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Biomedical subjects

E L de Beer

Publications and source records attributed to E L de Beer.

At least 19 recordsLinked to original sources
PubMed2000

Doxorubicin impairs crossbridge turnover kinetics in skinned cardiac trabeculae after acute and chronic treatment.

Crossbridge dynamics underlying the acute and chronic inotropic effects of doxorubicin (Dox) were studied by application of releasing length steps (amplitude, 0.5-10%) to skinned cardiac trabeculae. Acute incubation of trabeculae with 20 microM Dox for 30 min resulted in a decrease of the velocity of unloaded shortening (V(0), from 9.3 +/- 1.1 to 7.7 +/- 0.7 microm/s, P <.05) and in an increase of the rate of force redevelopment (tau(r), from 56 +/- 4 to 65 +/- 3 ms, P <.05) in response to step amplitudes ranging from 5 to 10%. In contrast, chronic Dox treatment in rats (2 mg/kg/week for 4 weeks) significantly impaired trabecular crossbridge dynamics after step releases of 0.5%. This was reflected by an increase of all time constants describing tension recovery: tau(1), from 10 +/- 1 to 14 +/- 1 ms; tau(2), from 65 +/- 6 to 82 +/- 6 ms; tau(3), from 92 +/- 7 to 293 +/- 67 ms; P <.05. In addition, V(0) was decreased (from 8.6 +/- 0.6 to 6.8 +/- 0.3 microm/s, P <.05) and tau(r) was increased (from 67 +/- 4 to 89 +/- 3 ms; P <.05) in the slack-test. We found that chronic Dox treatment resulted in a shift from the "high ATPase" alpha-myosin heavy chain (MHC) isoform toward the "low-ATPase" beta-MHC isoform in the ventricles (control: alpha-MHC 79 +/- 2% and beta-MHC 21 +/- 2%; Dox-treated: alpha-MHC 53 +/- 2% and beta-MHC 47 +/- 2%; P <.05). The present results show that acute Dox incubation affects the detachment rate of crossbridges, which leads to a delayed relaxation and an arrest of crossbridges in strongly bound states. In contrast, chronic Dox treatment leads to an impairment of both the attachment and detachment rates in the crossbridge cycle, which may be explained by an altered MHC isoform composition in ventricular myocardium. Interfering with Dox-induced alterations of crossbridge kinetics may provide a new strategy to prevent Dox-associated cardiotoxicity.

Animals↗
PubMed1998

Force generation and shift of mass between myosin and actin in skinned striated muscle fibres at low calcium concentrations.

Skinned muscle fibres from the gracilis muscle of the rabbit were used to record small angle X-ray diffraction spectra under various contractile conditions. The intracellular calcium concentration, expressed as pCa, was varied between 8.0 and 5.74. Equatorial diffraction spectra were fitted by a function consisting of five Gaussian curves and a hyperbola to separate the (1.0), (1.1), (2.0), (2.1) and Z-line diffraction peaks. The hyperbola was used to correct for residual scattering in the preparation. The ratio between the intensities of the (1.1) and (1.0) peaks was defined as the relative transfer of mass between myosin and actin, due to crossbridge formation after activation by calcium. The relation between the ratio and the relative force of the fibre (normalized to the force at pCa 5.74 and sarcomere length 2.0 microns) was linear. At high pCa (from pCa 6.34 to 8.0) no active force was observed, while the ratio still decreased. Sarcomere length was recorded by laser diffraction. The laser diffraction patterns did not show changes in sarcomere length due to activation in the high pCa range (between 8.0 and 6.34). From these results the conclusion is drawn that crossbridge movement occurs even at subthreshold calcium concentrations in the cell, when no active force is exerted. Since no force is generated this movement may be related to crossbridges in the weakly bound state.

Actins↗
PubMed1998

Impairment of the actin-myosin interaction in permeabilized cardiac trabeculae after chronic doxorubicin treatment.

The development of chronic cardiotoxicity in cancer patients treated with doxorubicin (DOX) and other anthracycline antineoplastic agents is a major dose-limiting factor. In a previous study, we demonstrated an acute effect of anthracyclines on the actin-myosin contractile system. Here, we report chronic effects of DOX both on the contractile system and on the function of the sarcoplasmic reticulum (SR). Male Wistar rats were treated with DOX (2 mg/kg, i.v., once a week for 4 weeks), whereas control rats received equal volumes of saline. Right ventricular trabeculae were isolated and skinned by exposure to Triton X-100 or saponin at 1, 2, 4, and 6 weeks after the final DOX administration. The maximal tension of trabeculae was similar between DOX-treated and control animals at 1 week posttreatment. At 2, 4, and 6 weeks posttreatment, the maximal tension of trabeculae of DOX-treated animals was significantly decreased by 27, 32, and 37%, respectively (P < 0.01). The rigor tension in trabeculae of DOX-treated animals was similar at 1 week posttreatment but significantly decreased at 2, 4, and 6 weeks posttreatment (by 25, 25, and 37%, respectively; P < 0.01). The ratio between rigor tension and maximal tension was significantly higher in DOX-treated groups as compared to controls (0.39 +/- 0.01 and 0.36 +/- 0.01; P < 0.05). Calcium sensitivity of DOX-treated preparations was significantly decreased as compared to controls (5.59 +/- 0.02 and 5.65 +/- 0.01; P < 0.05), whereas no effects were found on the cooperativity of the regulatory proteins, as measured by the Hill coefficient. The calcium release function of the SR, measured by caffeine (25 mM) stimulation in saponin-skinned trabeculae, was the same in DOX-treated and control groups at all posttreatment periods. The results of the present study show that long-term DOX treatment causes substantial impairment of the cross-bridge interaction in skinned trabeculae, which is reflected by a progressive attenuation of the contractile performance. The function of the SR, however, remains unaffected by DOX treatment in our preparations. The direct effect of chronic DOX treatment on the actin-myosin system provides an additional mechanism through which anthracyclines exert their cardiotoxic effects and may facilitate the development of cardioprotective strategies.

Actins↗
PubMed1997

Anthracyclines enhance tension development in cardiac muscle by direct interaction with the contractile system.

Anthracyclines are highly effective anticancer agents which induce a well described but incompletely understood cardiac toxicity. In this study, a direct action of several anthracyclines on the force generating mechanism of heart muscle preparations is described. To allow discrimination between membrane related effects and a direct action of anthracyclines on the actin-myosin contractile system, both inner and outer membranes of cardiac fibres were permeabilized. All anthracyclines tested in this study [doxorubicin (Dox), epirubicin, daunorubicin and idarubicin] showed positive inotropic actions. Dox and epirubicin, which are considered the most cardiotoxic drugs of the anthracycline family, significantly increased the maximal calcium activated tension by 33% (n = 8, P < 0.01) and by 26% (n = 8, P < 0.01) respectively. Daunorubicin and idarubicin increased the maximal tension by 12% and 9% respectively (P = n.s.). Other chemotherapeutic drugs (Taxol and 5-FU) had no effect on maximal tension. To elucidate the mechanism behind this Dox-induced increase in maximal tension, calcium sensitivity curves were measured and rigor experiments were performed. A small but significant increase in pCa50 value (+0.14 +/- 0.03, P < 0.05) was observed only after incubation with 20 microM Dox. Dox acted during the transition to force generating cross-bridges as reflected by the significant increase in rigor tension (12%, P < 0.05) after preincubation of cardiac fibres with Dox. Cycling of cross-bridges is a prerequisite for Dox to increase tension because no effect on tension was seen after Dox was added to fibres in an established rigor. In summary, anthracyclines increased the maximal tension in cardiac muscle fibres by direct interaction with the actin-myosin cross-bridges. Changes in calcium sensitivity are unlikely to contribute to the observed increase in maximal tension. The rise in tension as is seen in this experimental set-up may contribute to destruction of the contractile machinery of cardiac muscle. In agreement with this hypothesis is the observation that the more cardiotoxic anthracyclines induced the largest increase in maximal tension of the cardiac fibres.

Animals↗
PubMed1997

Strain dependence of the elastic properties of force-producing cross-bridges in rigor skeletal muscle.

Stretch and release experiments carried out on skinned single fibers of frog skeletal muscle under rigor conditions indicate that the elastic properties of the fiber depend on strain. For modulation frequencies below 1000 Hz, the results show an increase in Young's modulus of 20% upon a stretch of 1 nm/half-sarcomere. Remarkably, the strain dependence of Young's modulus decreases at higher frequencies to about 10% upon a 1-nm/half-sarcomere stretch at a modulation frequency of 10 kHz. This suggests that the cause of the effect is less straightforward than originally believed: a simple slackening of the filaments would result in an equally large strain dependence at all frequencies, whereas strain-dependent properties of the actin filaments should show up most clearly at higher frequencies. We believe that the reduction of the strain dependence points to transitions of the cross-bridges between distinct force-producing states. This is consistent with the earlier observation that Young's modulus in rigor increases toward higher frequencies.

Animals↗
PubMed1997

The effect of actin filament compliance on the interpretation of the elastic properties of skeletal muscle fibres.

Recently, X-ray diffraction studies provided direct evidence for an appreciable length change in the actin filament upon activation. This finding has profound implications on the interpretation of the elastic properties of skeletal muscle fibre. In this study we determined the compliance of the actin filament during activation, using the data obtained previously from quick stretch and release experiments on skeletal muscle fibres of the frog. The effects of filament compliance are demonstrated clearly in the elastic properties of partially activated fibres. The low-frequency elasticity increases linearly with tension, reflecting an increase in the number of force-producing cross-bridges. At higher frequencies, this linearity is lost. In this study we describe the data consistently in terms of a cross-bridge stiffness increasing linearly with tension and a constant Young's modulus for the actin filament of 44 MN m-2. This corresponds to a compliance of 23 pm microns-1 per kN m-2 tension developed. Using this value for the actin filament Young's modulus, its contribution to the elastic properties of skeletal muscle fibre of the frog is considered in rigor and relaxation. The filament compliance hardly affects the overall elasticity of the muscle fibre in relaxation. In contrast, it contributes to a large extent to the overall elasticity in rigor. Taking account of the filament compliance, we find that the Young's modulus in rigor exhibits an increase from 14 MN m-2 at frequencies below 500 Hz to 55 MN m-2 above 40 kHz.

Actins↗
PubMed1994

A fluorescence depolarization study of the orientational distribution of crossbridges in muscle fibres.

A fluorescence depolarization study of the orientational distribution of crossbridges in dye-labelled muscle fibres is presented. The characterization of this distribution is important since the rotation of crossbridges is a key element in the theory of muscle contraction. In this study we exploited the advantages of angle-resolved experiments to characterize the principal features of the orientational distribution of the crossbridges in the muscle fibre. The directions of the transition dipole moments in the frame of the dye and the orientation and motion of the dye relative to the crossbridge determined previously were explicitly incorporated into the analysis of the experimental data. This afforded the unequivocal determination of all the second and fourth rank order parameters. Moreover, this additional information provided discrimination between different models for the orientational behaviour of the crossbridges. Our results indicate that no change of orientation takes place upon a transition from rigor to relaxation. The experiments, however, do no rule out a conformational change of the myosin S1 during the transition.

Animals↗
PubMed1992

Tetragonal deformation of the hexagonal myofilament matrix in single skinned skeletal muscle fibres owing to change in sarcomere length.

Single skinned skeletal muscle fibres were immersed in solutions containing two different levels of activator calcium (pCa: 4.4; 6.0). Sarcomere length was varied from 1.6 to 3.5 microns and recorded by laser diffraction. Slack length was 2.0 microns. Small-angle equatorial X-ray diffraction patterns of relaxed and activated fibres at different sarcomere lengths were recorded using synchrotron radiation. The position and amplitude of the diffraction peaks were calculated from the spectra based on the hexagonal arrangement of the myofilament matrix, relating the position of the (1.0)- and (1.1)-diffraction peaks in this model by square root of 3. The diffraction peaks were fitted by five Gaussian functions (1.0, 1.1, 2.0, 2.1 and Z-line) and residual background was corrected by means of a hyperbola. The coupling of the position of the (1.0)- and (1.1)-peak was expressed as a factor: FAC = [d(1.0)/d(1.1)]/square root 3. In the relaxed state this coupling factor decreased at increasing sarcomere length (0.9880 +/- 0.002 at 2.0 microns; 0.900 +/- 0.01 at 3.5 microns). The coupling factor tends toward the one that will be obtained from the squared structure of actin filaments near the Z-discs. At shorter sarcomere lengths a decrease of the coupling factor has also been seen (0.9600 +/- 0.005 at 1.6 microns), giving rise to an increased uniform deformation of the hexagonal matrix, when sarcomere length is changed from slack length. From these experiments we conclude that a change in sarcomere length (from slack length) increases the deformation of the actin-myosin matrix to a tetragonal lattice.

Actin Cytoskeleton↗
PubMed1991

Length-dependent activation by Ba2+ and Sr2+ of skinned cardiac and skeletal muscle of the rabbit.

Over a wide range of sarcomere lengths, force activation by Ca2+, Ba2+, and Sr2+ was studied in papillary muscle and in fast skeletal fibers of the gracilis muscle of the rabbit, both skinned by means of freeze drying. The length-tension relations of Ba2+ activation differ significantly from those of Sr2+ and Ca2+ activation with respect to both the value and the position of the maximum. At (almost) full activation, force induced in gracilis muscle by Ba2+ was 50% of the developed force induced by Ca2+. The position of the Sr2+ sensitivity curve for papillary muscle preparations is independent of sarcomere length, in contrast to the position of the Ca2+ sensitivity curves. The binding of Sr2+ to the papillary preparation proves to be very stable as observed from the long-lasting relaxation after activation. Immersion of the papillary preparation in the relaxation fluid after activation with Ba2+ results in a tension transient: a rise in tension followed by a decrease was observed. The maximal value of the tension transient was up to twice the steady tension, dependent on Ba2+ concentration. The steady-state tension was approximately 50% of the Ca2(+)-induced tension. Ba2+ sensitivity curves are not sigmoidal but show a maximum. Above [Ba2+] greater than 10(-5) to 10(-4) M (dependent on sarcomere length) tension decreased. These observations suggest that two counteracting processes govern Ba2+ contraction in papillary muscle preparations, namely activation and inhibition.

Animals↗
PubMed1988

Caffeine suppresses length dependency of Ca2+ sensitivity of skinned striated muscle.

Freeze-dried skinned cardiac and skeletal muscle preparations of the rabbit were immersed in Ca2+-containing solutions with different concentrations of caffeine. The relation between the negative logarithm of the Ca2+ concentration (pCa) and normalized developed force was studied. The exact position of these Ca2+-sensitivity functions proved to be dependent on both the sarcomere length (monitored by means of laser diffraction) and caffeine concentration. High concentrations of caffeine induce a reversible fall in tension, particularly at low binding site saturation (low pCa) and long sarcomere lengths. At a concentration of 10 mM caffeine, the sarcomere length dependency of the Ca2+-sensitivity curves is markedly reduced for the rising part of the curve. Only the depressive effect of caffeine at high pCa remains. A possible mechanism of caffeine action is discussed.

Animals↗
PubMed1987

Relaxation time constant of isolated rabbit left ventricle.

Experiments were performed on isolated rabbit left ventricles. Controlled ejections during otherwise isovolumic contractions were studied. The time constant of relaxation was defined as the slope of the linear approximation of the ln(P)-t relation over a 40-ms period starting 20 ms after the minimum of the first time derivative of left ventricular pressure (dP/dt) of the isovolumic contraction. Variations in time of ejection, its amplitude, and velocity are applied independently. No direct effect of the variations in time and velocity of the ejection on the time constant of relaxation was found. This is in conflict with the findings of Hori et al. (Circ. Res. 55: 31-38, 1984). The difference is due to the influence of the recovery of pressure directly after the end of ejection in their study. This effect is present especially when ejection was timed to take place late in the contraction phase. The effect of the variation of the amplitude of the ejection on the time constant was similar to the effect of the end-diastolic pressure on the end-diastolic volume. It is concluded that the time constant of relaxation depends linearly on the same processes that are responsible for the height of the end-diastolic pressure.

Animals↗
PubMed1986

High-speed transient-recording microprocessor system for the analysis of asymmetrical diffraction spectra from striated muscle.

A microprocessor based digital recording system has been developed to study the fine structure and asymmetry of diffraction spectra from striated muscle during contraction. Two linear 256-element photodiode arrays provide analog videosignals of the diffraction lines imaged onto these charged coupled devices. The photodiode arrays are alternately read and the videosignals can be digitized and stored within 1.36 ms (two images of 256 points) with a spatial resolution of 5 nm. (In this paper the spatial resolution is considered to be the standard deviation of the first-order maximum of a monochromatic wave of the He/Ne laser measured from the diode-arrays, using ideal gratings with a spacing between 1.6 and 3.6 microns.) The system's memory with a capacity of 192 pairs of images of 256 points can be optimized by means of a threshold to contain about 2000 images without any loss of information. A transient recording approach makes the system capable of recording long term slow phenomena of up to 5 s as well as fast events and the combination of fast events within slow processes. The system presented here has a significantly improved time resolution and storage capacity when compared to other systems and is more versatile. This is the first system which enables the simultaneous examination of the fine structure and asymmetry of diffraction spectra.

Animals↗
PubMed1986

Immediate effects of diastolic loading variations on the left ventricular inotropic state in open chest dogs.

The influence of left ventricular filling and variations in end diastolic volume on cardiac performance was studied in the intact dog heart. Left ventricular filling volumes and stroke volumes were calculated on a beat to beat basis from measurements of natural mitral inflow and aortic outflow obtained by electromagnetic flow sensors. Instantaneous controlled modifications of end diastolic volume were performed through a cannula situated in the left ventricle and connected to a pump system outside the dog. This system enabled controlled increases or decreases of the end diastolic volume at any prechosen moment during the diastolic pause. Absolute volume variations in end diastolic volume and end systolic volumes could be calculated by combining the integrated flow signals from different consecutive beats. Left ventricular performance was evaluated in terms of end systolic volume and end systolic pressure variations. When the diastolic volume was abruptly increased by the pump system, natural mitral inflow decreased but end diastolic volume increased. The effect on diastolic pressure was dependent on the variation in filling rate, the amplitude of the infusion, the moment at which the infusion was started, and the diastolic pressure at the start of the infusion. Also stroke volume, maximal systolic pressure (Pmax), end systolic pressure, and end diastolic volume increased. The increased systolic performance was attributed to the increased end diastolic volume as expected according to Starling's law. When end diastolic volume was rapidly decreased during diastole by the pump, natural filling volumes increased to compensate for the volume loss by the pump. End diastolic volume was, however, smaller indicating that full compensation was not achieved. Evaluation of ventricular performance in terms of end systolic pressure and end systolic volume showed a decreased end systolic pressure and increased end systolic volume compared with the control values. The effect of a pump withdrawal was 1.62(0.38) times larger than could be explained on the basis of Starling's law. After the infusion of adrenaline the intrinsic depression disappeared and the influence of the volume withdrawal on cardiac performance was as expected from the Starling mechanism.

Animals↗
PubMed1984

The influence of velocity of length change on tension development in skeletal muscle: model calculations and experimental results.

Force responses obtained during constant velocity length changes on skeletal muscle tissue are simulated by means of two cross-bridge models proposed by Huxley and Simmons (1971, Nature 233, 533-538) and by Julian et al. (1974, Biophys. J. 14, 546-562). An implicit method was used for the numerical approximation in the simulations. The simulated force transients due to constant velocity length changes are found to be in qualitative agreement with re-investigated experimental results obtained from the whole sartorius muscle of the frog. A non-linear tension transient is observed, dependent both on amplitude and on velocity of release revealing an inflexion which gives the transient a shoulder shape. When velocity is increased the inflexion occurs earlier and at a lower tension value. A non-linear transient is observed during stretches performed at moderate velocities. Force responses are found to deviate concavely downwards from a linear time course. Simulations, however, predict a rather linear tension transient for comparable velocities. Implications of the experimental findings are discussed for both models.

Animals↗
PubMed1983

The effect of some sex hormones on the isovolumetric pressure curve of the rabbit's left ventricle.

The effect of some sex hormones (estradiol-17 alpha), estradiol-17 beta, estrone, progesterone and testosterone) on the mechanical activity of rabbit left ventricle was studied in concentrations within the physiological range. Investigations were carried out during the first ten minutes after the introduction of the steroid. Only progesterone and estradiol-17 beta affect the isovolumetric pressure curve; the other steroids do not exhibit any effect. The effects of estradiol-17 beta and progesterone counterbalance each other. Estradiol-17 beta enhances the rate of pressure development and decreases the time to reach peak pressure. Progesterone decreases both the rate of pressure development and the time to reach peak pressure.

Animals↗
PubMed1982

Direct action of estradiol-17 beta on the atrial action potential.

The effect of the two C-17 isomers of estradiol on the shape of the action potential of rat atrial tissue was studied by means of classical glass electrodes for different concentrations of estradiol. Resting potential and upstroke were not affected by estradiol, but the duration of the action potential was reduced. Only estradiol-17 beta exhibits an effect in a concentration dependent way, while estradiol-17 alpha has no effect at all. The ionic mechanism was studied by adding specific ionic blockers to the perfusate. Since the effect was much less pronounced when a slow inward current blocker was added, it was concluded that estradiol-17 beta acts mainly via the slow inward current channel. Only a small part of the interaction takes place via the potassium outward channel.

Action Potentials↗