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Biomedical subjects

J G Papp

Publications and source records attributed to J G Papp.

At least 73 records · Page 4Linked to original sources
PubMed1996

Effect of glimepiride and glibenclamide, inhibitors of ATP-dependent K(+)-channel, on ischaemia-reperfusion induced arrhythmias in rats.

Glibenclamide or glimepiride pretreatment (5 mg/kg i.p. 30 min prior to coronary ligation) significantly improved the survival rate during reperfusion after 6 min myocardial ischaemia in rats (82% or 67% vs. 17% in controls). Smaller dose of glibenclamide (0.01 mg/kg) did not influence the survival rate (31%), while glimepiride still offered a significant protection (61%). These results suggest that different KATP inhibitors may increase the chance to survive life-threatening arrhythmias during myocardial ischaemia-reperfusion.

Adenosine Triphosphate↗
PubMed1996

Effect of almokalant a specific inhibitor of IKr on myocardial ischaemia-reperfusion induced arrhythmias in rabbits.

The antiarrhythmic effect of almokalant, a new type III antiarrhythmic agent, was examined by occluding and releasing the left circumflex coronary artery for 10 min, respectively, in openchest, pentobarbital-anaesthetized albino rabbits. Almokalant pretreatment increased the number of animals developing no arrythmias (5/9 vs. 1/12 in controls), and decreased the incidence of ventricular fibrillation (1/9 vs. 9/12) during reperfusion. According to our results almokalant can protect the heart against arrhythmias induced by ischaemia and reperfusion.

Animals↗
PubMed1996

Nitric oxide activates an iberiotoxin-sensitive potassium channel in human saphenous vein.

Synthetic iberiotoxin (IBTX), an inhibitor of large conductance calcium-activated potassium channel (BKCa), was used to study the possible involvement of a specific hyperpolarizing ion channel in nitric oxide (NO)-induced venodilation. Serotonin (0.125 microM)-induced contraction of isolated human saphenous vein was dose-dependently relaxed with 50-1550 nanoM exogenous NO. 30 min preincubation of venous preparations with 90 nanoM IBTX decreased vasorelaxation induced by NO. In conclusion, a hyperpolarizing potassium channel, BKCa, may be involved in the venodilator effect of endogenous NO.

Dose-Response Relationship, Drug↗
PubMed1996

Long-term ischaemic preconditioning of the heart induced by repeated beta-adrenergic stress.

In the present study we tested the preconditioning effect of repeated beta adrenergic stress induced by Isoproterenol in chronically instrumented, conscious rabbits. We have found that at least 5 intravenous administrations of Isoproterenol, repeated at 10 min intervals, were necessary to induce a long-term cardiac adaptation manifested by a significant reduction of the harmful ischaemic changes due to cardiac stress 24 and 48 hours after preconditioning. These results suggest that a well-defined threshold level of the preconditioning stress is needed to trigger induction of metabolic changes leading to development of delayed and long-term cardiac adaptation.

Adrenergic beta-Agonists↗
PubMed1996

Effect of restacorin on the early and delayed after depolarization in dog Purkinje fibres.

The effect of restacorin and flecainide on the early afterdepolarization (EAD) and on the delayed afterdepolarization (DAD) was studied in dog cardiac Purkinje fibers by applying the conventional microelectrode technique. Restacorin and flecainide at 5 microM concentration partially abolished EAD. Further increase of the concentrations of the drugs to 10 microM EADs were completely abolished. The amplitude of DADs were significantly decreased by both restacorin (9.9 +/- 2.1 mV v.s. 2.9 +/- 1.8 mV, p < 0.01, n = 5) and flecainide (11.1 +/- 1.3 mV v.s. 0.6 +/- 0.6 mV, p < 0.01, n = 7). These results suggest that the well-established antiarrhythmic effect of restacorin and flecainide at least partially may be explained by their beneficial action against triggered abnormal automaticity.

Animals↗
PubMed1996

Comparison of the effects of restacorin and flecainide on various cardiac transmembrane potassium currents.

The effect of restacorin (5 microM) and flecainide (5 microM) on the transmembrane ionic currents was compared in dog and rabbit ventricular muscle by applying the conventional microelectrode and patch-clamp techniques. Neither restacorin nor flecainide influenced significantly the ATP-sensitive and inward rectifier potassium currents. Flecainide moderately decreased the amplitude of the transient outward current while restacorin did not change this current. The delayed rectifier potassium current was depressed markedly by flecainide and moderately by restacorin. These results suggest that although flecainide and restacorin cause similar changes in the various transmembrane ionic currents, there are some differences between the effects of the two antiarrhythmic compounds.

Action Potentials↗
PubMed1995

Electrophysiological effects of tiracizin and its metabolites in dog cardiac Purkinje fibers.

1. Conventional microelectrode technique was used to study the effects of tiracizin and its two main metabolites on the action potential parameters in dog cardiac Purkinje fibers. 2. Tiracizin induced a use-dependent depression of the maximal rate of depolarization during the upstroke of the action potential (EC50 = 0.323 +/- 0.059 microM, n = 5) and decreased the action potential duration (EC50 = 0.230 +/- 0.024 microM, n = 5). 3. The two main metabolites exerted similar effects, but only at concentrations about one order of magnitude higher than tiracizin. 4. It was concluded that the electrophysiological effects of tiracizin in dog Purkinje fibers correspond to those of Class I antiarrhythmic drugs also in cardiac Purkinje fibers. The main metabolites are less potent than the parent compound, therefore it is likely that their effects play a less important role in the beneficial effect of tiracizin in cardiac arrhythmias.

Action Potentials↗
PubMed1995

Pronounced antiarrhythmic effects of preconditioning in anaesthetized dogs: is adenosine involved?

Although there is good evidence that adenosine contributes to the ability of ischaemic preconditioning to reduce myocardial ischaemic damage (infarct size) there is no evidence that it contributes to the marked antiarrhythmic effects of this endogenous protective mechanism. We have examined this in anaesthetized open-chest mongrel dogs by administering the non-selective adenosine receptor blocking drug 8-sulfophenyltheophylline (8-SPT) (1 mg/kg) given by intracoronary administration 10 min before both 5 min preconditioning coronary artery occlusions and also before the prolonged 25 min LAD occlusion i.e. in a total dose of 3 mg/kg. The only haemodynamic effect of 8-SPT was a reduction in coronary (LAD) blood flow and an increase in cardiovascular resistance. It was difficult to precondition dogs in the presence of 8-SPT; the number of ventricular premature beats was significantly higher (61 +/- 6 v 8 +/- 4; P < 0.01) during the initial preconditioning occlusion and the incidence of ventricular fibrillation during the preconditioning procedure was higher in the presence of the drug (5/11 v 4/20; P < 0.05). Nevertheless, it was still possible to precondition these dogs in the presence of the drug. No VF occurred during the prolonged occlusion (cf. 50% in the controls) and the number of episodes of ventricular tachycardia, and the number of ventricular premature beats in dogs preconditioned in the presence of 8-SPT was similar to those in dogs preconditioned without 8-SPT and significantly (P < 0.01 or P < 0.05) less than in control, non-preconditioned dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1995

Cardiovascular effects of the calcium sensitizer, levosimendan, in heart failure induced by rapid pacing in the presence of aortic constriction.

1. The haemodynamic effects of a novel cardiotonic drug, levosimendan, which has both calcium-sensitizing and phosphodiesterase III (PDE III) inhibitory properties, were studied in conscious dogs in which heart failure had been induced by prolonged cardiac pacing in the presence of aortic constriction. These effects were compared with those in sham-operated dogs with essentially normal cardiac function. 2. Eighteen mongrel dogs were instrumented for the measurement of left ventricular pressure (LVSP, LVEDP) and contractile function (dP/dt; dP/dt/P). In twelve dogs a balloon catheter, positioned in the thoracic aorta, was inflated producing an approximate 60% reduction in effective aortic diameter. Twenty min later rapid ventricular pacing (240 beats mean-1) was commenced and maintained for 48 h by means of a bipolar pacing electrode introduced into the right ventricle. This electrode served also for recording changes in the endocardial electrogram in the absence of pacing. Six of these dogs were used to evaluate the haemodynamic changes of pacing-induced heart failure; a further six of these dogs the haemodynamic changes elicited by levosimendan under these conditions. Six sham-operated dogs (group 2) served as controls. 3. In six dogs (group 1) the haemodynamic alterations were assessed after the development of heart failure. In the presence of aortic constriction, 48 h continuous rapid cardiac pacing resulted in a marked deterioration in left ventricular function which remained stable for at least 48 h after cessation of pacing. Thus, there was a marked reduction in LVSP (15%), +dP/dtmax (35%), -dP/dtmax (36%) and also in dP/dt/P (29%), whereas LVEDP was increased considerably (from 6.4 +/- 1.4 to 20.0 +/- 2.2 mmHg). A marked elevation occurred in endocardial ST-segment (138%), lasting for 20 min.4. Levosimendan was administered intravenously in doses of 0.005, 0.01 and 0.03 micromol kg-1 to 2 groups of conscious dogs. In the sham-operated dogs (group 2), only the higher dose (0.03 micromol kg-1)produced significant increases in LVSP (19%), + dP/dtmax (37%), and in dP/dt/P (32%). In dogs with heart failure (group 3) doses of 0.005, 0.01 and 0.03 micromol kg-1 levosimendan resulted in an improve mentin +dP/dtmax (26%, 38% and 49%), -dP/dtmax (20%, 25% and 38%) and in dP/dt/P (19%, 34%and 50%) and reduction in the elevated LVEDP (from 20 =/- 2.2 mmHg to 16 +/- 1.0, 10 +/- 1.3 and 9 +/- 1.0 mmHg, respectively).5. Levosimendan proved to be a potent cardiotonic drug at the doses used, and was approximately three times more effective under conditions of impaired left ventricular function than in normal hearts.

Analysis of Variance↗
PubMed1995

Effect of selective inhibition of potassium channels on vasorelaxing response to cromakalim, nitroglycerin and nitric oxide of canine coronary arteries.

A comparative study was performed on the sensitivity of in-vitro vasorelaxation by nitroglycerin and cromakalim to block glibenclamide, a blocker of ATP-sensitive potassium channels, and iberiotoxin, a selective inhibitor of large-conductance calcium-activated potassium channels. In isolated canine coronary arteries preconstricted with 25 microM prostaglandin F2 alpha, nitroglycerin (0.005-1.8 microM) and cromakalim (0.15-9.6 microM) produced dose-dependent vasodilations. Glibenclamide (30 microM) had no significant effect on relaxation of the dose-response curve to nitroglycerin and almost completely abolished the relaxation by cromakalim, a known opener of ATP-sensitive potassium channels. Iberiotoxin (90 nM) decreased the maximal response to nitroglycerin and had no effect on the vasodilation induced by cromakalim. The effect of iberiotoxin on the vasorelaxing action of nitric oxide, the active metabolite of nitroglycerin, was also examined. In a low potassium chloride (14.4-20.4 mM) medium, as a contractile stimulus, iberiotoxin inhibited relaxations by exogenous nitric oxide (100-200 nM). Enhancement of potassium concentrations to 35.4-40.4 mM significantly decreased relaxation by nitric oxide and under these conditions the inhibitory action of iberiotoxin disappeared. The present study demonstrated that in canine coronary arteries, the functional role of two potassium channels can be separated by pharmacological means. Nitroglycerin-induced vasorelaxation may be mediated, at least in part, by its enzymatic breakdown product, nitric oxide that activates large-conductance calcium-activated potassium channels.

Animals↗
PubMed1995

Bradykinin as an endogenous myocardial protective substance with particular reference to ischemic preconditioning--a brief review of the evidence.

The present brief review summarizes the evidence for the possibility that endogenously released bradykinin plays a major role in protecting the heart against the consequences of acute myocardial injury. This evidence includes the facts that kinins are generated under myocardial ischemia; that when they are administered, they are cardioprotective (e.g., antiarrhythmic); that drugs that enhance the release of bradykinin from the ischemic heart reduce the ischemic injury and, conversely, drugs that block bradykinin receptors attenuate the reduction in ischemic injury resulting from the release of, or administration of, bradykinin. The possible mechanism of bradykinin in the cardioprotection afforded by ischemic preconditioning is summarized. Ischemic preconditioning can be defined as the marked reduction in the severity of ischemic changes that result from coronary artery occlusion when that occlusion is preceded by brief periods of myocardial ischemia, either regional or global, induced, for example, by complete or partial coronary artery occlusion or by rapid ventricular pacing. The possible mechanisms of cardioprotection elicited by bradykinin (and ischemic preconditioning) are summarized. The most likely is the generation of cyclic GMP within the ischemic myocardium following bradykinin-stimulated nitric oxide generation and release from endothelial cells.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Effects of Levosimendan, a cardiotonic agent targeted to troponin C, on cardiac function and on phosphorylation and Ca2+ sensitivity of cardiac myofibrils and sarcoplasmic reticulum in guinea pig heart.

A new cardiotonic agent, (R)-[[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)-phenyl] hydrazono]propanedinitrile (Levosimendan), has been developed and screened for its ability to bind to cardiac troponin C. In perfused hearts, low concentrations of 0.03 or 0.1 mumol/L Levosimendan increased +dP/dt, but did not affect the speed of relaxation and produced only a slight increase in spontaneous heart rate in the hearts perfused with 0.1 mumol/L of the drug. In these same hearts, perfusion with 0.03 mumol/L Levosimendan did not alter the 32P incorporation into troponin I or C protein, whereas a slight but significant increase was noted for phospholamban, with no detectable change in tissue cAMP levels. Administration of 0.1 or 0.3 mumol/L Levosimendan significantly increased myocardial cAMP levels as well as the phosphorylation of phospholamban, troponin I, and C protein. Levosimendan (0.03 to 10 mumol/L) reversibly increased force generated by detergent-extracted fiber bundles over a range of submaximally activating free Ca2+ concentrations with no significant effect on maximum force or on Ca2+ binding to myofilament troponin C. There was no direct effect of Levosimendan on Ca2+ uptake by vesicles of sarcoplasmic reticulum (SR). In contrast, under conditions optimal for cAMP-dependent phosphorylation, Levosimendan slightly but significantly lowered the concentration of Ca2+, yielding half-maximal uptake rates by the SR vesicles. Our results indicate that at low concentrations Levosimendan acts preferably as a Ca2+ sensitizer, whereas at higher concentrations its action as a phosphodiesterase inhibitor contributes to the positive inotropic effect.

Analysis of Variance↗
PubMed1995

Left ventricular dysfunction induced by occlusion of coronary arteries in conscious dogs.

The aim of the present study was to investigate stable left ventricular dysfunction resulting from severe myocardial ischemia in conscious dogs, in order to evaluate the action of cardiotonic agents under pathological conditions mimicking moderate cardiac failure. Mongrel dogs with a catheter implanted in the left ventricle were trained on a treadmill and subjected to a standardized exercise before and after a Harris-type ligation of the anterior descending branch of the left coronary artery in two stages. Two weeks later the lower third of the left circumflex coronary branch was also occluded, and the exercise test repeated for at least two additional weeks to evaluate the changes in the left ventricular function indicated by left ventricular systolic pressure, end-diastolic pressure, heart rate, positive and negative dP/dtmax and dP/dt/P. Noninvasive radionuclide investigations of the left ventricular function and myocardial perfusion were done before and after the development of cardiac failure. Following occlusion of the anterior descending and circumflex coronary arteries, the baseline end-diastolic pressure increased from 7.6 +/- 2.3 mmHg to 23.3 +/- 3.0 mmHg (p < 0.05) and increased even further during exercise (to 49.2 +/- 3.5 mmHg, p < 0.05). After the development of cardiac failure, no substantial change occurred in the end-diastolic pressure, either during rest or repeated exercise tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Hemodynamic effects of calcium-sensitizing agents.

Over the last few years the development of calcium-sensitizing agents has led to a new approach to the treatment of congestive heart failure (CHF). These novel inotropic agents act directly on the contractile protein systems and correct the reduced responsiveness of the myofilaments to calcium. The resultant favorable inotropic activity of this new class of cardiotonic agents may represent an important pharmacologic approach to the future treatment of acute and chronic CHF. This brief review summarizes the cardiotonic effects of calcium sensitizers, with particular emphasis on the hemodynamic actions of these drugs in various in vitro and in vivo heart preparations. We also attempt to draw conclusions for the therapeutic exploitation of these agents and delineate their possible role in the therapy of CHF.

Animals↗
PubMed1995

Classification of positive inotropic actions based on electrophysiologic characteristics: where should calcium sensitizers be placed?

A number of new positive inotropic agents with diverse mechanisms of action have been discovered over the past 20 years. Most of these cardiotonic drugs exhibit characteristic electrophysiologic profiles. This prompted us to propose a classification scheme based on electrophysiologic principles, modifying the categories recently suggested by another author. Class I actions designate positive inotropic mechanisms that enhance the transmembrane calcium current by various means, such as beta-receptor stimulation (dobutamine, class I/A), phosphodiesterase inhibition (milrinone, class I/B), direct stimulation of adenylate cyclase (forskolin, class I/C), or direct modulation of calcium channel gating (BAY K 8644, class I/D). Class II action includes mechanisms that lead to elevation of intracellular sodium activity either by inhibiting the Na,K pump (digitalis, class II/A) or by increasing transmembrane sodium influx (DPI 201-106, class II/B). Class III action involves a mechanism by which sensitivity of the myofilaments to calcium increases (EMD 53998, levosimendan). This mechanism is not associated with apparent electrophysiologic manifestations. Positive inotropism due to lengthening of the cardiac repolarization (almokalant) is considered as class IV action. The possible clinical implications of the various positive inotropic mechanisms are also discussed.

Animals↗
PubMed1994

Electrophysiologic effects of detajmium on isolated dog cardiac ventricular and Purkinje fibers.

We studied the electrophysiologic effects of the antiarrhythmic compound detajmium (Tachmalcor) on isolated dog and rabbit cardiac preparations, applying the conventional intracellular microelectrode techniques. In dog ventricular muscle fibers (37 degrees C, stimulation frequency 1 Hz), 1 microM detajmium did not change resting potential (RP), action potential amplitude (APA), AP duration measured at 90% of repolarization (APD90), or effective refractory period (ERP) significantly, but reduced maximum rate of depolarization (Vmax) significantly from 236.7 +/- 28.9 to 177.3 +/- 22.5 V/s (n = 6, p < 0.01). In dog Purkinje fibers (37 degrees C, stimulation frequency 1 Hz), 1 microM detajmium significantly decreased APA from 111.1 +/- 12.3 to 100.0 +/- 2.5 mV (n = 8, p < 0.003), APD90 from 359.0 +/- 17.5 to 262.1 +/- 12.3 ms (n = 8, p < 0.001) and Vmax from 687.5 +/- 57.2 to 523.7 +/- 58.2 V/s (n = 8, p < 0.001) without changing maximal diastolic potential or ERP/APD ratio significantly. The effect of detajmium on Vmax in both dog ventricular muscle and Purkinje fibers was frequency dependent. Fractional Vmax block was 0.185 +/- 0.008 1/AP. The recovery kinetics of Vmax (offset kinetics) was extremely slow (time constant = 348.16 +/- 57.43 s) considerably slower than most of those of other antiarrhythmic drugs yet reported. Detajmium in concentration < 32 microM did not influence the beta-adrenoceptors or slow response APs in dog ventricular tissue significantly. On the basis of its electrophysiologic effects, detajmium, like prajmaline, encainide, or flecainide, can be best classified as a class I/C antiarrhythmic drug according to the Vaughan Williams' classification scheme.

Action Potentials↗