实验性糖尿病大鼠心肌细胞膜完整性的改变

应用电生理和辣根过氧化物酶示踪技术观察链脲佐菌素引起的实验性糖尿病大鼠心肌细胞膜完整性的变化。实验结果表明,糖尿病大鼠心肌细胞动作电位波幅、最大舒张电位,阈电位和最大除极速度均比对照动物明显减低(P<0.001),而复极不同水平的动作电位时程比对照动物显著延长(P<0.001),糖尿病大鼠心肌中辣根过氧化物酶阳性的肌细胞数明显多于对照动物(P<0.05)。这些结果说明,糖尿病大鼠心肌细胞膜存在损伤的电位变化,并有肌膜通透性增大。提示心肌细胞膜完整性的损害在糖尿病性心肌病的发生机理中可能起一定作用。     

心肌细胞膜T型钙通道的研究进展

心肌细胞膜表面存在L和T型钙通道,T型钙通道在心脏起搏及调控细胞生长和繁殖方面的作用日益受到人们的重视.T型钙通道拮抗剂在心血管疾病治疗中具有重要作用,研制新型特异性T通道拮抗剂是心血管疾病治疗中的一个重要方向.     

活性氧对心肌细胞膜ATP酶活性的影响

本实验观察了羟自由基发生系统(Fe~(2 ) H_2O_2)及过氧化氢对心肌细胞膜ATP酶活性的影响。证实羟自由基可造成心肌细胞膜ATP酶活性下降及膜脂质过氧化反应增强,其作用可被羟自由基消除剂甘露醇所对抗。过氧化氢对心肌细胞膜ATP酶也有一定直接抑制作用,但若过氧化氢通过自由基反应产生了羟自由基,则可造成心肌细胞膜ATP酶活性的更大幅度下降。     

心肌缺血情况下心肌动作电位仿真研究

研究缺血情况下心肌细胞动作电位的幅度、形状、持续时间等参数对认识心肌缺血的本质及其治疗有非常重要的意义，这些参数取决于该细胞在此受激周期的离子活动。然而各个离子电流之间互相影响，很难通过实验考察各个电流成分对动作电位的影响，临床上有关缺血情况下心各电流成分变化对动作电位影响的定量知识比较缺乏。本文利用计算机仿真研究了心肌缺血情况四种离子电流参数变化对动作电位的影响。     

心室肌细胞膜电位与膜通道的动力学结构研究

本文利用Beeler-Reuter模型，对心室肌细胞膜电位及膜通道在恒定的Na^ 电导下进行了双参数分岔分析，发现五个动力学性质不同的区域，其中两个区域具有双稳吸引子，当漏电流及慢电导选择适合的参数，心肌纤维会产生自发节律，此为某些异位起博点产生的原因，在漏电流及慢电导参数平面上存在一个小的区域，振荡态与静息态共存，揭示临床上房性停搏的内在机理。     

红细胞膜通道力学效应的探讨

在考察红细胞双凹碟形体形成的基础上,讨论了红细胞的输氧功能与红细胞变形的关系,揭示了红细胞膜通道的力学效应:当红细胞呈双凹碟形时,PiPo的地方,红细胞膜通道有释放出氧的现象,其氧的总流率为 J=Lo_2(Pio_2-Poo_2) Lp(Pi-Po) 式中Lo_2为O_2分压差引起的膜通道对氧的流导,PiO_2、Poo_2为膜内外的氧分压;Lp为由于压差引起的膜通道对氧的流导。     

大鼠在体心肌缺血再灌注损伤细胞膜钙转运通道蛋白mRNA的表达变化

目的 探讨大鼠心肌在体缺血再灌注(IR)损伤后细胞膜钙转运通道蛋白的mRNA变化对钙超载的作用。方法 12只SD大鼠按随机数字法分为IR组和对照组。IR组通过结扎（缺血20 min）后松解(再灌注60 min)前降支造成心肌IR,对照组则免除结扎松解前降支。应用生理记录仪连续监测两组大鼠缺血开始前及再灌注60 min后心率、平均动脉压等血流动力学指标。全自动生化仪检测缺血前及再灌注60 min后两组大鼠血钙及肌钙蛋白T(cTnT)的水平。荧光定量PCR检测再灌注60 min后两组大鼠左心室缺血区和右心室心肌细胞膜钙转运通道蛋白即心肌细胞膜钠钙交换器1(NCX1),L型钙通道(LVDCC)α-1C和胞膜钙转运ATP酶1(PMCA1 )mRNA的表达。结果两组大鼠缺血前的心率、平均动脉压均高于再灌注60 min后,而两组间缺血前和再灌注60 min后的心率、平均动脉压差异则无统计学意义。两组血浆Ca2+浓度在缺血前与再灌注60 min后差异无统计学意义,同时间点两组之间的差异也没有统计学意义。缺血前IR组与对照组血浆cTnT浓度水平相近,缺血60 min后IR组血浆cTnT浓度较对照组升高[(4.29±2.22) μg/L比(1.62±0.60)μg/L,P=0.031];两组血浆cTnT浓度在缺血前与再灌注60 min后差异也有统计学意义（均P＜0.05）。NCX1,LVDCCα-1C和PMCA1的mRNA表达在再灌注60 min后同心室两组间和同组内左右心室之间的差异均无统计学意义（NCX1：对照组左心室为50±4,右心室为47±9;IR组左心室为55±6,右心室为53±11;LVDCCα-1C:对照组左心室为33±7,右心室为30±7;IR组左心室为28±3,右心室为37±5;PMCA1,对照组左心室为70±10,右心室为53±11;IR组左心室为66±12,右心室为78±8;均P＞0.05）。结论 大鼠在体心肌缺血20 min再灌注60 min后,NCX1、LVDCCα-1C和PMCA1的mRNA表达水平均无显著改变,提示钙超载并非由细胞膜钙转运通道蛋白数量改变引起。     

豚鼠气道平滑肌ATP敏感钾通道电流的动力学特性

气道平滑肌的主要作用是调节气道的紧张度和口径,而钾通道开放剂可经ATP敏感钾通道(ATP-sensitive potassiumchannel,KATP通道)使气道平滑肌松弛,此作用能被KATP通道特异性阻断剂优降糖阻断[1]。     

溶血磷脂酸对大鼠心肌细胞膜Na+-Ca2+交换的影响

本研究采用蔗糖梯度离心法制各大鼠心肌细胞膜,观察溶血磷脂酸（ ＬＰＡ）对心肌细胞膜 Ｎａ~＋－Ｃａ~(２＋)交换的影 响。结果发现ＬＰＡ（１～２０ｎｍｏｌ／Ｌ）呈剂量依赖性和时间依赖性刺激Ｎａ~＋一Ｃａ~（２＋）交换活性增加。Ｇｐｐ（ＮＨ）ｐ呈剂量依赖 性替代ＬＰＡ刺激的Ｎａ~＋－Ｃａ~(２＋)交换活性;ＰＴＸ可抑制ＬＰＡ对Ｎａ~＋－Ｃａ~(２＋)交换的激活;Ｇｅｎｉｓｔｅｉｎ,Ｐｒｏｐｒａｎｏｌｏｌ,Ｐｒａｚｏｓｉｎ,Ａｔｒｏｐｉｎｅ,Ｌｏｓａｒｔａｎ,ＢＱ１２３和磷脂酰胆碱对ＬＰＡ诱导的Ｎａ~＋－Ｃａ~２＋交换活性无影响,而磷脂酰丝氨酸可增加对照和ＬＰＡ 两组的 Ｎａ~＋－Ｃａ~(２＋)交换活性。这些结果表明 ＬＰＡ可通过 ＰＴＸ敏感的 Ｇ蛋白刺激大鼠心肌细胞膜 Ｎａ~＋－Ｃａ~(２＋)交换活性。     

心肌细胞数学模型及其在模拟电生理变化中的应用

以心肌细胞数学模型的历史发展为线索,综述了有关心肌细胞的数学模型及其在模拟电生理中的应用。     

神经系统动力学数学模型的研究进展

随着人们对大脑研究的进一步深入,诞生了神经系统动力学这一门新兴学科,大脑的数学模型是该学科研究的基础。本文介绍了一系列具有代表性和广阔应用范围的神经元数学模型,并就此展开讨论,对其发展前景作了展望;最后,将其与复杂网络研究相结合,提出了有价值的研究方向。     

Myofilament Kinetics in Isometric Twitch Dynamics

To better understand the relationship between kinetic processes of contraction and the dynamic features of an isometric twitch, studies were conducted using a mathematical model that included: (1) kinetics of cross bridge (XB) cycling; (2) kinetics of thin filament regulatory processes; (3) serial and feedback interactions between these two kinetic processes; and (4) time course of calcium activation. Isometric twitch wave forms were predicted, morphometric features of the predicted twitch wave form were evaluated, and sensitivities of wave form morphometric features to model kinetic parameters were assessed. Initially, the impulse response of the XB cycle alone was analyzed with the findings that dynamic constants of the twitch transient were much faster than turnover number of steady-state XB cycling, and, although speed and duration of the twitch wave form were sensitive to XB cycle kinetic constants, parameters of wave shape were not. When thin filament regulatory unit (RU) kinetics were added to XB cycle kinetics, the system impulse response was slowed with only little effect on wave shape. When cooperative neighbor interactions between RU and XB were added, twitch wave shape (as well as amplitude, speed and duration) proved to be sensitive to variation in cooperativity. Importantly, persistence and shape of the falling phase could be strongly modified. When kinetic coefficients of XB attachment were made to depend on sarcomere length, changes in wave shape occurred that did not occur when only sliding filament mechanisms were operative. Indeed, the force–length relationship proved to be highly sensitive to length-dependent XB attachment in combination with cooperative interactions. These model findings are the basis of hypotheses for the role of specific kinetic events of contraction in generating twitch wave form features. © 2001 Biomedical Engineering Society. PAC01: 8715La, 8719Rr, 8719Ff, 8710+e, 8717Aa, 8717-d, 8716Ka, 8715By     

Simulation of rabbit A-type retinal horizontal cell that generates repetitive action potentials

Rabbit A-type retinal horizontal cells are classified into at least two types: cells that generate repetitive action potentials and those that do not. A mathematical model of these two types of cells based on the ionic current mechanisms has been proposed. Although the response of the former cell to 1-s positive current injection has so far been investigated by both electrophysiological and computational approaches, how this cell responds to much longer current injection has not been investigated. In the present study, I use this model to investigate the response of the former cell to a much longer current injection. Computer simulation indicates that when the stimulation period is relatively short, the membrane potential returns to the resting potential after current injection. In this case, the cell can repeatedly generate repetitive action potentials in response to stimulation. In contrast, when the stimulation period is relatively long, the membrane potential does not return to the resting potential but maintains the depolarized level even after current injection. In this case, the cell cannot repeatedly generate repetitive action potentials. When the present results were compared with those of the previous study, the difference in the response pattern after stimulation between the two types of horizontal cells was revealed.     

A computer simulation model of a rubella epidemic

This paper presents a deterministic computer simulation model of the rubella epidemic process. The model consists of four difference equations which relate the number of infectant individuals in a closed population to the number of susceptible individuals, the number of immune individuals, the contact rate, the birth and death rates, and the proportion of vaccinated susceptibles. After computer simulation, the model is validated using data from the East North Central section of the United States. Satisfactory agreement between predicted and reported cases is obtained. It is demonstrated that under reporting of actual cases is a significant factor in modeling the epidemic process. The efficiency of various vaccination programs in eradicating rubella is investigated.     

Nerve stimulation with an electrode of finite size: differences between constant current and constant voltage stimulation

Differences between constant current and constant voltage nerve stimulation are controversial. To elucidate this controversy, exact solutions are found for the electrical potential and current of a conducting electrode of finite size placed near a boundary of altered conductivity. Substantial differences in the effects of a finite and a point stimulator are predicted. This was strongly dependent on the stimulator-boundary distance, the conductivity of the media, and the curvature of the boundary. The difference between constant voltage and constant current stimulation was smaller than the effects of changes in medium conductivity and electrode distance. A poorly conducting boundary layer surrounding the stimulator minimized these differences.     

Dynamics of cardiac period responses after prolonged vagal stimulation in the dog

In 12 dogs anesthetised with α-chloralose and urethane, and β-adrenergic blocked with propranolol, the cervical vagi were stimulated for 60 seconds with supramaximal constant current pulses at frequencies between 2.0 and 10 Hz. The time course of the recovery of the cardiac period response, after cessation of vagal stimulation, was analyzed using nonlinear curve fitting techniques. It was found that the recovery phase could be reliably fitted with a function consisting of the sum of up to three exponential terms. The first term has a moderate rate constant of 0.2260±0.0112 S⁻¹ (SE) and is independent of vagal stimulus frequency and the preceding bradycardia. We propose that this term is associated with a recovery from the bradycardia with a rate constant indicative of the reduction of acetylchloline at the pacemaker caused by hydrolysis and washout. The second term has a small rate constant of 0.0499±0.0014 s⁻¹ (SE) and a negative gain. This term describes the time course of the post vagal tachycardia observed at cessation of stimulation. It is also independent of stimulus frequency and the preceding bradycardia. The third term has a large and variable rate constant (range: 0.247–8.01 s⁻¹) and becomes increasingly dominant when the preceding bradycardia is large. We propose that this third component arises from a rapid return of the pacemaker focus to the dominant location prior to vagal stimulation. The mathematical characterisation of this component is important to permit the accurate derivation of the time courses of the remaining two components. Curvilinear relationships exist between the gain parameters for each of the exponential terms and the preceding bradycardia.     

Dynamics of the short-term regulation of arterial pressure: Frequency dependence and role of arterial compliance

The purpose of this study was to investigate the role of the interaction between peripheral resistance regulation and arterial compliance in the overall short-term regulation of mean arterial pressure. A nonlinear model previously proposed was linearised about control values of mean arterial pressure and cardiac output so that it could be reformulated in terms of transfer functions. The resulting pressure to pressure open-loop transfer function H(s) consists of a complex conjugate pair of poles (pertaining to the resistance regulating system) and a real pole (pertaining to the arterial system, 1/(R₀ C), R₀=control resistance). Such a structure suggests an interaction between the resistance regulation and the arterial compliance (C). Quantitative evaluation of this interaction was obtained by estimating the model parameters during partial vena cava occlusions in four cats. Using these parameters the time response of the open-loop control system to a pressure step was found to be underdamped and oscillatory in all four cats (damping factor ξ ranged from 0·20 to 0·66), the amplitude of oscillations depending on the value of ξ and on the relative amplitude of the arterial time constant (compliance and peripheral resistance) with respect to the time constant 1/(ξω_n). Bode diagrams of H(jω) showed that the resonance peak due to the resistance regulating system may not be detectable, either because of the relatively high value of ξ or because it is masked by the pole of the arterial system.     

A Mathematical Model of Gas Exchange in an Intravenous Membrane Oxygenator

Acute respiratory distress syndrome (ARDS) is a pulmonary edemic condition which reduces respiratory exchange in 150,000 people per year in the United States. The currently available therapies of mechanical ventilation and extracorporeal membrane oxygenation are associated with high mortality rates, so intravenous oxygenation represents an attractive, alternative support modality. We are developing an intravenous membrane oxygenator (IMO) device intended to provide 50% of basal oxygen and carbon dioxide exchange requirements for ARDS patients. A unique aspect of the IMO is its use of an integral balloon to provide active mixing. This paper describes a mathematical model which was developed to quantify and optimize the gas exchange performance of the IMO. The model focuses on balloon activated mixing, uses a lumped compartment approach, and approximates the blood-side mass transfer coefficients with cross-flow correlations. IMO gas exchange was simulated in water and blood, for a variety of device geometries and balloon pulsation rates. The modeling predicts the following: (1) gas exchange efficiency is reduced by a buildup of oxygen in the fluid near the fibers; (2) the IMO gas exchange rate in blood is normally about twice that in water under comparable conditions; (3) a balloon diameter of about 1.5 cm leads to optimal gas exchange performance; and (4) in vivo positioning can affect gas exchange rates. The numerically predicted gas transfer rates correlate closely with those experimentally measured in vitro for current IMO prototypes. © 1998 Biomedical Engineering Society. PAC98: 8710+e, 8790+y, 8265Fr     

A Predictive Model of Therapeutic Monoclonal Antibody Dynamics and Regulation by the Neonatal Fc Receptor (FcRn)

We constructed a novel physiologically-based pharmacokinetic (PBPK) model for predicting interactions between the neonatal Fc receptor (FcRn) and anti-carcinoembryonic antigen (CEA) monoclonal antibodies (mAbs) with varying affinity for FcRn. Our new model, an integration and extension of several previously published models, includes aspects of mAb-FcRn dynamics within intracellular compartments not represented in previous PBPK models. We added mechanistic structure that details internalization of class G immunoglobulins by endothelial cells, subsequent FcRn binding, recycling into plasma of FcRn-bound IgG and degradation of free endosomal IgG. Degradation in liver is explicitly represented along with the FcRn submodel in skin and muscle. A variable tumor mass submodel is also included, used to estimate the growth of an avascular, necrotic tumor core, providing a more realistic picture of mAb uptake by tumor. We fitted the new multiscale model to published anti-CEA mAb biodistribution data, i.e. concentration-time profiles in tumor and various healthy tissues in mice, providing new estimates of mAb-FcRn related kinetic parameters. The model was further validated by successful prediction of F(ab′)₂ mAb fragment biodistribution, providing additional evidence of its potential value in optimizing intact mAb and mAb fragment dosing for clinical imaging and immunotherapy applications.