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Biomedical subjects

F Verdonck

Publications and source records attributed to F Verdonck.

At least 55 records · Page 3Linked to original sources
PubMed1994

New Na(+)-H+ exchange inhibitor HOE 694 improves postischemic function and high-energy phosphate resynthesis and reduces Ca2+ overload in isolated perfused rabbit heart.

BACKGROUND: Experiments were carried out using the new Na(+)-H+ exchange inhibitor (3-methylsulfonyl-4-piperidinobenzoyl)guanidine methanesulfonate (HOE 694) to assess the role of Na(+)-H+ exchange in myocardial ischemic and reperfusion injury. METHODS AND RESULTS: Three groups of rabbit hearts (n = 5 in each) were perfused with blood and were subjected to 45 minutes of global normothermic (37 degrees C) ischemia, followed by 1 hour of reperfusion. Group 1 was the control group (vehicle only); in group 2, HOE 694 (1 mumol/L) was administered before ischemia (pretreatment group); and in group 3, HOE 694 was given only during reperfusion to separate actions exerted during ischemia from those specifically obtained during reperfusion. End-diastolic pressure rise at 1 hour of reperfusion was reduced by administration of HOE 694 starting before ischemia (from 52.2 +/- 8.5 mm Hg in group 1 to 17.6 +/- 4.5 mm Hg in group 2, P < .01) or starting on reperfusion (28.8 +/- 5.4 mm Hg in group 3, P < .05 versus group 1). Left ventricular developed pressure (LVDP) and its derivative (dP/dt) recovered better in HOE 694-pretreated hearts (LVDP, 79 +/- 9.9 mm Hg in group 2 versus 24.8 +/- 10 mm Hg in group 1; dP/dt, 1580 +/- 198 mm Hg/s versus 340 +/- 221 mm Hg/s, P < .01). In hearts treated only on reperfusion, some improvement was observed, which, however, did not reach statistical significance. Coronary flow on reperfusion was higher in groups 2 and 3 compared with controls, and no "no-reflow" was observed. Two additional groups of hearts were perfused with phosphate-free Krebs-Henseleit solution to enable studies with 31P nuclear magnetic resonance (NMR). ATP was better preserved in HOE 694-pretreated (62 +/- 4.9% of preischemic value) than in control hearts (44 +/- 3.3%) at the end of 30 minutes of reperfusion, and phosphocreatine resynthesis was higher (109 +/- 3.7% versus 86 +/- 5.4%). HOE 694 did not affect the time course of intracellular acidosis during ischemia but suppressed a small alkaline overshoot occurring early in reperfusion (pH 6.96 +/- 0.02 in HOE 694-pretreated hearts versus 7.14 +/- 0.05 in control hearts). Electron microscopy with Ca2+ staining of the blood-perfused hearts showed that clumping of Ca2+ aggregates in mitochondria was prevented by HOE 694. CONCLUSIONS: Postischemic dysfunction was associated with a rise in end-diastolic pressure. This rise was effectively blocked by HOE 694. The drug was most effective when hearts were treated before ischemia, although partial protection was observed when administration was started on reperfusion. The action of HOE 694 strengthens the idea that Na(+)-H+ exchange during both ischemia and reperfusion contributes to contractile dysfunction.

Adenosine Triphosphate↗
PubMed1993

Inhibition of sodium and calcium overload pathology in the myocardium: a new cytoprotective principle.

Ca2+ overload is known to play a major role in cell dysfunctioning in ischaemia/reperfusion and in cardiac glycoside intoxication. Suppression of Ca2+ overload or its consequences may therefore improve cellular function in these pathological conditions. Recent evidence suggests that Ca2+ overload occurs secondary to Na+ overload. Both depressed efflux and increased influx mechanisms have been mentioned as factors contributing to Na+ load. Prevention of this initial Na+ overload, without interfering with the normal Na+ current during the action potential, may therefore represent a novel pharmacological approach in the management of Ca2+ overload. The new cardioprotective drug R 56865 potently protects the heart against Ca2+ overload: ischaemia induced and ouabain induced arrhythmias and cell death are prevented in the absence of negative inotropism (no L-type Ca2+ channel blockade). At least three interactions at the cellular level may be held responsible for protection in these conditions. First, excessive Na+ entry into myocardial cells due to non-inactivating Na+ channels in depolarised cells is inhibited at concentrations that do not affect action potential configuration or contractile force. This leads to prevention of Na+ overload and subsequent Ca2+ overload and cell death. Second, R 56865 inhibits the transient inward current in Ca(2+)-(over)loaded cells, thus effectively preventing after-depolarisations and triggered propagated contractions. It has been proposed that R 56865, independent of its action on Na+ loading, might reduce oscillatory Ca2+ release from the intracellular Ca2+ stores, without interfering with the normal release mechanisms. Third, the drug attenuates K+ efflux in Na+ and Ca2+ loaded cells. In this way, R 56865 may contribute to prevention of action potential shortening and inhomogeneous repolarisation.(ABSTRACT TRUNCATED AT 250 WORDS)

Benzothiazoles↗
PubMed1993

Na+ pump current-voltage relationships of rabbit cardiac Purkinje cells in Na(+)-free solution.

1. The Na+ pump current (Ip) of isolated, single rabbit cardiac Purkinje cells in Na(+)-free solution was measured at 32-34 degrees C by means of whole-cell recording. 2. The Ip amplitude was studied as a function of clamp potential (Vc) and external concentration of various monovalent cations known to activate the Na(+)-K+ pump. 3. Under conditions which strongly activated Ip the Ip-Vc curve of the cells displayed a positive slope at membrane potentials negative to -20 mV and little variation at more positive potentials. 4. The Ip-Vc relationship showed an extended region of negative slope at positive and negative potentials in solutions containing low concentrations of activator cations which caused little Ip activation. A positive slope of the Ip-Vc curve was occasionally observed at clamp potentials negative to -60 mV under these conditions. 5. The shape of the Ip-Vc relation was independent of the cation species used as external Ip activator. 6. At zero membrane potential half-maximum Ip activation (K0.5(Vc = 0 mV) occurred at 0.05 mM Tl+, 0.08 mM K+, 0.4 mM NH4+ and 1.5 mM Cs+. The Hill coefficient derived amounted to 0.9 for Tl+, 1.2 for K+, 1.04 for NH4+ and 1.5 for Cs+. 7. The concentrations of external activator cations required for half-maximum Ip activation increased with depolarization. The voltage dependence of the K0.5 values could be described by a single exponential function for clamp potentials positive to -40 mV. 8. The steepness of the function is determined by a factor alpha, indicating the apparent fraction of an elementary charge which moves in the electrical field across the sarcolemma when external monovalent cations bind to the Na(+)-K+ pump. 9. The alpha values were calculated to be 0.32 for Tl+, 0.24 for K+, 0.29 for NH4+ and 0.18 for Cs+. Possible interpretations of the alpha values are considered. 10. It is suggested that binding of external monovalent activator cations to the Na(+)-K+ pump (or a process related to the binding) is voltage dependent. This potential-dependent process determines mainly the shape of the Ip-Vc curve in cardiac Purkinje cells superfused with Na(+)-free media containing low concentrations (< K0.5(Vc = 0 mV)) of K+ or its congeners.

Animals↗
PubMed1992

The kinetics of the inhibition by dihydroouabain of the sodium pump current in single rabbit cardiac Purkinje cells.

The kinetics of the inhibition by dihydroouabain (DHO) of the Na pump current were studied in isolated rabbit cardiac Purkinje cells by means of whole-cell recording. A fast exchange of the extracellular solution at the membrane of the cell studied was performed via two multi-barrelled pipettes nearby. Judging from the steady-state inhibition of the Na pump current at various DHO concentrations half maximal inhibition occurred at 1 x 10(-5) mol/l DHO in a medium containing 2 mmol/l K+ and at 3.5 x 10(-5) mol/l DHO in a solution containing 10.8 mmol/l K+. Assuming a reversible one-to-one binding reaction, the time course of DHO binding and unbinding was analysed under a variety of conditions. It was shown that the antagonistic effect of K+ on the inhibition of the pump current was entirely due to a decrease of the association rate constant of DHO binding to the sodium pump at higher K+ concentrations. The association rate constant amounted to 1 x 10(4) (mol/l)-1.s-1 at 2 mmol/l K+ and to 2.8 x 10(3) (mol/l)-1.s-1 at 10.8 mmol/l K+. The dissociation rate constant of DHO unbinding remained unchanged (approximately 0.06 s-1). The equilibrium dissociation constant KD for the inhibition of the pump current by DHO decreased by a factor 3 to 5 if the Na+ concentration of the patch pipette solution was augmented from 5 to 50 mmol/l. Increasing DHO concentrations inhibited the pump current increasingly faster and to a larger extent. The KD values derived showed little variation with the concentration of DHO applied.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Preferential block of the veratridine-induced, non-inactivating Na+ current by R56865 in single cardiac Purkinje cells.

The effect of the cardioprotective agent R56865 on the veratridine (VTD)-modified sodium current was investigated in single rabbit cardiac Purkinje cells and ventricular myocytes. A steady, tetrodotoxin (TTX)-sensitive Na+ current (the non-inactivating Na+ current) was absent in most cells studied. In the presence of veratridine (15 x 10(-6) M) a non-inactivating Na+ current could be elicited at membrane potentials between -80 to +60 mV, with a maximum at about 0 mV. R56865 blocked this current effectively. The concentration for half maximal inhibition of the non-inactivating Na+ current was 2 x 10(-7) M. Blockade of this Na+ current by R56865 increased with depolarization. R56865 was much more effective in inhibiting the non-inactivating Na+ current than in inhibiting time-dependent Na+ currents elicited by short depolarizing pulses. The blocking effect of R56865 on the steady state influx of Na+ may contribute to cardioprotection in depolarized cells and in cells with modified Na+ channels as may occur during ischemia and reperfusion.

Animals↗
PubMed1991

Changes of the subsarcolemmal Na+ concentration in internally perfused cardiac cells.

Transients of Na+/K+ pump and of Na+/Ca2+ exchange current occur during whole-cell recording from cardiac cells upon quick changes of active Na+ efflux. The transients reflect a temporary loss of control of the subsarcolemmal Na+ concentration. Even in the steady state the control is not complete is certain cells. Quantitative studies on ion transport by whole-cell recording are meaningful only if an adequate control of the submembranal ionic composition is demonstrated.

Animals↗
PubMed1991

Dependence of Na+ pump current on external monovalent cations and membrane potential in rabbit cardiac Purkinje cells.

1. The effect of membrane potential and various extracellular monovalent cations on the Na+ pump current (Ip) was studied on isolated, single Purkinje cells of the rabbit heart by means of whole-cell recording. 2. Ip was identified as current activated by external K+ or its congeners NH4+ and Tl+. The current was blocked by dihydroouabain (1-5 x 10(-4) M) over the whole range of membrane potentials tested. 3. In Na(+)-containing solution half-maximum Ip activation (K0.5) occurred at 0.4 mM-Tl+, 1.9 mM-K+ and 5.7 mM-NH4+ (holding potential, -20 mV). 4. The pump current (Ip)-voltage (V) relationship of the cells in Na(+)-containing media with K+ or its congeners at the tested concentrations greater than K0.5 displayed a steep positive slope at negative membrane potentials between -120 and -20 mV. Little voltage dependence of Ip was observed at more positive potentials up to +40 mV. At even more positive potentials Ip measured at 2 and 5.4 mM-K+ decreased. 5. Lowering the concentration of K+ or its congeners below the K0.5 value in Na(+)-containing solution induced a region of negative slope of the Ip-V curve at membrane potentials positive to -20 mV. 6. The shape of the Ip-V relationship remained unchanged when the K+ concentration (5.4 mM) of the Na(+)-containing medium was replaced by NH4+ or Tl+ concentrations of similar potency to activate Ip (20 mM-NH4+ or 2 mM-Tl+). 7. In Na(+)-free, choline-containing solution half-maximum Ip activation occurred at 0.13 mM-K+ (holding potential, -20 mV). 8. At negative membrane potentials the positive slope of the Ip-V curve was flatter in Na(+)-free than in Na(+)-containing media. A reduced voltage dependence of Ip persisted, regardless of whether choline ions or Li+ were used as a Na+ substitute. 9. Lowering the K+ concentration of the Na(+)-free, choline-containing solution to 0.05 mM evoked an extended region of negative slope in the Ip-V relationship at membrane potentials between -40 and +60 mV. 10. It is concluded that the apparent affinity of the Na(+)-K+ pump towards K+ in cardiac Purkinje cells depends on both the membrane potential and the extracellular Na+ concentration. 11. The region of negative slope of the Ip-V curve observed in cells which were superfused with media containing low concentrations of K+ or its congeners strongly suggests the existence of at least two voltage-sensitive steps in the cardiac Na(+)-K+ pump cycle.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1990

Consequences of CO2 acidosis for transmembrane Na+ transport and membrane current in rabbit cardiac Purkinje fibres.

1. The influence of sarcolemmal Na(+)-H+ exchange on intracellular Na+ activity (aiNa), intracellular pH (pHi) and membrane holding current (Ih) was investigated in rabbit cardiac Purkinje fibres. pHi and aiNa were measured with liquid sensor ion-selective microelectrodes. A two-microelectrode voltage clamp was used while recording pHi or aiNa.pHi was varied by alternating a nominally CO2-free HEPES buffer and a CO2-HCO3-buffer. 2. The intrinsic buffer capacity was calculated from the decrease in pHi after addition of CO2. The most accurate estimate was obtained when transmembrane pHi regulation was blocked and equalled 18.4 +/- 1.0 mequiv H+/pH unit (mean +/- S.E.M.). 3. aiNa started to rise when pHi fell below 7.0. A hyperpolarization paralleled the increase in aiNa. The magnitude of the rise in aiNa and the hyperpolarization were steeply dependent on pHi. 4. Inhibition of the Na(+)-K+ pump by K(+)-free superfusion increased aiNa. The rate of rise in aiNa was highly dependent on pHi. The rates of rise in 5% (pHi = 7.00 +/- 0.03), 7% (pHi = 6.89 +/- 0.04) and 15% CO2 (pHi = 6.74 +/- 0.02) at constant external pH (pHo) relative to the rate in HEPES solution (pHi = 7.24 +/- 0.02) were: 1.5 +/- 0.2, 2.4 +/- 0.1 and 3.1 +/- 0.2. The acid-induced rise in aiNa was abolished by 2 mM-amiloride. 5. Extracellular acidosis slowed down the recovery of pHi and depressed the rate of rise in aiNa upon intracellular acidification. When both pHi and pHo were decreased to 6.7 the acid-dependent rate increase fell to about 10% of the value found at pHo 7.4. 6. The tetrodotoxin (TTX)-sensitive Na+ current was not influenced by the change in pHi in the range 6.7-7.2. 7. Intracellular acidosis was associated with an early aiNa-independent depolarization and an inward shift in Ih. Current-voltage plots revealed that the initial inward current shift reversed at -81.5 mV on average, showed inward rectification and was largely depressed in the presence of 1 mM-Ba2+. These observations indicate a decrease in K+ conductance when pHi falls. 8. The increase in aiNa elicited a Na(+)-K+ pump-dependent outward current which could override the initial aiNa-independent current shift. At a pHo of 6.7 the initial fall in Ih remained, while the secondary outward current was largely depressed. 9. The rate of active Na+ extrusion and Na(+)-K+ pump current were suppressed by about 30% at pHi 6.7 compared to pHi 7.2.(ABSTRACT TRUNCATED AT 400 WORDS)

Acidosis↗
PubMed1989

Activation of the Na pump current by external K and Cs ions in cardioballs from sheep Purkinje fibres.

The Na pump current (Ip) was measured at 30-33 degrees C as a function of the extracellular K+ or Cs+ concentrations ([K]o; [Cs]o) by means of whole cell recording from cardioballs isolated from sheep Purkinje fibres. The results show that the magnitude of Ip is an s-shaped, saturating function of [K]o or [Cs]o, respectively. Half maximal Ip activation occurs at 1.2 mM Ko or 3.2 mM Cso (clamp potential: -20 mV). These values are appreciably lower than earlier measurements on sheep Purkinje fibres indicated. The Hill coefficients for Ip activation by external K+ or Cs+ were calculated to be 1.94 and 1.73, respectively. The numbers suggest that Ip activation requires at least two external activator cations.

Animals↗
PubMed1988

Exogenous palmitoyl carnitine and membrane damage in rat hearts.

In rat hearts perfused using the Langendorff technique, a cellular release of myoglobin (an index of sarcolemmal damage) was induced in a dose-dependent way by palmitoyl carnitine concentrations exceeding 1.6 microM in the perfusion solution. From 0.7 to 64.5 mmoles palmitoyl carnitine/kg dry wt were taken up by the heart tissues exposed for 30 min to extracellular palmitoyl carnitine concentrations ranging between 0.7 and 100 microM. The steep S-shaped curve relating the cellular myoglobin release provoked by Ca2+ readmission after Ca2+-free perfusion (the calcium paradox) to the perfusion temperature was shifted to lower temperatures by 2 to 3 degrees C in the presence of 1.6 microM palmitoyl carnitine. The loss of myoglobin induced by a mechanical distention of the left ventricular wall during Ca2+-free perfusion was nearly doubled in the presence of 1.6 microM palmitoyl carnitine. Isolated rod-shaped myocytes turned round within 20 min when the extracellular palmitoyl carnitine concentration exceeded 1.6 microM. It is concluded that the presence of palmitoyl carnitine in the perfusion medium at concentrations below those usually adopted in the literature to study the effects of palmitoyl carnitine on the sarcolemmal function induces membrane disruption and exacerbates the membrane damage caused by other factors. The tissue amphiphile content is probably critical to these effects.

Animals↗
PubMed1986

The contribution of Na and K ions to the pacemaker current in sheep cardiac Purkinje fibres.

The ionic components of the pacemaker current are quantitatively analysed in sheep cardiac Purkinje fibres by simultaneous measurements of the intracellular Na activity (alpha iNa) and the membrane current under voltage clamp. The pacemaker current is operationally defined as the Cs inhibited membrane current (ICs) in Ba containing media at clamp potentials negative to -60 mV. At these potentials solutions containing CsCl (0.2-5 mM) shift the holding membrane current into the outward direction and simultaneously decrease alpha iNa. The Cs effects on membrane current and alpha iNa display a similar voltage dependence. A Cs inhibited Na influx contributes to ICs. The ratio ICs/(Cs inhibited Na influx in electrical units) is less than 1 at membrane potentials positive to the potassium equilibrium potential EK and greater than 1 at potentials negative to EK. The ratio is close to 1 at EK suggesting Na ions to be the only carriers of the current at EK whereas K ions contribute to ICs at potentials different from EK. The effects of Cs on the Cs inhibited Na influx and ICs show a very similar dose dependence. The effect is half maximum at approximately 0.2 mM CsCl (in 21.6 mM K; clamp potential: -85 mV). An increase of the external K concentration augments ICs and the Cs inhibited Ca influx. Na and K ions carrying ICs probably cross the membrane via an identical channel. The permeability of the channel for K+ is about 10-20 times larger than for Na+. The ICs reversal potential of a fibre bathed in a medium containing 5.4 mM K is estimated to be -50 to -60 mV.

Animals↗
PubMed1982

An identification of the K activated Na pump current in sheep Purkinje fibres.

The cell membrane of sheep Purkinje fibers hyperpolarizes transiently on returning to K containing media after several minutes in K free solution. To analyse this 'K activated response' voltage clamp experiments and measurements of the internal Na activity (aiNa) are performed in fibres bathed in solution containing 0.2-2 mM BaCl2. Compared to the response in Tyrode solution the transient hyperpolarization beyond the resting potential is increased in Ba containing media. The response is blocked by 10(-4) M dihydroouabain. During the response, in Ba treated fibres, aiNa and a transient outward current decline with the same time constant at all clamp potentials tested. The transient outward current is most probably due to a temporary increase in electrogenic Na pumping. Both the amplitude and the time constant of the pump current show little voltage dependence. The electrogenic fraction of the active Na efflux is estimated to be about 39% and is independent of aiNa. Ba ions facilitate the analysis of the pump current in voltage clamped fibres because K depletion is reduced and changes of the I-V relationship by K depletion are minimized. It is concluded that activation of the electrogenic Na pump is mainly responsible for the K activated response of fibres in Ba containing media.

Animals↗
PubMed1977

Reduction of potassium permeability by chloride substitution in cardiac cells.

1. The efflux of radioactive K and Cl ions was measured in cow Purkinje fibres and ventricular preparations of cow, cat and frog. The effect of K and Cl was studied by changing the extracellular K concentration between zero and 54 mM, and by substituting Cl ions by acetylglycinate, isethionate, benzenesulphonate, propionate and nitrate. 2. In the absence of Cl the rate coefficient for 42K efflux showed a pronounced fall, which was more pronounced the higher the K concentration. This effect was not related to the change in membrane potential. The rate coefficient for 42K efflux increased in the presence of higher extracellular K concentrations. 3. 36Cl efflux increased in the presence of reduced as well as increased extracellular K concentrations. 4. The calculated permeability coefficient for K (PK) was maximal at 5-4 mM-K, decreased slightly at higher K concentrations, but fell markedly in K-free solutions, (to about 1/5 of the value in 5-4 mM-K). In Cl-free medium PK reduced to 0-67 of the value in the Cl medium, irrespective of the K concentration. 5. The calculated PCl was greater in K-free and 16-2 mM-K than in 5-4 mM-K. 6. The ratio PK/PCl showed important changes as a function of extracellular K concentration: the value was 5 in 5-4 mM-K and fell to 2 and 0-5 respectively in 16-2 and K-free solutions. 7. The results suggest that part of the changes in membrane resistance measured by electrical methods in Cl-free media is due to a simultaneous decrease in K conductance.

Animals↗