Biomedical subjects

C A Ward

Publications and source records attributed to C A Ward.

At least 19 recordsLinked to original sources

PubMed2005

Surface excess properties from energy transport measurements during water evaporation.

When water evaporates at high rates, recent studies indicate thermal conduction to the interface does not provide enough energy to evaporate water at the observed rate and that it is perhaps thermocapillary convection that transports the remaining energy. This possibility is examined by applying the Gibbs dividing-surface approximation to develop an expression for the energy transported along the interface. When this energy transport rate is compared with that required to evaporate the liquid at the observed rate, it is found that a Gibbs excess property, the "surface-thermal capacity," can be evaluated. A series of 19 evaporation experiments has been conducted under conditions for which there was no buoyancy-driven convection and for which the evaporation rate was progressively increased. For Marangoni numbers, (Ma) less than approximately 100, the interface was quiescent and thermal conduction (the Stefan condition) correctly predicted the energy transport rate to the surface. For experiments with 100 22,000, the interfacial flow was turbulent and viscous dissipation became important.

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PubMed2005

Thermocapillary transport of energy during water evaporation.

When evaporation occurs at a spherical water-vapor interface maintained at the circular mouth of a small funnel, studies of the energy transport have indicated that thermal conduction alone does not provide enough energy to evaporate the liquid at the observed rate. If the Gibbs model of the interface is adopted and the "surface-thermal capacity" is assigned a value of 30.6+/-0.8 kJ/(m2 K), then for evaporation experiments with the interfacial temperature in the range -10 degrees C< or =TLV< or =3.5 degrees C and Marangoni number (Ma) in the range 100<Ma<22,000, it was found that if energy transport by both thermocapillary convection and thermal conduction were taken into account, conservation of energy was fully satisfied. The question addressed herein is whether the assigned value of the surface-thermal capacity is an ad hoc empirical parameter or a property of the water-vapor interface that can be used in other circumstances. Accordingly, a series of experiments has been conducted in which water evaporated at cylindrical interfaces that were, on average, 4.4 times larger in area than that of the spherical interfaces used to measure the surface-thermal capacity initially. It is shown that using the value of the surface-thermal capacity determined at a spherical interface, the energy transported by thermocapillary convection and thermal conduction at a cylindrical interface is sufficient to evaporate the liquid at the observed rate. Knowing the value of the surface-thermal capacity also allows the local evaporation flux to be calculated from the measured temperature profiles in the liquid and vapor phases. The calculated local evaporation flux can then be used with statistical rate theory to calculate the vapor-phase pressure along the interface. The predicted mean vapor-phase pressure is in close agreement with that measured, and the predicted pressure gradient is consistent with that expected when thermocapillary convection is present.

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PubMed2005

Surface-thermal capacity of from measurements made during steady-state evaporation.

When D2O(l) evaporates into its vapor under steady-state conditions with the temperature field in the liquid arranged so that there is no buoyancy-driven convection and the Marangoni number is less than approximately 100, it is found that the interface is quiescent and thermal conduction to the interface supplies energy at a sufficient rate to evaporate the liquid. However, if the evaporation rate is raised so that the Marangoni number goes above approximately 100, the interface is transformed: a fluctuating thermocapillary flow occurs, and thermal conduction no longer supplies energy at a sufficient rate to evaporate the liquid. An energy analysis indicates conservation of energy can be satisfied only if thermocapillary convection is taken into account, and the surface-thermal capacity csigma is assigned a value of 32.5+/-0.8 kJ/(m2 K) when the temperature is in the range -10 degrees C< or =TLV< or =3.7 degrees C. This value is consistent with that found previously for H2O, and application of the Gibbs model gives a qualitative explanation for the value. Once the value of the surface-thermal capacity is known, the local heat flux along the interface can be calculated and statistical rate theory can be used to predict the local vapor-phase pressure on the interface. Since this theory introduces no adjustable parameters, the predicted pressure can be compared directly with that measured: this comparison indicates the mean of the pressures predicted to exist on the interface is in close agreement with those measured approximately 20 cm above the interface, and the small pressure gradient along the interface is consistent with the thermocapillary convection predicted from the interfacial temperature gradient.

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PubMed2005

Actions of emigrated neutrophils on Na(+) and K(+) currents in rat ventricular myocytes.

Interactions between neutrophils and the ventricular myocardium can contribute to tissue injury, contractile dysfunction and generation of arrhythmias in acute cardiac inflammation. Many of the molecular events responsible for neutrophil adhesion to ventricular myocytes are well defined; in contrast, the resulting electrophysiological effects and changes in excitation-contraction coupling have not been studied in detail. In the present experiments, rat ventricular myocytes were superfused with either circulating or emigrated neutrophils and whole-cell currents and action potential waveforms were recorded using the nystatin-perforated patch method. Almost immediately after adhering to ventricular myocytes, emigrated neutrophils caused a depolarization of the resting membrane potential and a marked prolongation of myocyte action potential. Voltage clamp experiments demonstrated that following neutrophil adhesion, there was (i) a slowing of the inactivation of a TTX-sensitive Na(+) current, and (ii) a decrease in an inwardly rectifying K(+) current. One cytotoxic effect of neutrophils appears to be initiated by enhanced Na(+) entry into the myocytes. Thus, manoeuvres that precluded activation of Na(+) channels, for example holding the membrane potential at -80 mV, significantly increased the time to cell death or prevented contracture entirely. A mathematical model for the action potential of rat ventricular myocytes has been modified and then utilized to integrate these findings. These simulations demonstrate the marked effects of (50-fold) slowing of the inactivation of 2-4% of the available Na(+) channels on action potential duration and the corresponding intracellular Ca(2+) transient. In ongoing studies using this combination of approaches, are providing significant new insights into some of the fundamental processes that modulate myocyte damage in acute inflammation.

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PubMed2004

Turbulent transition of thermocapillary flow induced by water evaporation.

Water has been examined for thermocapillary convection while maintained just outside the mouth of a stainless-steel, conical funnel where it evaporated at different but steady rates. Evaporation at a series of controlled rates was produced by reducing the pressure in the vapor-phase to different but constant values while maintaining the temperature of the water a few millimeters below the interface at 3.56+/-0.03 degrees C in each case. Since water has its maximum density at 4 degrees C, these conditions ensured there would be no buoyancy-driven convection. The measured temperature profile along the liquid-vapor interface was found to be approximately axisymmetric and parabolic with its minimum on the center line and maximum at the periphery. The thermocapillary flow rate was determined in two ways: (1) It was calculated from the interfacial temperature gradient measured along the interface. (2) The deflection of a 12.7-microm-diameter, cantilevered probe inserted into the flow was measured and the liquid velocity required to give that deflection determined. The values determined by the two methods agree reasonably. As the vapor-phase pressure was reduced, the thermocapillary flow rate increased until a limiting value was reached. When the pressure was reduced further, certain of the variable relations underwent a bifurcation and the power spectrum of the probe displacement indicated it was a periodic function with frequency locking. These results suggest that thermocapillary flow plays an important role in the energy transport near the interface of evaporating water. In particular, it appears that the subinterface, uniform-temperature layer, reported in earlier studies, results from the mixing produced by the thermocapillary flow. The Stefan boundary condition is often applied to determine the energy flux to an interface where phase change is occurring; however, when there is strong convective flow parallel to the interface, the normal Stefan condition does not give an adequate description of the energy transport.

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PubMed2001

Interfacial conditions during evaporation or condensation of water.

Steady-state evaporation and condensation experiments have been conducted with water under conditions where buoyancy-driven convection is not present. The temperature profile in each phase has been measured. At the interface, independently of the direction of the phase change, a temperature discontinuity has been found to exist in which the interfacial vapor temperature is greater than that in the liquid. In a thin layer immediately below the interface the temperature is uniform in a layer ( approximately 0.5 mm) and below that the temperature profile is linear, indicating thermal conduction. The uniform temperature layer indicates a mixing process occurs near the interface that could result from surface-tension driven (Marangoni-Bénard) convection and/or from "energy partitioning" that is necessary to account for the measured temperature discontinuity near the interface. When the measured interfacial properties are used with the expression for the phase change rate that is obtained from statistical rate theory, it is found that the predictions are in close agreement with the measurements.

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PubMed2001

Gradient of sodium current across the left ventricular wall of adult rat hearts.

1. Gradients of ion channels across the left ventricular (LV) wall have been well characterized and it has been shown that disruption of such gradients leads to altered rates of repolarization across the wall, which is associated with the generation of arrhythmias. 2. We have hypothesized that a transmural gradient of I(Na) is present and have directly measured this current in adult rat myocytes isolated from both the epicardial and endocardial layers of the left ventricle. Currents were also recorded in right ventricular (RV) myocytes for comparison. 3. Peak inward I(Na) currents, at -30 mV, were -49.7 +/- 2.5 pA pF(-1) (n = 22), -32.9 +/- 3.2 pA pF(-1) (n = 16) and -49.7 +/- 3.7 pA pF(-1) (n = 24) for RV, LV epicardial and LV endocardial myocytes, respectively. No differences in the voltage dependence of inactivation, the voltage dependence of steady-state inactivation, or reactivation were reported. 4. Our results demonstrate that a gradient of sodium current density is present across the LV wall of adult rat hearts.

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PubMed2001

alpha(4)-integrin mediates neutrophil-induced free radical injury to cardiac myocytes.

Previous work has demonstrated that circulating neutrophils (polymorphonuclear leukocytes [PMNs]) adhere to cardiac myocytes via beta(2)-integrins and cause cellular injury via the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme system. Since PMNs induced to leave the vasculature (emigrated PMNs) express the alpha(4)-integrin, we asked whether (a) these PMNs also induce myocyte injury via NADPH oxidase; (b) beta(2)-integrins (CD18) still signal oxidant production, or if this process is now coupled to the alpha(4)-integrin; and (c) dysfunction is superoxide dependent within the myocyte or at the myocyte-PMN interface. Emigrated PMNs exposed to cardiac myocytes quickly induced significant changes in myocyte function. Myocyte shortening was decreased by 30-50% and rates of contraction and relaxation were reduced by 30% within the first 10 min. Both alpha(4)-integrin antibody (Ab)-treated PMNs and NADPH oxidase-deficient PMNs were unable to reduce myocyte shortening. An increased level of oxidative stress was detected in myocytes within 5 min of PMN adhesion. Addition of an anti-alpha(4)-integrin Ab, but not an anti-CD18 Ab, prevented oxidant production, suggesting that in emigrated PMNs the NADPH oxidase system is uncoupled from CD18 and can be activated via the alpha(4)-integrin. Addition of exogenous superoxide dismutase (SOD) inhibited all parameters of dysfunction measured, whereas overexpression of intracellular SOD within the myocytes did not inhibit the oxidative stress or the myocyte dysfunction caused by the emigrated PMNs. These findings demonstrate that profound molecular changes occur within PMNs as they emigrate, such that CD18 and associated intracellular signaling pathways leading to oxidant production are uncoupled and newly expressed alpha(4)-integrin functions as the ligand that signals oxidant production. The results also provide pathological relevance as the emigrated PMNs have the capacity to injure cardiac myocytes through the alpha(4)-integrin-coupled NADPH oxidase pathway that can be inhibited by extracellular, but not intracellular SOD.

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PubMed2001

Altered cellular calcium regulatory systems in a rat model of cirrhotic cardiomyopathy.

BACKGROUND & AIMS: Decreased cardiac contractility has been observed in cirrhosis, but the cause remains unclear. Because cardiomyocyte contraction depends on Ca2+ influx entering via L-type Ca2+ channels (I(Ca,L)s) to activate Ca2+ release from the sarcoplasmic reticulum, we postulated that the Ca2+ transients may be abnormal in cirrhotic cardiomyocytes. We aimed to investigate the status of the cellular Ca2+-regulatory system in a rat model of cirrhotic cardiomyopathy. METHODS: Cirrhosis was induced by bile duct ligation. The I(Ca,L) protein expression was detected by Western blotting. Ca2+ currents were measured electrophysiologically. The intracellular Ca2+ system, which includes the ryanodine receptor 2 (RYR2), sarcoplasmic reticulum Ca2+-pump adenosine triphosphatase (SERCA2), and Ca2+-binding protein were quantitatively assayed by reverse-transcription polymerase chain reaction and Western blots and functionally by 3H-ryanodine binding and radiolabeled Ca2+ uptake. RESULTS: I(Ca,L) protein expression was reduced in cirrhotic rats compared with controls, and the peak inward Ca2+ current was significantly less. At all membrane potentials examined, I(Ca,L)s current densities from cirrhotic animals were consistently lower, and the response to maximal isoproterenol stimulation was also significantly lower. Protein expression and messenger RNA transcription for RYR2, SERCA2, and calsequestrin were quantitatively unchanged, and 3H-ryanodine binding characteristics and Ca2+ uptake were also unaltered. CONCLUSIONS: We conclude that the decreased cardiac contractility in cirrhotic cardiomyocytes is caused by dysfunction of the Ca2+-regulatory system. Plasma membrane I(Ca,L)s are quantitatively reduced and functionally depressed, whereas intracellular systems are intact.

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PubMed2000

Tamoxifen inhibits Ca2+ uptake by the cardiac sarcoplasmic reticulum.

Ca2+ transients in isolated cardiac ventricular myocytes and the amount of Ca2+ that could be released from the sarcoplasmic reticulum (SR) in these cells by caffeine were reduced in the presence of tamoxifen. To examine the effects of tamoxifen on the cardiac muscle SR directly, isolated SR vesicles and fluorimetry methods were used to measure the uptake of Ca2+ by the SR and the ATPase activity of the SR Ca2+ pump. SR Ca2+ uptake was inhibited by tamoxifen at concentrations greater than 2.4 microM. Half-maximal inhibition was seen at approximately 5 microM. Inhibition of uptake was not due to the development of a substantial tamoxifen-dependent leak of Ca2+ from the SR or to a direct inhibitory effect of tamoxifen on the ATPase activity of the SR Ca2+ pump. In addition to its effect on SR Ca2+ uptake, tamoxifen also reduced the rate at which stored Ca2+ could be released from the SR by the Ca2+ ionophore 4-bromo A23187. Our results are consistent with the hypothesis that tamoxifen inhibits an ion current that accompanies Ca2+ movement across the SR membrane. This possibility is also consistent with the known inhibitory action of tamoxifen on some types of Cl- and K+ channels.

Animals↗

PubMed2000

Effect of hydrogen peroxide on the membrane currents of sinoatrial node cells from rabbit heart.

The effects of H(2)O(2) on pacemaker activity and underlying membrane currents were studied in isolated rabbit sinoatrial (SA) node cells using perforated patch current- and voltage-clamp methods. Short-term exposure (<10 min) of the nodal cells to H(2)O(2) (200 microM) resulted in an initial shortening of spontaneous action potential cycle length (from 445 +/- 60 to 398 +/- 56 ms; P < 0.05) and a prolongation of action potential duration. H(2)O(2) (100 microM) significantly increased peak L-type Ca(2+) current (I(Ca,L)) from -384 +/- 77 to -439 +/- 84 pA (116 +/- 2%, n = 6). Additionally, the persistent or non-inactivating component of I(Ca,L) was increased from -52 +/- 3 to -88 +/- 14 pA (174 +/- 19%, n = 6). The hyperpolarization-activated current (I(f)) was decreased from -228 +/- 62 to -161 +/- 72 pA after exposure to H(2)O(2) (n = 7). There were no changes in the delayed rectifier K(+) current (I(K)) (n = 7). H(2)O(2)-induced Ca(2+) currents were blocked by 2 microM nicardipine (n = 6), 2 mM Ni(2+) (n = 2), and the protein kinase C (PKC) inhibitor bisindolylmaleimide (10(-7) M; n = 4) but not by 20 microM tetrodotoxin. These results suggest that H(2)O(2) can increase the spontaneous pacing rate in rabbit SA node cells by enhancing I(Ca,L) and that this effect is mediated by a PKC-dependent pathway.

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PubMed1999

Chronic phospholamban-sarcoplasmic reticulum calcium ATPase interaction is the critical calcium cycling defect in dilated cardiomyopathy.

Dilated cardiomyopathy and end-stage heart failure result in multiple defects in cardiac excitation-contraction coupling. Via complementation of a genetically based mouse model of dilated cardiomyopathy, we now provide evidence that progressive chamber dilation and heart failure are dependent on a Ca2+ cycling defect in the cardiac sarcoplasmic reticulum. The ablation of a muscle-specific sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) inhibitor, phospholamban, rescued the spectrum of phenotypes that resemble human heart failure. Inhibition of phospholamban-SERCA2a interaction via in vivo expression of a phospholamban point mutant dominantly activated the contractility of ventricular muscle cells. Thus, interfering with phospholamban-SERCA2a interaction may provide a novel therapeutic approach for preventing the progression of dilated cardiomyopathy.

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PubMed1999

Emigrated neutrophils regulate ventricular contractility via alpha4 integrin.

We have previously shown that CD18 and alpha4 integrin were important in the adherence of emigrated neutrophils to cardiac myocytes. Whether either of these molecules is important in myocyte dysfunction is unclear. In this study, we measured contractility as an index of myocyte function. Control contractility was compared with shortening response in myocytes exposed to neutrophils in the presence and absence of anti-CD18 or anti-alpha4 antibodies. Control unloaded cell shortening, expressed as a percentage of resting cell length, measured 10.06+/-1.16% (n=10) at 5 minutes. Circulating neutrophils caused a 35% reduction in cell shortening, an event prevented by anti-CD18, but not by anti-alpha4 antibody. When emigrated neutrophils were added to the myocytes, a profound reduction (50%) in unloaded cell shortening was noted. A significant increase in CD18 and alpha4 integrin was found on emigrated neutrophils. Addition of anti-CD18 antibody did not protect the myocyte from the emigrated neutrophils, whereas the addition of an anti-alpha4 antibody significantly reduced neutrophil-induced cell shortening, despite some neutrophils still adhering to the myocytes. Furthermore, emigrated neutrophils were able to cause myocytes to go into contracture within 5 minutes in the presence of neutrophils with or without anti-CD18 antibody. In addition to the impairment in unloaded cell shortening, at later times (10 minutes), neutrophils also caused a 40% reduction in the rate of contraction and relaxation. The addition of either anti-CD18 or anti-alpha4 antibody protected the myocytes from these changes. The data suggest that immunosuppression of CD18 on emigrated neutrophils was only partially effective in reducing myocyte dysfunction. In contrast, immunosuppression of the alpha4 integrin alone was sufficient to dramatically reduce all parameters of cell dysfunction measured in this study.

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PubMed1997

Ionic mechanism of the effects of hydrogen peroxide in rat ventricular myocytes.

1. Whole-cell and amphotericin-perforated patch-clamp techniques have been used to study the effects of hydrogen peroxide (H2O2) on action potentials and underlying ionic currents in single myocytes from the ventricles of adult rat hearts. 2. The results obtained differed markedly depending on the recording method utilized. Conventional whole-cell recordings, in which the myoplasm is dialysed with the contents of the pipette, failed to show any significant effects of H2O2 on the action potential or cell shortening. In contrast, when action potentials were recorded with the amphotericin-perforated patch method, H2O2 (50-200 microM) produced a marked prolongation of the action potential and an increase in cell shortening. 3. Voltage-clamp recordings with the amphotericin-perforated patch method showed that H2O2 caused no significant changes in either the Ca(2+)-independent transient outward K+ current (Ito) or the inwardly rectifying K+ current (IK1). 4. Application of tetrodotoxin (TTX; 8 x 10(-6) M), a Na+ channel blocker, largely inhibited the effects of H2O2 on the action potential. Moreover, anthopleurin A (4 x 10 (-7) M), which augments Na+ current (INa) by slowing its inactivation, mimicked the effects of H2O2 on the action potential of ventricular myocytes. These effects on INa were also blocked almost completely by TTX. 5. The hypothesis that H2O2 can augment INa by slowing its kinetics of inactivation was tested directly using ensemble recordings from cell-attached macropatches. These results demonstrated a significant enhancement of late opening events when H2O2 (200 microM) was included in the recording pipette. A corresponding slowing of inactivation of the ensemble INa was observed. 6. The possibility that protein kinase C (PKC) is an intracellular second messenger for the observed effects of H2O2 was examined using the blocker bisindolylmaelimide (BIS; 10(-7) M). Bath application of BIS prior to H2O2 exposure significantly delayed and also attenuated the development of the action potential prolongation. 7. These results demonstrate marked electrophysiological effects of H2O2 in rat ventricle. The dependence of these effects on recording methods suggests involvement of an intracellular second messenger, and the results with the PKC inhibitor, BIS, support this possibility. The most prominent effect of H2O2 on the ionic currents which underlie the action potential is a slowing of inactivation of the TTX-sensitive INa. Recent molecular studies have demonstrated a PKC phosphorylation site on the rat cardiac Na+ channel isoform and have also shown that PKC activation can slow inactivation of INa.

Action Potentials↗

PubMed1997

Potassium currents in atrial and ventricular myocytes from a rat model of cirrhosis.

The underlying mechanisms for the electrophysiological abnormalities that develop as a consequence of cirrhosis of the liver have been studied by recording three different K+ currents in mammalian heart tissue. Single myocytes from the atria and ventricles of sham-operated and bile ductligated (BDL) cirrhotic adult rats were current and voltage clamped using standard whole cell methods. In ventricular myocytes from cirrhotic animals, measurements of the current-voltage relationships, voltage dependence of inactivation, and reactivation kinetics of K+ currents showed that the only significant functional changes (within the physiological range of membrane potentials) were decreases in the density of expression of 1) I(t), a Ca(2+)-independent transient outward K+ current, and 2) Isus, a delayed rectifier K+ current. The decreases in I(t) and Isus contribute to the prolonged Q-T interval of the electrocardiogram that has been described in cirrhotic patients. Measurement of K+ currents in atrial myocytes demonstrated that there were no significant differences in any of the K+ current densities between sham and BDL animals, although reactivation kinetics of I(t) were slowed somewhat.

Animals↗

PubMed1997

Emigrated rat neutrophils adhere to cardiac myocytes via alpha 4 integrin.

Previous work has shown that neutrophils isolated from whole blood adhere to cardiac-myocytes via CD18 (beta 2 integrin) to cause injury to the heart cells. In vitro, we have found that upon endothelial transmigration, neutrophils can also express alpha 4 beta 1; however, whether this contributes to neutrophil adhesion to parenchymal cells remains entirely unknown. Unstimulated and tumor necrosis factor-alpha-stimulated rat cardiac myocytes adherent to gelatin-coated coverslips supported N-formyl-Met-Leu-Phe (fMLP)-induced neutrophil (isolated from whole blood) adhesion entirely via CD18 (blocked with monoclonal antibody [mAb] WT-3). Emigrated neutrophils spontaneously adhered to cardiac myocytes also entirely via CD18. However, if fMLP was used to restimulate emigrated neutrophils, the adhesion to cardiac myocytes was entirely independent of CD18. Although an anti-alpha 4 integrin antibody (mAb TA-2) alone did not reduce the emigrated neutrophil-myocyte interaction, dual administration of TA-2 and WT-3 reduced adhesion by 81%. alpha 4 integrin was expressed in small amounts on the surface of circulating neutrophils, increased following transmigration, and then increased > 5-fold after restimulation of these emigrated neutrophils. In the presence of the anti-CD18 antibody, a fibronectin fragment (FN-40) but not a vascular cell adhesion molecule-1 antibody (mAb 5F10) inhibitied neutrophil-myocyte interactions by 80%. Similar results were seen when the rat chemokine CINC-gro was used instead of fMLP, suggesting that the alpha 4-dependent adhesion was not specific to fMLP. These data demonstrate that alpha 4 integrin can be physiologically induced to increase in number and avidity after neutrophil emigration and that this adhesion molecule can cause firm adhesion to fibronectin on parenchymal cells, including rat cardiac myocytes.

Animals↗

PubMed1996

Block of Na+ channel by bepridil in isolated guinea-pig ventricular myocytes.

The effects of bepridil, a potent antiarrhythmic agent, on the Na+ current (INa) of single guinea-pig ventricular myocytes were studied using the whole-cell patch-clamp technique. Bepridil inhibited INa in a dose-dependent manner without causing any change in the I-V. relationship for INa. Bepridil suppressed INa with Kd values of 342 and 40 microM when cells were clamped to holding potentials of -140 and -90 mV, respectively. 10 microM bepridil shifted the steady-state inactivation curve for INa toward more negative potentials by 7.7 mV (n = 6). Bepridil also produced marked use-dependent block with a rapid onset. Recovery of INa from inactivation was retarded (time constant 290 ms) at a holding potential of -140 mV in the presence of 10 microM bepridil. When the onset of INa block was studied in experiments using a double-pulse protocol, bepridil blocked INa by 11.5% after a 4-ms pre-pulse, but significantly blocked it after pre-pulses longer than 16 ms. These results suggest that: (1) bepridil has a higher affinity for the inactivated state than the resting state of Na+ channel; (2) the drug also produces an open channel block; and (3) the drug shows a lidocaine-like fast kinetic block of Na+ current.

Animals↗

PubMed1996

Signal transduction mechanisms in the ischemic and reperfused myocardium.

The cellular mechanisms regulating myocardial dysfunction during ischemia and subsequent reperfusion are complex. As can be determined from this review, it is clear that signal transduction pathways are altered during these conditions, which may explain, in part, the pathophysiology of ischemia and reperfusion. With respect to beta-adrenoceptor signal transduction, adaptive changes during ischemia and reperfusion ensure that this critical pathway for the regulation of cardiac function remains intact. Additionally, although the relative contribution of alpha 1-adrenoceptors to the regulation of cardiac function is minimal in normal myocardium, these receptors clearly exacerbate conditions associated with the generation of arrhythmias during reperfusion. It is likely that this enhancement of arrhythmogenesis is related to the activation of NHE by a PKC-dependent mechanisms. The importance of non-receptor-mediated signal transduction as a mediator of ischemia and reperfusion injury has long been established with respect to products of membrane lipid breakdown. As discussed, recent evidence now suggests that other compounds formed during ischemia and reperfusion, such as reactive oxygen species and NO, are also linked to cellular second messenger systems. In conclusion, as signal transduction is critical for normal myocardial function, signal transduction pathways are of even more importance during ischemia and reperfusion. There is an increasing interest in the role of non-receptor-mediated signal transduction as a mediator of ischemia and reperfusion injury and it is hoped that these pathways may represent new levels for therapeutic intervention.

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