the ouabain-resistant component. When the data from the different groups were pooled, a statistically significant inverse relationship between DLIS and erythrocyte 86Rb uptake was observed. Furthermore, in a subgroup of samples in which determinations were made before and after boiling in the same samples, an inverse correlation was found between changes in DLIS and changes in ouabain-sensitive (but not ouabain-resistant) 86Rb uptake. 4. Plasma extracts incubated with albumin at a physiological concentration significantly decreased (by approximately 20%) the inhibition of 86Rb uptake observed. 5. These findings support the existence of one or more endogenous compounds which both bind to antidigoxin antibodies and inhibit transmembrane cation transport. Part of this inhibition may, however, not involve the sodium pump. Furthermore, this chemically unidentified substance(s) may be bound to plasma proteins which partly reduce its action in vivo.     

Effects of tacrine on insulin secretion and 86Rb+ and 45Ca++ efflux from rat pancreatic islets.

Tacrine (1,2,3,4-tetrahydro-9-aminoacridine), a drug that has attained interest because of its ability to alleviate symptoms in Alzheimer's type of dementia, was found to stimulate insulin secretion from isolated rat pancreatic islets. The insulinotropic effect of the drug was observed at 8.3 mM but not at 3.3 mM glucose and was dependent on extracellular Ca++. From perifused 86Rb(+)-prelabeled islets, tacrine inhibited the fractional efflux of 86Rb+ at 3.3 mM glucose, but stimulated 86Rb+ efflux at 8.3 mM glucose. These effects persisted in the absence of extracellular Ca++. Tacrine also stimulated 45Ca++ efflux from perifused 45Ca(++)-prelabeled islets at 8.3 mM but had no effect on 45Ca++ efflux at 3.3 mM glucose or in the absence of extracellular Ca++. It is concluded that tacrine potentiates glucose-stimulated insulin secretion by a mechanism that is dependent on extracellular Ca++ and involves an increased Ca++ influx. The increased Ca++ influx is either secondary to a decreased K+ permeability induced by an inhibition of ATP-dependent K+ channels and/or due to a direct effect of tacrine on glucose-activated Ca++ channels.     

Differential effects of diazoxide, cromakalim and pinacidil on adrenergic neurotransmission and 86Rb+ efflux in rat brain cortical slices.

The effects of diazoxide, cromakalim and pinacidil on depolarization-evoked tritium overflow from the rat brain cortical slices preloaded with [3H]noradrenaline were studied. Diazoxide inhibited both transmural nerve stimulation (TNS)- and 25 mM K(+)-evoked tritium overflows more potently than cromakalim. Diazoxide effects were only partially antagonized and cromakalim ones were totally reversed by 1 microM glibenclamide. Diazoxide, but not cromakalim, reduced the 45 mM K(+)-evoked tritium overflow, which was not antagonized by glibenclamide. Both diazoxide and cromakalim stimulated 86Rb+ efflux to a similar extent, the effects being completely abolished by glibenclamide. Glibenclamide (> or = 3 microM) by itself enhanced the TNS-evoked tritium overflow. Pinacidil increased both TNS- and K+ (25 and 45 mM)-evoked tritium overflows with little effect on 86Rb+ efflux. Pinacidil-induced increase in the TNS-evoked tritium overflow was still observed in the presence of cocaine or hydrocortisone. Pinacidil failed to affect the inhibitory action of xylazine on the TNS-evoked tritium overflow, whereas phentolamine attenuated it. These results indicate that ATP-sensitive K+ channels are present in the adrenergic nerve endings of rat brain. These channels seem to be pharmacologically different from those reported for vascular smooth muscles and pancreatic beta-cells.     

心房颤动患者心率变异性与左心房大小的关系研究

目的 探讨心房颤动患者心率变异性与左心房大小的相关性.方法 42例持续性心房颤动患者行24h动态心电图检查,检测心率变异性时域指标,并进行超声心动图检查,记录左心房、左心室直径、左心室射血分数等参数,再分析以上两者的相关性.结果 ①心率变异性各指标实测值与超声心动图各参数无关;②以平均心室率矫正后的有关心率变异指标与患者左心房、左心室直径大小呈负相关(P＜0.01),其中以RMSSDDdiff(白天NN间期之差的均方根值与预期值之差)相关性最强(P＜0.01);③多因素逐步回归分析显示,左心房大小直径是影响心率变异性的独立的指标.结论 心房颤动患者的心率受多重影响,在作HRV分析时须以平均心室率矫正;HRV有关指标与左心房、左心室直径大小相关,而左心房直径增大是心率变异性减低的独立影响因子.     

Lack of pharmacodynamic interactions between quinidine and digoxin in isolated atrial muscle of guinea pig heart

Quinidine has been reported to have no effect on the positive inotropic action of digoxin observed in isolated cardiac muscle preparations. This is surprising because quinidine has been shown to reduce Na+ influx in cardiac muscle. The conditions which increase Na+ influx stimulate the glycoside binding to Na+- and K+-activated Mg++-dependent ATP phosphohydrolase (Na+,K+-ATPase), and therefore quinidine may be expected to have an opposite effect. Thus, the effects of quinidine on cardiac muscle and its possible interactions with digoxin were re-evaluated using electrically paced left atrial muscle preparations of guinea pig heart. Quinidine caused a frequency- and concentration-dependent decrease in maximal upstroke velocity and amplitude of the action potential without altering resting membrane potential. In addition, quinidine prolonged action potential duration markedly in a frequency-dependent manner. Despite action potential prolongation, the alkaloid reduced net Na+ influx as determined by a decrease in steady-state ouabain-sensitive 86Rb+ uptake. Under these conditions, however, quinidine failed to reduce the rate of onset or the maximal positive inotropic effect of digoxin; or did it reduce digoxin binding to Na+,K+- ATPase in beating atrial muscle preparations. Benzocaine, which reduced net Na+ influx without increasing the action potential duration, also failed to affect the peak inotropic effect of digoxin or the glycoside binding. Quinidine had no direct effects on glycoside binding to isolated cardiac Na+,K+-ATPase. Moreover, [3H]ouabain binding to isolated enzyme was relatively insensitive to changes in Na+ concentrations between 1 and 8 mM although binding was stimulated clearly by Na+ above 8 mM. These results indicate that quinidine, at therapeutic concentrations, does not interact pharmacodynamically with digoxin in isolated cardiac muscle.     

Alterations by glyburide of effects of BRL 34915 and P 1060 on contraction, 86Rb efflux and the maxi-K+ channel in rat portal vein

Effects of the K+ channel blocking agent, glyburide, on the actions of two K+ channel openers, BRL 34915 (cromakalim) and P 1060 (Leo), a potent pinacidil derivative (N-(t-butyl)-N"-cyano-N'-3-pyridyl-guanidine), were ascertained. Tension responses and 86Rb fluxes in rat portal vein strips and single channel electrophysiological recordings in enzymatically dissociated rat portal vein cells were obtained. Glyburide (0.3 microM) increased spontaneous contractile activity and caused concentration-dependent shifts in the relaxation responses to BRL 34915 and P 1060. Increases in 86Rb efflux were obtained only at much higher concentrations of BRL 34915 or P 1060, and these increases were blocked only at higher concentrations of glyburide (5.0 microM). BRL 34915 and P 1060 specifically increase the open-state probability of the Ca+(+)-activated K+ (maxi-K+) channel, and these actions are blocked by glyburide and also by charybdotoxin. Changes in single channel activity and contractile responsiveness occur at similar concentrations of agonists and antagonists. Thus, the membrane channel in rat portal vein affected by glyburide, BRL 34915 and P 1060 appears to be the Ca+(+)-activated maxi-K+ channel (that does not show ATP dependence under the conditions of these experiments). Concentrations of agonists and antagonists effective on maxi-K+ channel activity correspond to those affecting contractile responsiveness and are lower than those eliciting changes in 86Rb flux.     

应变及应变率成像技术评价左心房功能的研究进展

左心房功能在预测心血管事件发生中的重要性日益引起人们的关注, 应变及应变率成像技术为评价左心房功能提供了新方法。随着该技术的不断发展, 其在评价左心房功能的应用中越来越广泛和深入。本文对应变及应变率成像评价左心房功能方面的研究进展进行综述。     

Relevance of transthoracic left atrial appendage wall velocity measurement in addition to left atrial volume for noninvasive and quantitative assessment of left atrial thrombogenesis in patients with atrial fibrillation and normal D-dimer levels

Purpose

This study examined the role of left atrial (LA) appendage wall velocity (LAAWV) measurement in addition to LA size for the noninvasive assessment of thrombogenesis in patients with atrial fibrillation (AF) and normal plasma D-dimer levels.

Methods

In 58 non-valvular AF patients, LAAWV and the LA volume index (LAVI) were determined by transthoracic echocardiography. LA appendage flow velocity and severity of spontaneous echo contrast (SEC) were determined by transesophageal echocardiography.

Results

LAAWV was strongly correlated with LA appendage flow velocity (r = 0.82), and LAVI was weakly correlated with LA appendage flow velocity (r = ?0.37). As SEC severity increased, LAAWV decreased (p < 0.001) and LAVI increased (p < 0.001). Among 52 patients with normal D-dimer levels, LAAWV < 10 cm/s had 71 % sensitivity and 94 % specificity for diagnosing severe SEC. Severe SEC was not found in 18/32 large LAVI patients (>34 mL/m²), but 17 of the 18 patients (94 %) had LAAWV < 10 cm/s. Severe SEC was found in 3/20 patients with normal LAVI, but all of them showed LAAWV < 10 cm/s.

Conclusion

The noninvasive measurement of transthoracic LAAWV in addition to LA volume is clinically relevant for quantitatively assessing thrombogenesis in AF patients with normal D-dimer levels.

     

实时三维超声心动图诊断二尖瓣脱垂并左心房肌束形成1例

患者男,57岁,发现心脏杂音3个月.查体:心尖搏动扩大,抬举样搏动,心尖部可闻及全收缩期4级吹风样杂音,向左腋下传导.常规二维超声:左心增大,左心房内探及一肌束回声,横跨左心房,长约46 mm,一端连于卵圆窝处,另一端连于左心房左外侧壁,未见交通口;二尖瓣前叶增厚,近内交界区部分瓣叶(A3区)收缩期脱向左心房,致其关闭不拢;三尖瓣瓣环扩大,约33 mm,关闭不拢(图1).CDFI:收缩期于二尖瓣口探及中大量偏心性反流信号,反流束偏向左心房后侧,速度约7.0 m/s,提示:①二尖瓣腱索断裂并二尖瓣前瓣脱垂,二尖瓣关闭不全并中大量反流;②左心房内肌束形成.实时三维超声心动图:心尖四腔切面左心房可探及肌束横跨其内,通过旋转及切割,从心尖向心底观察及从左心房左外侧向内侧观察,均可立体发现一根肌束横跨左心房,连续完整,一端连于卵圆窝处,另一端连于左心房左外侧壁部位,未见交通口(图2);提示左心房肌束形成.行左心房肌束切除术十二尖瓣置换术,术中见左心增大;二尖瓣环扩大,A3 区见一根主腱索延长、断裂,瓣口重度反流;三尖瓣瓣环扩大,瓣口轻中度反流;左心房内见类似房间隔的白色肌束组织形成,一端连于卵圆窝处,另一端连于左心房左外侧壁部位.     

组织速度成像结合应变率成像技术对房颤状态下左心耳功能的评价

目的应用应变率成像（SRI）结合组织速度（TVI）显像技术评价持续性房颤患者左心耳机械运动特点以及变化特点。方法对29例患者和31例对照者行经食管超声检查,比较各节段运动速度（PSV和PDVE）以及局部心肌沿长轴的应变率（Ssr和Dsr）变化特点。结果对照组左心耳壁顶部Ssr、Dsr、PSV和PDVE均高于其余节段（P〈0.01,0.05）。房颤组左心耳顶部Ssr、PSV仅高于间隔壁及侧壁中段（P〈0.05）,心耳顶部Dsr仅高于间隔壁中段（P〈0.05）。对照组心耳顶部Ssr、PSV与左心耳面积变化率（LAA-EF）和左心耳充盈速度（LAA-EV）呈正相关（r=0.724、0.637、0.656、0.712,P〈0.001）,房颤组心耳顶部PSV与LADd呈线性负相关（r=-0.66,P〈0.001）。房颤组各节段Ssr、Dsr、PSV以及PDVE较对照组均降低（P〈0.01）。结论左心耳顶部Ssr以及PSV决定了心耳整体的排空能力,房颤患者由于心耳壁舒缩功能明显降低导致的心耳壁运动不协调。TVI和SRI技术相结合,能更为全面地反映左心耳功能变化特点。     

Automated measurements of isolated heart muscle contractions: Effects of halothane, calcium, and magnesium on guinea pig left atrial muscle

An in vitro method for automatically measuring muscle contraction force has been demonstrated in a study of the effects of the inhalation anesthetic halothane followed by calcium chloride or magnesium sulfate on isolated guinea pig left atrial muscle. An automated computer-controlled system was used to collect muscle contraction force waveforms and to analyze contraction waveforms for comparison of variables before and after drug administration. Two concentrations of halothane (0.5 and 1.5%) were administered to the atrial preparation for 30 minutes and followed by calcium chloride or magnesium sulfate. Six variables (latency, time to peak tension, peak tension, maximum rate of change of pressure, force time integral, and relaxation time) were automatically determined from averaged stimulus-response curves. Results were normalized and compared with controls administered only calcium and magnesium and with controls administered no drugs. The automated system greatly simplified data collection and accumulation and statistical analysis of multiple responses. The system made possible averaging and analysis of more data with less variability than is normally obtained with manual systems. The results confirm several known actions of these agents. Halothane prolongs latency (9 and 21% for 0.5 and 1.5% halothane, respectively) and shortens time to peak tension (6 and 17% for 0.5 and 1.5% halothane, respectively) and relaxation time (17 and 39% for 0.5 and 1.5% halothane, respectively). At high halothane concentrations (1.5%), calcium chloride shortens latency (10%) and prolongs time to peak tension (11%); magnesium sulfate prolongs latency (14%) and shortens time to peak tension (10%).     

Automated measurements of isolated heart muscle contractions: Effects of halothane,calcium, and magnesium on guinea pig left atrial muscle

An in vitro method for automatically measuring muscle contraction force has been demonstrated in a study of the effects of the inhalation anesthetic halothane followed by calcium chloride or magnesium sulfate on isolated guinea pig left atrial muscle. An automated computer-controlled system was used to collect muscle contraction force waveforms and to analyze contraction waveforms for comparison of variables before and after drug administration. Two concentrations of halothane (0.5 and 1.5%) were administered to the atrial preparation for 30 minutes and followed by calcium chloride or magnesium sulfate. Six variables (latency, time to peak tension, peak tension, maximum rate of change of pressure, force time integral, and relaxation time) were automatically determined from averaged stimulus-response curves. Results were normalized and compared with controls administered only calcium and magnesium and with controls administered no drugs. The automated system greatly simplified data collection and accumulation and statistical analysis of multiple responses. The system made possible averaging and analysis of more data with less variability than is normally obtained with manual systems. The results confirm several known actions of these agents. Halothane prolongs latency (9 and 21% for 0.5 and 1.5% halothane, respectively) and shortens time to peak tension (6 and 17% for 0.5 and 1.5% halothane, respectively) and relaxation time (17 and 39% for 0.5 and 1.5% halothane, respectively). At high halothane concentrations (1.5%), calcium chloride shortens latency (10%) and prolongs time to peak tension (11%); magnesium sulfate prolongs latency (14%) and shortens time to peak tension (10%).     

Relationship between left atrial appendage emptying and left atrial function using cardiac magnetic resonance in patients with atrial fibrillation: comparison with transesophageal echocardiography

To compare cardiac magnetic resonance (CMR) quantifications of left atrium (LA) function and left atrial appendage (LAA) emptying depending on the presence of LA spontaneous echogenic contrast (LA-SEC) on transesophageal echocardiography (TEE) in patients with atrial fibrillation (AF). A total of 48 patients with AF underwent sequential CMR examination and TEE in preparation for catheter ablation. The CMR protocol included cine and velocity encoding (VENC) sequences for evaluation of both LA function and LAA emptying. The peak blood velocity of LAA just before left ventricle systole was defined as the LAA emptying velocity (LAA-EV). Depending on the presence of LA-SEC on TEE, patients were divided into two groups, the SEC group (n?=?15) and the non-SEC group (n?=?33). Mean LAA-EV was significantly greater in the non-SEC group than in the SEC group (54.5?±?24.8 ml/s vs. 26.0?±?22.6 ml/s, P?<?0.01). LAA-EV had a significant positive relationship (P?<?0.05) with LAA backflow velocity, as assessed using TEE. Use of an optimal LAA-EV cutoff value of 35 ml/s to predict LA-SEC yielded a sensitivity of 80.0?%, a specificity of 75.7?%, and positive and negative predictive values of 58.8 and 83.9?%, respectively. Using VENC-CMR, LAA-EV is associated with LA function and can be useful for predicting LA-SEC in patients with AF.     

应变率成像及三维超声评估尿毒症患者左心房收缩功能

目的 探讨应变率成像(SRI)和三维超声评价尿毒症患者左心房收缩功能的临床价值. 方法 应用二维、三维超声心动图和SRI分别测量44例尿毒症患者(男23例,女21例)和40名正常人(男20名,女20名)左心室后壁厚度(LVPWT)、室间隔厚度(IVST)和左心室舒张末期内径(LVID)、左心房各壁上段心房收缩期应变率峰值(SRa)、三维左心房最大容积(LAVmax)、左心房最小容积(LAVmin)和左心房收缩前容积(LAVp).计算左心室重量指数(LVMI)、左心房射血分数(LAEF)及左心房主动收缩排空容积(LASV). 结果 相同性别的两组间LVMI均在正常值范围内,差异无统计学意义;相同性别的两组间左心房壁SRa、LAEF及LASV的差异有统计学意义(P＜0.05). 结论 SRI及三维超声能在左心室结构无明显改变的情况下,能够早期发现尿毒症患者左心房收缩功能的改变.     

应变/应变率技术评价超重及肥胖患者左心房功能的研究

目的 应用应变/应变率技术评价超重及肥胖者左心房功能的变化.方法 30例超重者(28kg/m2 ＞BMI≥24 kg/m2),30例肥胖者(BMI≥28 kg/m2)及30例正常人.应用超声心动图及应变/应变率技术测量左心房5个壁10个节段左房应变(S)、左室收缩期左房应变率峰值(SSR)、左室舒张早期左房应变率峰值(ESR)及左室舒张晚期左房应变率峰值(ASR),并计算出平均值进行比较.结果 与正常组相比,超重组平均SSR及平均ESR减低,肥胖组平均S、平均SSR及平均ESR降低,超重组平均ASR降低;肥胖组平均ESR较超重组降低.结论 超重者左房储存器、管道及助力泵功能均受损,肥胖者左房储存器及管道功能受损更为明显,而助力泵功能未见明显受损.左房的三个功能相互调节来维持左室充盈.应变及应变率技术可用来评价超重及肥胖者左房功能改变.