Biomedical subjects

T Bányász

Publications and source records attributed to T Bányász.

At least 19 recordsLinked to original sources

PubMed2004

Reopening of L-type calcium channels in human ventricular myocytes during applied epicardial action potentials.

AIMS: Present study was performed to compare the dynamics of human L-type calcium current (ICa,L) flowing during rectangular voltage pulses, voltage ramps, and action potentials (APs) recorded from epicardiac and endocardiac canine ventricular cells. METHODS: ICa,L was recorded in single myocytes isolated from undiseased human hearts using the whole cell voltage clamp technique. RESULTS: The decay of ICa,L was monotonic when using rectangular pulses or endocardial APs as voltage commands, whereas the current became double-peaked (displaying a second rise and fall) during epicardial (EPI) APs or voltage ramps used to mimic EPI APs. These ICa,L profiles were associated with single-hooked and double-hooked phase-plane trajectories, respectively. No sustained current was observed during the AP commands. Kinetics of deactivation and recovery from inactivation of human ICa,L were determined using twin-pulse voltage protocols and voltage ramps, and the results were similar to those obtained previously in canine cells under identical experimental conditions. CONCLUSIONS: ICa,L can inactivate partially before and deactivate during the phase-1 repolarization of the epicardiac AP, and reopening of these channels seems to be associated with formation of the dome.

Action Potentials↗

PubMed2003

Differences in electrophysiological and contractile properties of mammalian cardiac tissues bathed in bicarbonate - and HEPES-buffered solutions.

AIM: The aim of this study was to compare the action potential configuration, contractility, intracellular Ca2+ and H+ concentrations in mammalian cardiac tissues bathed with Krebs and Tyrode solutions at 37 degrees C. RESULTS: In Langendorff-perfused guinea-pig hearts, loaded with the fluorescent Ca2+-indicator Fura-2, or H+-sensitive dye carboxy-SNARF, shifts from Krebs to Tyrode solution caused intra-cellular acidification, increased diastolic pressure and [Ca2+]i, decreased systolic pressure and [Ca2+]i, leading to a reduction in the amplitude of [Ca2+]i transients and pulse pressure. Contractility was also depressed in canine ventricular trabeculae when transferred from Krebs to Tyrode solution. Shifts from Krebs to Tyrode solution increased the duration of action potentials in multicellular cardiac preparations excised from canine and rabbit hearts but not in isolated cardiomyocytes. All these changes in action potential morphology, contractility, [Ca2+]i and [H+]i were readily reversible by addition of 26 mmol L(-1) bicarbonate to Tyrode solution. Effects of dofetilide and CsCl, both blockers of the delayed rectifier K current, on action potential duration were compared in Krebs and Tyrode solutions. Dofetilide lengthened rabbit ventricular action potentials in a significantly greater extent in Tyrode than in Krebs solution. Exposure of canine Purkinje fibres to CsCl evoked early after depolarizations within 40 min in all preparations incubated with Tyrode solution, but not in those bathed with Krebs solution. CONCLUSION: It is concluded that the marked differences in action potential morphology, [Ca2+]i, [H+]i and contractility observed between preparations bathed with Krebs and Tyrode solutions are more likely attributable to differences in the intracellular buffering capacities of the two media.

Action Potentials↗

PubMed2003

The role of transmembrane chloride current in afterdepolarisations in canine ventricular cardiomyocytes.

The physiological role of chloride currents (Icl) in cardiac cells is poorly understood. The aim of the present study was to reveal the role of Icl in the genesis of early and delayed afterdepolarisations (EADs and DADs, respectively). First we identified Icl under action potential voltage clamp conditions as the anthracene-9-carboxylic acid (ANTRA) (0.5 mmol/l)-sensitive current. The ANTRA-sensitive current was large and outwardly directed at the beginning, while it was moderate and inwardly directed at the end of the action potential. Application of ANTRA under current clamp conditions decreased the depth of the incisura, shifted the plateau upwards and lengthened the duration of action potentials. The effect of ANTRA was studied in three models of afterdepolarisations: the ouabain-induced DAD model, the caesium-induced EAD model, and in the presence of subthreshold concentration of isoproterenol. Preincubation of the cells with 0.5 mmol/l ANTRA failed to induce afterdepolarisations. Ouabain (200 nmol/l) alone caused DADs in 62.5% of the cells within 15 min. When ouabain was applied in the presence of ANTRA, 60% of the myocytes transiently displayed EADs before the development of DADs, and all cells developed DADs within 7 min. Isoproterenol (5 nmol/l) alone failed to induce afterdepolarisations. However, 75% of the cells produced DADs within 6 min when superfused with isoproterenol in the presence of ANTRA. Incubation of the myocytes with 3.6 mmol/l CsCl caused EADs in 71.4% of the cells within 30 min. Application of CsCl in the presence of ANTRA resulted in immediate depolarisation of the membrane from -79.6 +/- 0.4 to -54.2 +/- 3.5 mV. Summarizing our results we conclude that the ANTRA-sensitive current is an important mechanism of defence against afterdepolarisations. Suppression of Icl may thus increase the incidence and accelerate the rate of development of both EADs and DADs.

Action Potentials↗

PubMed2001

Different effects of endothelin-1 on calcium and potassium currents in canine ventricular cells.

Effects of endothelin-1 (ET-1) on the L-type calcium current (ICa) and delayed rectifier potassium current (IK) were studied in isolated canine ventricular cardiomyocytes using the whole-cell configuration of the patch-clamp technique. ET-1 (8 nM) was applied in three experimental arrangements: untreated cells, in the presence of 50 nM isoproterenol, and in the presence of 250 microM 8-bromo-cAMP. In untreated cells, ET-1 significantly decreased the peak amplitude of ICa by 32.3+/-4.8% at +5 mV (P<0.05) without changing activation or inactivation characteristics of ICa. ET-1 had no effect on the amplitude of IK, Ito (transient outward current) or IK1 (inward rectifier K current) in untreated cells; however, the time course of recovery from inactivation of Ito was significantly increased by ET-1 (from 26.5+/-4.6 ms to 59.5+/- 1.8 ms, P < 0.05). Amplitude and time course of intracellular calcium transients, recorded in voltage-clamped cells previously loaded with the fluorescent calcium indicator dye Fura-2, were not affected by ET-1. ET-1 had no effect on force of contraction in canine ventricular trabeculae. Isoproterenol increased the amplitude of ICa to 263+/-29% of control. ET-1 reduced ICa also in isoproterenol-treated cells by 17.8+/-2% (P<0.05); this inhibition was significantly less than obtained in untreated cells. IK was increased by isoproterenol to 213+/-18% of control. This effect of isoproterenol on IK was reduced by 31.8+/-4.8% if the cells were pretreated with ET-1. Similarly, in isoproterenol-treated cells ET-1 decreased IK by 16.2+/-1.5% (P<0.05). Maximal activation of protein kinase A (PKA) was achieved by application of 8-bromo-cAMP in the pipette solution. In the presence of 8-bromo-cAMP ET-1 failed to alter ICa or IK It was concluded that differences in effects of ET-1 on ICa and IK may be related to differences in cAMP sensitivity of the currents.

Action Potentials↗

PubMed2001

Effects of the antiarrhythmic agent EGIS-7229 (S 21407) on calcium and potassium currents in canine ventricular cardiomyocytes.

Based on earlier pharmacological studies performed using conventional microelectrodes EGIS-7229 (S 21407), the novel antiarrhythmic candidate, was suggested to have a combined mode of action in cardiac tissues isolated from various mammalian species. In order to characterize the electrophysiological effects of the compound, its effects on calcium and potassium currents of isolated canine ventricular cardiomyocytes were studied in the present work using the whole cell configuration of the patch clamp technique. L-type Ca current (ICa) was significantly depressed by EGIS-7229 at concentrations of 3 microM or higher with no concomitant changes in the voltage-dependence of activation and time course of inactivation of ICa. The drug reversibly suppressed the rapid component of the delayed rectifier K current (IKr) in a concentration-dependent manner, having a K0.5 value of 1.1+/-0.1 microM and a slope factor of close to unity (1.23+/-0.16), indicating that probably one single binding site of high affinity may be involved in binding of EGIS-7229 to the IKr channel. In contrast, no changes in the slow component of the delayed rectifier K current (IKs) was observed with the compound up to the concentration of 100 microM, even if the current was fully activated by 8-bromo-cAMP. At a concentration of 10 microM or higher, EGIS-7229 caused also a moderate but significant reduction in the inward rectifier K current (IK1) and the transient outward K current (Ito) with no change in the voltage-dependence of activation and steady-state inactivation of Ito. Present results indicate that EGIS-7229 can be considered as a selective IKr blocker at low (1 microM) concentration; however, its combined (class III + IV) mechanism of action is evident at concentrations of 3 microM or higher. Suppression of ICa may explain the lack of development of early afterdepolarizations in the presence of EGIS-7229, predicting a relatively safe clinical application in contrast to pure class III compounds.

Analysis of Variance↗

PubMed2001

Effects of EGIS-7229 (S 21407), a novel class III antiarrhythmic drug, on myocardial refractoriness to electrical stimulation in vivo and in vitro.

The I(Kr) blocker EGIS-7229 (S-21407), displays class Ib and class IV effects that may alter its pharmacologic profile compared with those of pure I(Kr) blockers. Therefore, the concentration- and frequency-dependent effects of EGIS-7229, and of the I(Kr) blockers d,l-sotalol and dofetilide, on the effective refractory period (ERP) were measured in isolated right ventricular papillary muscle of the rabbit in vitro. The effects of these drugs on right ventricular fibrillation threshold (RVFT) at increasing intravenous doses were also determined in anesthetized cats. Dofetilide and d,l-sotalol increased ERP in a concentration-dependent manner (dofetilide: 3-100 nM; d,l-sotalol: 3-100 microM) with strong reverse frequency dependence at high concentrations. EGIS-7229 concentration dependently lengthened ERP at 1-30 microM. Its effect on ERP was clearly reverse frequency dependent at 3 microM, but this feature of the drug diminished at 10 microM and was not apparent at 30 microM. The effect of EGIS-7229 (30 microM) on ERP was devoid of reverse frequency dependence as it was more effective (31%) than dofetilide (16 %) at high-pacing rate (3 Hz), whereas it was less effective (50%) than dofetilide (70%) at slow-pacing rate (1 Hz). Reverse frequency-dependent ERP effect of dofetilide (100 nM) was similarly abolished by the addition of lidocaine (30 microM). EGIS-7229 (1-8 mg/kg iv), d,l-sotalol (1-8 mg/kg iv), and dofetilide (10-80 microg/kg iv) caused a dose-dependent increase in RVFT. The minimum effective dose of d,l-sotalol and EGIS-7229 was 1 and 2 mg/kg, respectively, whereas that of dofetilide was 10 microg/kg. EGIS-7229 induced a smaller peak effect in RVFT than sotalol or dofetilide. In conclusion, EGIS-7229 markedly increased refractoriness to electrical stimulation in vitro and in vivo. Compared with pure I(Kr) blockers, the benefits of EGIS-7229 seem to be a greater lengthening of effective refractory period at rapid stimulation rates, suggesting a strong antiarrhythmic action, and a smaller effect at slow stimulation rates, suggesting low potential to induce early afterdepolarizations.

Animals↗

PubMed2000

Cardiovascular effects of BRX-005 comparison to bimoclomol.

Concentration-dependent effects of BRX-005, the novel heat shock protein coinducer, cardioprotective and vasoprotective agent, on intracellular calcium transients and contractility were studied in Langendorff-perfused guinea pig hearts loaded with the fluorescent calcium indicator dye Fura-2. BRX-005 increased peak left ventricular pressure, the rate of force development and relaxation significantly in a concentration-dependent manner. The amplitude of [Ca2+]i transients was left unaltered by the drug. In contrast to BRX-005, bimoclomol increased both contractility and the amplitude of [Ca2+]i transients. In canine ventricular cardiomyocytes high concentrations of BRX-005 had no effect on depolarization, whereas bimoclomol suppressed action potential upstroke markedly. In guinea pig pulmonary artery preparations precontracted with phenylephrine, BRX-005 induced concentration-dependent relaxation. This effect of BRX-005 was independent of the integrity of endothelium indicating that vasorelaxant effect of the drug develops directly on vascular smooth muscle.

Action Potentials↗

PubMed2000

Effects of bimoclomol, the novel heat shock protein coinducer, in dog ventricular myocardium.

The effects of the novel HSP-coinducer bimoclomol was studied on action potentials, ionic currents and [Ca2+]i transients in isolated canine ventricular myocytes using conventional microelectrode techniques and whole cell voltage clamp combined with fluorescent [Ca2+]i measurements. Contractility was studied in right ventricular trabeculae. All preparations were paced with a frequency of 0.2 Hz. Bimoclomol (100 microM) shortened action potential duration measured at 50% repolarization, but lengthened action potentials at the 90% repolarization level, decreased action potential amplitude and maximum depolarization velocity in a reversible manner. In voltage clamped myocytes, the drug activated a steady-state outward current at positive membrane potentials leaving the peak inward current unaffected. [Ca2+]i transients, measured under voltage clamp control, were increased in amplitude and had accelerated decay kinetics in the presence of the compound, in addition to reduction of diastolic [Ca2+]i. Bimoclomol significantly decreased the force of contraction in right ventricular trabeculae. Comparison of present data to previous results indicate that the cardiac effects of bimoclomol strongly depend on actual experimental conditions. The reduced contractility in spite of the increased amplitude of [Ca2+]i transients suggests that 100 microM bimoclomol may decrease calcium sensitivity of the contractile apparatus.

Action Potentials↗

PubMed2000

Electrophysiological effects of fluoxetine in mammalian cardiac tissues.

Fluoxetine is a widely used antidepressant compound having selective serotonin reuptake inhibitor properties. In this study, the actions of fluoxetine were analyzed in guinea pig, rat, rabbit and canine ventricular myocardiac preparations using conventional microelectrode and whole cell voltage clamp techniques. Low concentrations of fluoxetine (1-10 micromol/l) caused significant shortening of action potential duration (APD) and depression of the plateau potential in guinea pig and rabbit papillary muscles and single canine ventricular myocytes. In rat papillary muscle, APD was not affected by fluoxetine (up to 100 micromol/l), however, the drug decreased the force of contraction with EC50 of 10 micromol/l. Fluoxetine (10 micromol/l) also decreased the maximum velocity of depolarization and action potential overshoot in each species studied. At this concentration no effect was observed on the resting membrane potential; high concentration (100 micromol/l), however, caused depolarization. In voltage clamped canine ventricular myocytes, fluoxetine caused concentration-dependent block of the peak Ca2+ current at 0 mV with EC50 of 5.4+/-0.94 micromol/l and Hill coefficient of 1.1+/-0.14 (n=6). In addition, 10 micromol/l fluoxetine shifted the midpoint of the steady-state inactivation curve of the Ca2+ current from -20.7+/-0.65 to -26.7+/-1 mV (P<0.001, n=8) without changing its slope factor. These effects of fluoxetine developed rapidly and were fully reversible. Fluoxetine did not alter voltage-dependence of activation or time constant for inactivation of I(Ca). Fluoxetine had no effect on the amplitude of K+ currents (I(K1) and I(to)). The inhibition of cardiac Ca2+ and Na+ channels by fluoxetine may explain most cardiac side effects observed occasionally with the drug. Our results suggest that fluoxetine may have antiarrhythmic (class I + IV type), as well as proarrhythmic properties (due to impairment of atrioventricular or intraventricular conduction and shortening of repolarization). Therefore, in depressed patients with cardiac disorders, ECG control may be suggested during fluoxetine therapy.

Action Potentials↗

PubMed2000

Electrophysiological effects of bimoclomol in canine ventricular myocytes.

Concentration-dependent effects of bimoclomol, a novel heat shock protein (HSP) coinducer, were studied on the parameters of action potential and transmembrane ionic currents in enzymatically dispersed canine ventricular cardiomyocytes using conventional microelectrode and whole cell voltage clamp techniques. Bimoclomol (10-100 microM) decreased the maximum velocity of depolarization (Vmax) and amplitude of action potentials in a concentration-dependent manner. These effects were fully reversible after a 5-min period of washout in drug-free medium. Action potential duration measured at 50% or 90% level of repolarization (APD-50 and APD-90, respectively) was markedly shortened by bimoclomol. Both APD-50 and APD-90 were decreased, but the reduction in APD-50 was more pronounced. The APD-shortening effect of bimoclomol was significantly reduced in the presence of 20 nM charybdotoxin (inhibitor of the Ca-dependent K current) or 0.5 mM anthracene-9-carboxylic acid (inhibitor of the Ca-dependent Cl current) or 1 microM glibenclamide (inhibitor of the ATP-sensitive K current). In the presence of anthracene-9-carboxylic acid, APD-90 was lengthened by bimoclomol. The APD-shortening effect of bimoclomol was also partially antagonized by chelation of intracellular Ca2+ by application of the cell permeant form of BAPTA, or when using 10 mM EGTA-containing patch pipettes to record action potentials. The Vmax-depressant effect of bimoclomol was not affected by charybdotoxin, anthracene-9-carboxylic acid, glibenclamide, or BAPTA load. In voltage clamped cardiomyocytes bimoclomol (100 microM) had no effect on the amplitude of I(Ca), but decreased significantly the inactivation time constant of I(Ca) (from 19.8+/-1.6 ms to 16.8+/-1.2 ms at 0 mV). Bimoclomol also decreased significantly the amplitude of I(K1) (from -20.5+/-1.1 pA/pF to -16.6+/-0.8 pA/pF at -135 mV), causing reduction in slope of the negative branch of the I-V curve. At positive potentials, however, bimoclomol increased outward current. The bimoclomol-induced current, therefore, was studied in the presence of BaCl2, when I(K1) current was blocked. The bimoclomol-induced current had a reversal potential close to -90 mV. Bimoclomol (100 microM) had no effect on the amplitude or kinetic properties of the transient outward K current (I(to)) and the delayed rectifier K current (I(K)). It is concluded that bimoclomol exerts both Ca-independent (inhibition of I(Na) and I(K1), activation of the ATP-sensitive K current) and Ca-dependent effects (mediated by Ca-activated Cl and probably K currents) in canine ventricular myocytes.

Action Potentials↗

PubMed2000

Effects of endothelin-1 on calcium and potassium currents in undiseased human ventricular myocytes.

Endothelins have been reported to exert a wide range of electrophysiological effects in mammalian cardiac cells. These results are controversial and human data are not available. Our aim was to study the effects of endothelin-1 (ET-1, 8 nmol/l) on the L-type calcium current (ICa-L) and various potassium currents (rapid component of the delayed rectifier, IKr; transient outward current, Ito; and the inward rectifier K current, IK1) in isolated human ventricular cardiomyocytes. Cells were obtained from undiseased donor hearts using collagenase digestion via the segment perfusion technique. The whole-cell configuration of the patch-clamp technique was applied to measure ionic currents at 37 degrees C. ET-1 significantly decreased peak ICa-L from 10.2+/-0.6 to 6.8+/-0.8 pA/pF at +5 mV (66.7% of control, P<0.05, n=5). This reduction of peak current was accompanied by a lengthening of inactivation. The voltage dependence of steady-state activation and inactivation was not altered by ET- 1. IKr, measured as tail current amplitudes at 40 mV, decreased from 0.31+/-0.02 to 0.06+/-0.02 pA/pF (20.3% of control, P<0.05, n=4) after exposure to ET-1. ET-1 failed to change the peak amplitude of Ito, measured at +50 mV (9.3+/-4.6 and 9.0+/-4.4 pA/pF before and after ET-1, respectively), or steady-state IK1 amplitude, measured at the end of a 400-ms hyperpolarization to -100 mV (3.6+/-1.4 and 3.7+/-1.4 pA/pF, n=4). The present results indicate that in undiseased human ventricular myocytes ET-1 inhibits both ICa-L and IKr; however, the degree of suppression of the two currents is different.

Action Potentials↗

PubMed2000

In vivo and in vitro acute cardiovascular effects of bimoclomol.

Effects of bimoclomol, the novel heat shock protein (HSP) coinducer, was studied in various mammalian cardiac and rabbit aortic preparations. Bimoclomol decreased the ST-segment elevation induced by coronary occlusion in anesthetized dogs (56% and 80% reduction with 1 and 5 mg/kg, respectively). In isolated working rat hearts, bimoclomol increased coronary flow (CF), decreased the reduction of cardiac output (CO) and left ventricular developed pressure (LVDP) developing after coronary occlusion, and prevented ventricular fibrillation (VF) during reperfusion. In rabbit aortic preparations, precontracted with phenylephrine, bimoclomol induced relaxation (EC(50)=214 microM). Bimoclomol produced partial relaxation against 20 mM KCl, however, bimoclomol failed to relax preparations precontracted with serotonin, PGF(2) or angiotensin II. All these effects were evident within a few minutes after application of bimoclomol. A rapid bimoclomol-induced compartmental translocation of the already preformed HSPs may explain the protective action of the compound.

Animals↗

PubMed2000

Biphasic effect of bimoclomol on calcium handling in mammalian ventricular myocardium.

1. Concentration-dependent effects of bimoclomol, the novel heat shock protein coinducer, on intracellular calcium transients and contractility were studied in Langendorff-perfused guinea-pig hearts loaded with the fluorescent calcium indicator dye Fura-2. Bimoclomol had a biphasic effect on contractility: both peak left ventricular pressure and the rate of force development significantly increased at a concentration of 10 nM or higher. The maximal effect was observed between 0.1 and 1 microM, and the positive inotropic action disappeared by further increasing the concentration of bimoclomol. The drug increased systolic calcium concentration with a similar concentration-dependence. In contrast, diastolic calcium concentration increased monotonically in the presence of bimoclomol. Thus low concentrations of the drug (10 - 100 nM) increased, whereas high concentrations (10 microM) decreased the amplitude of intracellular calcium transients. 2. Effects of bimoclomol on action potential configuration was studied in isolated canine ventricular myocytes. Action potential duration was increased at low (10 nM), unaffected at intermediate (0.1 - 1 microM) and decreased at high (10 - 100 microM) concentrations of the drug. 3. In single canine sarcoplasmic calcium release channels (ryanodine receptor), incorporated into artificial lipid bilayer, bimoclomol significantly increased the open probability of the channel in the concentration range of 1 - 10 microM. The increased open probability was associated with increased mean open time. The effect of bimoclomol was again biphasic: the open probability decreased below the control level in the presence of 1 mM bimoclomol. 4. Bimoclomol (10 microM - 1 mM) had no significant effect on the rate of calcium uptake into sarcoplasmic reticulum vesicles of the dog, indicating that in vivo calcium reuptake might not substantially be affected by the drug. 5. In conclusion, the positive inotropic action of bimoclomol is likely due to the activation of the sarcoplasmic reticulum calcium release channel in mammalian ventricular myocardium.

Action Potentials↗

PubMed1999

EGIS-7229, the new combined class III antiarrhythmic agent: lack of EAD inducing effect.

EGIS-7229 is a novel antiarrhythmic candidate having multiple mechanisms of action with class III predominance. In this study, the effects of EGIS-7229 and sotalol on action potential duration (APD) and incidence of early afterdepolarizations (EADs) were studied and compared in rabbit papillary muscle by using conventional microelectrode techniques. In control bathing solution, both drugs increased APD in a concentration-dependent manner; however, the prolongation of APD was greater with sotalol than with EGIS-7229 when the same drug concentrations were compared. EAD developed in 3 of the 11 preparations (27%) bathed with a solution containing 3.6 mmol/l CsCl + 2 mmol/l KCl within the first 120 min of superfusion. The addition of 100 micromol/l sotalol to this superfusate increased the incidence of EAD to 83% (10 from 12), whereas the addition of the same concentration of EGIS-7229 prevented the development of EAD in all of the 9 preparations studied. These differences in incidence of EAD are likely attributable to differences in drug-induced increases of APD-50 in the presence of CsCl. Prolongation of APD-90 showed less correlation with incidence of EAD than changes in APD-50. On the basis of these in vitro results, high concentrations of EGIS-7229 cannot be expected to be torsadogenic in vivo--in contrast with sotalol--presumably owing to the combined class III + IV activity of the compound.

Action Potentials↗

PubMed1998

Evaluation of apoptosis and cell proliferation in experimentally induced renal cysts.

Cell proliferation and apoptosis in renal cysts induced by streptozotocin, alloxan and ferric-nitrilotriacetate were investigated in rats. In the kidneys of all treated animals dilated tubules at the cortico-medullary region, large cysts, glomerular cysts and tubular dilation in the medullary area were found. Both cell proliferation and apoptosis were increased in the epithelium of the non-dilated tubules, in the mesangial and interstitial cells. Cells lining the dilated tubules or cysts demonstrated apoptosis but their proliferating activity was low. By calculating the proliferation-apoptosis ratio we found that alloxan did not change the balance between the two mechanisms. Meanwhile streptozotocin resulted in an increased apoptosis and ferric-nitrilotriacetate in an increased cell proliferation. p53 expression might be responsible for the uncontrolled proliferation in rats treated with ferric-nitrilotriacetate as this oncoprotein was diffusely present in tubular cell nuclei. The observed apoptosis seemed to be independent of bcl-2 oncoprotein expression. We assume that the initial factor in such cystogenesis should be a cellular injury due to direct toxic or to the diabetogenic effect of the drugs. The latter is more likely as all the animals were hyperglycemic and insulin treatment following administration of streptozotocin prevented the morphologic changes.

Alloxan↗

PubMed1998

Intracellular calcium and electrical restitution in mammalian cardiac cells.

The role of calcium current and changes in intracellular calcium concentration ([Ca2+]i) in regulation of action potential duration (APD) during electrical restitution process was studied in mammalian ventricular preparations. Properly timed action potentials were recorded from multicellular preparations and isolated cardiomyocytes using conventional microelectrodes and EGTA-containing patch pipettes. APD increased monotonically in canine and guinea pig ventricular preparations with increasing diastolic interval (DI), while in rabbit papillary muscles the restitution process was biphasic: APD first lengthened, then shortened as the DI increased. When the restitution process was studied in single cardiomyocytes using EGTA-containing patch pipettes, the restitution pattern was similar in the three species studied. Similarly, no difference was observed in the recovery time constant of calcium current (/Ca-L) measured under these conditions in voltage clamped myocytes. Loading the myocytes with the [Ca2+]i-chelator BAPTA-AM had adverse effects in rabbit and canine cells. In rabbit myocytes steady-state APD lengthened and the late shortening component of restitution was abolished in BAPTA-loaded cells. In canine myocytes BAPTA-load shortened steady-state APD markedly, and during restitution, APD decreased with increasing DI. The late shortening component of restitution, observed in untreated rabbit preparations, was greatly reduced after nifedipine treatment, but remained preserved in the presence of 4-aminopyridine or nicorandil. Beat to beat changes in APD, peak/Ca-L and [Ca2+]i, measured using the fluorescent dye, Fura-2, were monitored in rabbit ventricular myocytes after a 1-min period of rest. In these cells, the shortening of APD was accompanied by a gradual reduction of the peak/Ca-L and elevation of diastolic [Ca2+]i during the initial eight post-rest action potentials. It is concluded that elevation of [Ca2+]i shortens, while reduction of [Ca2+]i lengthens APD in rabbit, but not in canine ventricular myocytes. These differences may probably be related to different distributions of [Ca2+]i-dependent ion currents and/or to differences in calcium handling between the two species.

Action Potentials↗

PubMed1998

Altered [3H]ouabain binding to cardiac muscle in insulin-dependent and non-insulin-dependent diabetic rats.

The aim of this study was to determine the ouabain receptor density, Na+,K(+)-ATPase function and contractile properties of cardiac muscle in insulin-dependent and non-insulin-dependent rat diabetes mellitus (IDDM and NIDDM, respectively) and the reversibility of the diabetes-induced changes by insulin or thyroxin substitution. IDDM and NIDDM were induced in Wistar rats by streptozotocin injection. Contractile parameters were measured in isolated left ventricular trabeculae. [3H]Ouabain binding to myocardium was measured in right and left ventricular strips obtained from diabetic animals and their age-matched controls. Both the maximum [3H]ouabain binding capacity (Bmax) and the Kd for [3H]ouabain binding, as well as maximum 86Rb+ uptake and rate of contraction, were decreased in IDDM myocardium compared with controls. Insulin or thyroxin substitution reversed the reduction in Bmax and contraction rate, but not the decrease in Kd. In young, but not old, control animals, both Bmax and maximum 86Rb+ uptake were higher in the right ventricular myocardium than in the left one. In contrast to changes observed in IDDM, both Bmax and Kd for [3H]oubain binding were increased in the left but not in the right ventricle of NIDDM animals. NIDDM caused no alterations in contractile properties. Prominent differences were observed in [3H]ouabain binding characteristics and myocardial contractility between young and old control animals. Bmax of [3H]ouabain binding and rate of contraction were inversely proportional in all preparations studied. It is concluded that IDDM and NIDDM induce different alterations in myocardial Na+,K(+)-ATPase, and these changes may influence the contractile properties of cardiac muscle.

Animals↗

PubMed1997

Electrophysiological effects of EGIS-7229, a new antiarrhythmic agent, in isolated mammalian and human cardiac tissues.

The cellular electrophysiological effects of EGIS-7229 (5-chlor-4-[N-(3,4-dimethoxy-phenyl-ethyl)-amino-propylamino]-3 (2H)-pyridazinone fumarate), a novel antiarrhythmic agent, was studied using conventional microelectrode techniques in canine cardiac Purkinje fibers and papillary muscle preparations obtained from man, rabbits and guinea pigs. Low concentration of EGIS-7229 (3 mumol/l) selectively lengthened action potential duration (both APD50 and APD90) in all preparations. The effect of higher concentrations (30-100 mumol/l) of EGIS-7229 on action potential duration was variable depending on the preparation studied: in rabbit and human papillary muscles both APD50 and APD90 were lengthened, in canine Purkinje fibers APD90 was lengthened but APD50 was shortened, while in guinea pig papillary muscles both APD50 and APD90 were shortened by high concentrations of the drug. At these higher concentrations EGIS-7229 also decreased the maximum velocity of action potential upstroke (Vmax) and depressed the plateau of action potentials without affecting the resting membrane potential or action potential amplitude. Both reduction of Vmax and lengthening of APD were frequency dependent. The former effect was more prominent at higher pacing frequencies, while the latter was more pronounced at lower driving rates. In guinea pig papillary muscle, the time constant of recovery from Vmax-block was 719 +/- 33 ms (n = 18) and the rate of onset of the block was 1.81 +/- 0.06 AP-1 (n = 16) in the presence of 100 mumol/l EGIS-7229. EGIS-7229 had a complex action on refractoriness in guinea pig papillary muscles: ERP was lengthened at low concentrations (3 to 10 mumol/l), unchanged at 30 mumol/l and shortened at 100 mumol/l. The ratio of ERP/APD90, however, was significantly increased at concentrations higher than 3 mumol/l. In canine Purkinje fiber, when the delayed rectifier K current (IK) was blocked by d-sotalol (60 mumol/l) and APD was shortened back to its control value by additional application of nicorandil (15 mumol/l), APD was not affected by 3 mumol/l but was shortened by 30 mumol/l of EGIS-7229. 100 mumol/l EGIS-7229 shortened APD in guinea pig papillary muscle. This effect of EGIS-7229 was effectively prevented by nifedipine pretreatment (10 mumol/ l). In this preparation, EGIS-7229 also decreased the Vmax of the slow action potential, evoked in the presence of 20 mmol/l external K+ plus 0.5 mmol/l Ba2+. It is likely that EGIS-7229 at low concentrations blocks IK in human, canine, rabbit and guinea pig cardiac preparations, but at higher concentrations also inhibits Ca and Na currents. Therefore, EGIS-7229 appears to carry mixed class III, IV and IB antiarrhythmic properties.

Action Potentials↗