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Biomedical subjects

J G Papp

Publications and source records attributed to J G Papp.

At least 37 records · Page 2Linked to original sources
PubMed2000

Effect of glibenclamide and glimepiride treatment on the development of myocardial infarction in rats.

The effect of glibenclamide and glimepiride, two orally active antidiabetic sulphonylurea derivatives, on the development of myocardial infarction has been compared. Permanent coronary artery ligation was induced in rats and the development of infarction was evaluated by a computer-assisted method after nitroblue-terazolium staining. Seven-day coronary ligation produced enlargement of the left ventricular cavity, scar thinning and thickening of the non-infarcted myocardium. Glibenclamide treatment (5 mg/kg b.i.d. intraperitoneally) decreased the infarct volume (29.1 +/- 3.5% vs. 39.1 +/- 3.2% in controls), that occurred primarily as a result of more significant thinning of the scar tissue (1.6 +/- 0.04 mm vs. 2.0 +/- 0.13 mm in controls). Glibenclamide also inhibited the thickening of the non-infarcted ventricular septum (2.1 +/- 0.10 mm vs. 2.9 +/- 0.10 mm in controls). In contrast to the effects of glibenclamide, glimepiride treatment (5 mg/kg b.i.d. intraperitoneally) inhibited the enlargement of the left ventricular cavity (15.2 +/- 1.1% vs. 19.9 +/- 1.2% of the left ventricular volume in controls), it did not precipitate scar thinning and did not influence the development of hypertrophy of the non-infarcted myocardium. These results suggest that glimepiride treatment might inhibit the development of left ventricular dilatation after myocardial infarction. Glibenclamide treatment, however, producing a thinning of the scar tissue may further precipitate morphological changes that can contribute to the development of heart failure.

Animals↗
PubMed1999

Delayed protection against ventricular arrhythmias by monophosphoryl lipid-A in a canine model of ischaemia and reperfusion.

Bacterial endotoxin reduces the severity of ventricular arrhythmias which occur when a coronary artery is occluded several hours later. We have now examined in anaesthetised dogs the effects on ischaemia and reperfusion-induced arrhythmias, of a non-toxic derivative component of the endotoxin molecule of the lipid-A (monophosphoryl lipid-A). This was given intravenously, in doses of 10 and 100 microg kg(-1), 24 h prior to coronary artery occlusion. Arrhythmia severity was markedly reduced by monophosphoryl lipid-A. During ischaemia, ventricular premature beats were reduced from 315+/-84 in the vehicle controls to 89+/-60 (with the lower dose of monophosphoryl lipid-A) and 53+/-23 (P<0.05) with the higher dose. The incidence of ventricular tachycardia was reduced from 75% to 25% (P<0.05) and 31% (P<0.05), and the number of episodes of ventricular tachycardia from 13.4+/-4.9 per dog to 1.1+/-1.1 (P<0.05) and 1. 2+/-0.9 (P<0.05) after doses of 10 and 100 microg kg(-1), respectively. The incidence of ventricular fibrillation during occlusion and reperfusion in the control group was 96% (15/16), i.e., only 6% (1/16) dogs survived the combined ischaemia-reperfusion insult. Monophosphoryl lipid-A (100 microg kg(-1)) significantly reduced the incidence of occlusion-induced ventricular fibrillation (from 50% to 7%; P<0.05), and increased survival following reperfusion to 54% (P<0.05). Monophosphoryl lipid-A also significantly reduced ischaemia severity as assessed from ST-segment elevation recorded from epicardial electrodes as well as the degree of inhomogeneity of electrical activation within the ischaemia area. There were no haemodynamic differences prior to coronary occlusion between vehicle controls and monophosphoryl lipid-A-treated dogs. These results demonstrate that monophosphoryl lipid-A reduces arrhythmia severity 24 h after administration. Although the precise mechanisms are still unclear, there is some evidence that nitric oxide and prostanoids (most likely prostacyclin) may be involved because the dual inhibition of nitric oxide synthase and cyclooxygenase enzymes by administration of aminoguanidine and meclofenamate abolished the marked antiarrhythmic protection resulted from monophosphoryl lipid-A treatment 24 h previously.

Animals↗
PubMed1999

Vasoactive substances produced by cultured rat brain endothelial cells.

The vasoactive substances synthesized by primary cultures of rat brain endothelial cells were investigated and compared to those from two, immortalized cell lines, RBE4 and GP8. The vasoactivity of endothelium-derived substances was measured on isolated canine coronary artery. Vascular tone was significantly decreased by both primary and GP8, but not by RBE4 cells. Indomethacin pretreatment of primary and GP8 cells turned vasorelaxation into contraction while N(omega)-nitro-L-arginine pretreatment decreased the vasorelaxation induced by primary, but not by GP8 cells. Eicosanoid production was determined after incubation with [14C]arachidonic acid. The predominant vasoactive eicosanoid was prostaglandin E2 in both primary and GP8 cells. RBE4 cells synthetized mainly prostaglandin E2 and thromboxane B2 and significantly less prostaglandin E2 than did either primary or GP8 cells. The capacity of cerebral endothelium to regulate vascular tone by production of dilator and constrictor substances can be preserved under certain circumstances in immortalized cell lines.

Animals↗
PubMed1999

Comparison of the efficacy of glibenclamide and glimepiride in reperfusion-induced arrhythmias in rats.

The effect of glibenclamide and glimepiride, two orally active antidiabetic sulphonylurea derivatives, was investigated on the development of reperfusion-induced arrhythmias and it was compared to their blood glucose lowering action. Arrhythmias were produced by reperfusion following 6 min coronary artery ligation in anaesthetised rats. Glimepiride pretreatment (0.001-0.01-0.1-5.0 mg/kg i.p., 30 min before coronary occlusion) significantly decreased the incidence of irreversible ventricular fibrillation and increased the survival rate during reperfusion (64%, 61%, 60%, and 67% vs. 27% in controls). Glibenclamide produced similar effect (81% survival) only in a dose of 5 mg/kg, while smaller doses were ineffective. The minimal hypoglycaemic dose and the dose required to inhibit significantly the oral glucose loading-induced hyperglycaemia were similar (1 and 0.1 mg/kg, respectively) after glibenclamide and glimepiride. It is concluded that although the blood glucose lowering potency of glibenclamide and glimepiride is rather similar, glimepiride appears to be more potent than glibenclamide in preventing reperfusion-induced cardiac arrhythmias.

Anesthesia↗
PubMed1999

Application of neural networks in structure-activity relationships.

Methodology and application of artificial neural networks in structure-activity relationships are reviewed focusing on the most frequently used three-layer feedforward back-propagation procedure. Two applications of neural networks are presented and a comparison of the performance with those of CoMFA and a classical QSAR analysis is also discussed.

Drug Design↗
PubMed1999

Repeated cardiac pacing extends the time during which canine hearts are protected against ischaemia-induced arrhythmias: role of nitric oxide.

Right ventricular pacing in lightly anaesthetized dogs (4x5 min periods at a pacing rate of 220 beats/min) protects against the consequences of coronary artery occlusion when this is initiated 24 h after the pacing stimulus. The main purpose of the present experiments was to determine whether repeating the pacing stimulus, at a time when protection from the initial stimulus had faded (48 h), prolonged the protection afforded against ischaemia-induced ventricular arrhythmias and other ischaemic changes (epicardial ST-segment mapping; changes in the degree of electrical inhomogeneity in the ischaemic region). Dogs were paced on two occasions, with a 48 h period between and, at different times (48, 72 and 96 h) after the second pacing stimulus, were re-anaesthetized and subjected to occlusion of the left anterior descending coronary artery. There was a marked reduction in the severity of ischaemia-induced arrhythmias 48 and 72 h after the second pacing stimulus (reduction in occlusion-induced and reperfusion-induced ventricular fibrillation, e.g. at 72 h 0/11 during occlusion and only 3/11 following reperfusion, compared to 7/21 and 10/21 respectively in the controls P<0.05). The protection had disappeared 96 h following the second pacing stimulus. Changes in ST-segment elevation and in the degree of inhomogeneity largely followed these changes in the severity of ventricular arrhythmias. The results suggest the possibility of maintaining protection against life-threatening arrhythmias following coronary occlusion by repeating a preconditioning pacing stimulus. We also demonstrate that this prolonged protection afforded by repeated cardiac pacing is mediated by nitric oxide, since the marked antiarrhythmic effect observed, e.g. 72 h after the second pacing stimulus, was abolished when S-(2-aminoethyl)-isothiourea (AEST), a particularly selective inhibitor of iNOS, had been administered before coronary artery occlusion.

Animals↗
PubMed1999

Effects of pituitary adenylate cyclase-activating polypeptide on the cyclooxygenase pathway of rat platelets and on platelet aggregation.

Several data suggest that pituitary adenylate cyclase-activating polypeptide (PACAP) is involved in the regulation of local circulation. One possible role of PACAP in the regulation of circulation is that, it may modify the cyclooxygenase pathway of the arachidonate cascade in platelets. Our study was designed to study the effect of PACAP on the cyclooxygenase pathway of rat platelets and on platelet aggregation. PACAP (10(-7) and 10(-6) M) significantly inhibited the cyclooxygenase pathway of platelets, mostly the thromboxane synthesis. Pretreatment with a PACAP receptor antagonist, PACAP(6-38), or with an inhibitor of protein kinase A, H-89, shows that the effects of PACAP on the cyclooxygenase pathway were diminished. In the aggregation studies, PACAP inhibited both the arachidonic acid-induced and the thrombin-induced platelet aggregation. It can be concluded that PACAP inhibits the cyclooxygenase pathway of rat platelets via a specific PACAP receptor-activated, cAMP-dependent pathway, and these effects of PACAP are involved in the inhibition of platelet aggregation.

Animals↗
PubMed1999

Pharmacological modification of the dispersion of repolarization in the heart: importance of the M cells.

Several in vitro and in vivo investigations have provided data supporting the existence of M cells in the deep subepicardial layers of the ventricles in a number of species. Characterized by unique electrophysiological and pharmacological features, this population of cells is regarded to have a significant role in creating dispersion of repolarization in the ventricular wall and thus contribute importantly to arrhythmogenesis, in particular to intramural reentry and triggered activity. Focusing on M cells, the authors summarize recent findings and concepts concerning the pharmacological heterogeneity of different cell and tissue types found within the ventricles and explore how these differences may contribute to electrocardiographic manifestations. On the basis of literary data and of their own results they conclude that studying the electrical and pharmacological inhomogeneity within the ventricular wall may provide a better understanding of the pathophysiological processes that give rise to cardiac rhythm disturbances and the mechanisms by which antiarrhythmic agents act to suppress and in some cases aggravate arrhythmias.

Arrhythmias, Cardiac↗
PubMed1998

Comparison of the antiarrhythmic and the proarrhythmic effect of almokalant in anaesthetised rabbits.

In this study the antiarrhythmic and the proarrhythmic activities of almokalant, a selective class III antiarrhythmic agent, were compared. The antiarrhythmic effect of the drug was tested in pentobarbital-anaesthetised rabbits. Arrhythmia was evoked by occluding and releasing the left circumflex coronary artery. Almokalant in a dose of 250 nmol/kg i.v., significantly decreased the incidence of reperfusion induced ventricular fibrillation (21% vs. 75% in the control group) and increased the proportion of surviving animals during reperfusion (86% vs. 42%). The proarrhythmic effect of almokalant was examined during alpha1-adrenoceptor stimulation in chloralose-anaesthetised rabbits. Almokalant (75 nmol/kg per min) triggered torsade de pointes arrhythmias in 8 animals out of 11. The dose of almokalant (mean+/-S.E.M.) required to produce this effect was 1181+/-519 nmol/kg. It is concluded that, although almokalant is an effective antiarrhythmic agent against ischaemia-reperfusion induced arrhythmias, it has marked proarrhythmic activity during alpha1-adrenoceptor stimulation.

Adrenergic alpha-Agonists↗
PubMed1998

The dopamine receptor agonist Z1046 reduces ischaemia severity in a canine model of coronary artery occlusion.

Z1046, (S)-6[[6-[[2-(2-methoxyphenoxy)ethyl]amino]propyl]amino]-5,6,7,8-tetra-h ydro-1,2-naphtalenediol dihydrochloride, is an agonist at both dopamine D1 and D2 receptors. Since stimulation of dopamine D2 receptors inhibits noradrenaline release, and because cardiac noradrenaline release has been implicated in the genesis of early ischaemia-induced, life-threatening ventricular arrhythmias, the effect of Z1046 has been examined for its effects on coronary artery occlusion in chloralose urethane anaesthetised mongrel dogs. Z1046 (10 microg kg(-1) intravenously or 1 microg kg(-1) by local intracoronary injection) decreased heart rate and reduced arterial blood pressure and coronary blood flow, effects prevented by the prior administration of domperidone (40 microg kg(-1) i.v.). The ischaemic changes induced by a 25-min occlusion of the left anterior descending coronary artery (including ST-segment elevation and ventricular ectopic activity) were much less marked in those dogs administered Z1046 and survival from the combined ischaemia reperfusion insult was increased from 7% to 36% (P < 0.05). These effects of Z1046 were partly attenuated by domperidone. We conclude that the anti-ischaemic effects of Z1046 are due to inhibition of cardiac sympathetic responses. Studies using rat isolated perfused mesenteric vascular bed preparations subjected to sympathetic nerve stimulation confirmed that Z1046 inhibits synaptic transmission without modifying vascular responses to noradrenaline.

Animals↗
PubMed1998

Effect of disopyramide on potassium currents in rabbit ventricular myocytes.

The effects of disopyramide (1-30 microM) on the 4-aminopyridine sensitive transient outward current (I(to)), on the rapid component of the delayed rectifier potassium current (I(Kr)) and on the inward rectifier potassium current (I(kl)) were studied in single rabbit ventricular myocytes at 35 degrees C by applying the whole-cell configuration of the patch clamp technique. Disopyramide significantly decreased the amplitude of I(to) (from 1510 +/- 122 pA at control to 1015 +/- 21 pA after 30 microM disopyramide at +50 mV; n = 5). This effect was not voltage- or use-dependent. Disopyramide (10 microM) influenced neither the recovery from inactivation of I(to) nor the steady-state inactivation curve. The drug dose dependently decreased the time constant of the fast component of the decay of I(to) (tau(f) = 6.41 +/- 0.25 ms, n = 24 for control; and 2.20 +/- 0.38 ms, n = 5 after 30 microM disopyramide at +50 mV). The fractional block caused by 30 microM disopyramide as a function of time was well fitted by a single exponential function with time constant of 1.48 +/- 0.18 ms (n = 5), most likely reflecting the binding kinetics of the drug to the open channel. The offset kinetics of the drug was estimated by using a double-pulse protocol and its time constant was 3.9 +/- 0.5 ms. Disopyramide (30 microM) did not influence significantly the onset of inactivation measured at -20 mV. The estimated EC50 value for the I(to) block by disopyramide was 14.1 microM. Our results are consistent with an open-channel block of I(to) by disopyramide, however, a weak, drug-induced increase of the rate of inactivation and a moderate tonic block cannot be excluded. The amplitude of the outward tail current attributed to I(Kr) was depressed dose dependently by disopyramide (after clamping the cells back to the holding potential from +30 mV, 139.5 +/- 10.9 pA for control, and 30.7 +/- 3.2 pA in the presence of 10 microM disopyramide; n = 11). The estimated EC50 was 1.8 microM. I(to) is thus less sensitive to disopyramide than I(Kr). I(kl) was not influenced significantly by disopyramide, even when applied in the highest tested concentration (30 microM). It is concluded that in rabbit ventricular myocytes disopyramide blocks not only I(Kr), but also I(to), both of which may play an important role in the well established repolarization lengthening and antiarrhythmic effects of the drug.

Animals↗
PubMed1998

Delayed rectifier potassium current in undiseased human ventricular myocytes.

OBJECTIVE: The purpose of the study was to investigate the properties of the delayed rectifier potassium current (IK) in myocytes isolated from undiseased human left ventricles. METHODS: The whole-cell configuration of the patch-clamp technique was applied in 28 left ventricular myocytes from 13 hearts at 35 degrees C. RESULTS: An E-4031 sensitive tail current identified the rapid component of IK (IKr) in the myocytes, but there was no evidence for an E-4031 insensitive slow component of IK (IKs). When nifedipine (5 microM) was used to block the inward calcium current (ICa), IKr activation was fast (tau = 31.0 +/- 7.4 ms, at +30 mV, n = 5) and deactivation kinetics were biexponential and relatively slow (tau 1 = 600.0 +/- 53.9 ms and tau 2 = 6792.2 +/- 875.7 ms, at -40 mV, n = 7). Application of CdCl2 (250 microM) to block ICa altered the voltage dependence of the IKr considerably, slowing its activation (tau = 657.1 +/- 109.1 ms, at +30 mV, n = 5) and accelerating its deactivation (tau = 104.0 +/- 18.5 ms, at -40 mV, n = 8). CONCLUSIONS: In undiseased human ventricle at 35 degrees C IKr exists having fast activation and slow deactivation kinetics; however, there was no evidence found for an expressed IKs. IKr probably plays an important role in the frequency dependent modulation of repolarization in undiseased human ventricle, and is a target for many Class III antiarrhythmic drugs.

Action Potentials↗
PubMed1998

Polarographic detection of nitric oxide released from cardiovascular compounds in aqueous solutions.

In order to detect the concentration of nitric oxide, known to be one of the biologically active principles of certain cardiovascular compounds, a highly selective polarographic/amperometric device was used. The nitric oxide-releasing properties of sodium nitroprusside, nitroglycerine, nicorandil, and the molsidomine metabolite, 3-morpholinosydnonimine, were compared in the following cell-free experimental solutions in vitro: in Krebs-Henseleit solution with and without a sulfhydryl donor, L-cysteine, in an acidic, reducing medium, and in Krebs-Henseleit solution with superoxide dismutase enzyme. Sodium nitroprusside released similar concentrations of nitric oxide in Krebs-Henseleit solution and in the acidic, reducing medium. L-Cysteine inhibited the release of nitric oxide at physiological pH. In the presence of nitroglycerine, nitric oxide signals were detected in the acidic, reducing environment and in L-cysteine-rich Krebs-Henseleit solution but not in the absence of the sulfhydryl donor. Amperometric signals could not be detected after adding nicorandil in all the experimental conditions used. 3-Morpholinosydnonimine released nitric oxide only in the presence of the superoxide dismutase enzyme. Our results suggest that the polarographic electrode is able to detect the release of nitric oxide from sodium nitroprusside, nitroglycerine, and 3-morpholinosydnonimine in the absence of biological material. The present observations support the importance of the chemical environment during the detection of nitric oxide from donor compounds in the common in vitro bathing systems.

Cardiovascular Agents↗
PubMed1998

Comparison of the cellular electrophysiological characteristics of canine left ventricular epicardium, M cells, endocardium and Purkinje fibres.

Electrophysiological differences among M cells, epicardium, endocardium and Purkinje fibres of the canine ventricle were studied over a wide range of stimulation cycle lengths, and the pharmacological response of these cell types to the sodium channel blocker tetrodotoxin, calcium channel blocker nifedipine and ATP-sensitive potassium channel activator pinacidil was compared. The experiments were carried out by applying standard intracellular microelectrode technique in isolated dog left ventricular preparations. The results confirmed the existence of M cells in the canine ventricle, in addition, the distribution of the rate of rise of the action potential upstroke and action potential amplitude values reflecting probably the inhomogeneity of the fast sodium current in these cells was revealed. It was also demonstrated that M cells differ from Purkinje fibres in some aspects which were not expected from previous investigations: (1) The early portion of the action potential duration restitution curve in M cells is more similar to that of endocardial and epicardial cells than to Purkinje fibres. (2) The plateau phase of the action potentials in Purkinje fibres developed at a more negative potential range than that in the other cell types studied. (3) The pharmacological response to tetrodotoxin and pinacidil in M cells resembles to that in the endocardial and epicardial cells more than in the Purkinje fibres. Our results provide further evidence in support of the existence of M cells but also indicate that there are important electrophysiological as well as pharmacological differences between M cells and Purkinje fibres.

Action Potentials↗
PubMed1998

Suppression of erythromycin-induced early afterdepolarizations and torsade de pointes ventricular tachycardia by mexiletine.

Erythromycin is a selective IKr-blocking, action potential duration (APD)-prolonging drug, which may induce early afterdepolarizations (EADs) and torsade de pointes ventricular tachycardia. The successful termination of an erythromycin-induced clinical torsades de pointes by the authors with mexiletine prompted them to investigate in vitro whether erythromycin is able to induce EADs in Purkinje fibers and, if so, whether EADs are suppressible or not by mexiletine. Electrically stimulated canine Purkinje fibers (n = 9) were superfused with erythromycin (200 mg/l) and action potentials were recorded by an intracellular microelectrode technique. Erythromycin induced a pronounced prolongation of APD and the appearance of EADs in all Purkinje preparations (9/9). After the addition of mexiletine (10 mM), a marked shortening of APD and the disappearance of EADs (7/9) were observed. Mexiletine, an inhibitor of the tetrodotoxin-sensitive window Na(+)-current, may prevent IKr-blocking drug-induced torsade de pointes ventricular tachycardia by abolishing APD prolongation and EADs.

Action Potentials↗
PubMed1998

Endothelium-dependent vasorelaxant and anti-aggregatory effect and mechanism of action of some antifibrinogen RGD (Arg-Gly-Asp-containing) peptides.

Vasorelaxation caused by some antifibrinogen RGD (Arg-Gly-Asp-containing) peptides and their basic mechanism of action was studied on rabbit isolated thoracic aortic rings preconstricted with 0.25 microM phenylephrine. GRGDS (Gly-Arg-Gly-Asp-Ser-OH) and RGDV (Arg-Gly-Asp-Val-OH) caused dose-dependent relaxation. RGDS (Arg-Gly-Asp-Ser-OH) had a biphasic effect (a transient relaxation followed by a contraction) while GRGDS-[SE] (Gly-Arg-Gly-Asp-Ser(SO3)-OH) did not change the isometric tone of precontracted aortic preparations. GRGDS and RGDV exerted no relaxing effect on endothelium-denuded blood vessels suggesting that the vascular action of these peptides was entirely dependent on the presence of functionally intact endothelium. L-NG-Nitro-arginine (30 microM) attenuated the relaxation induced by GRGDS and abolished that induced by RGDV. All of the four RGD congeners inhibited ADP-induced aggregation of human platelets. These findings indicate that the relaxant effect of RGDV is mediated exclusively by the nitric oxide pathway, but GRGDS could cause, besides nitric oxide release, the release of another substance which is different from nitric oxide. Because the rank order of the vasorelaxant potencies of RGD peptides differed from that found for their anti-aggregatory activities, a vascular effector mechanism mediated by an RGD-recognizing structure other than the known glycoprotein IIb/IIIa-like RGD-binding site is suggested.

Animals↗
PubMed1998

Differential efficacy of vasodilators in hypercholesterolaemic rabbits.

The effects of hypercholesterolaemia on the endothelium-dependent and -independent vascular reactivity of the superior mesenteric artery has been examined in anaesthetized rabbits in-vivo. Rabbits were fed with either standard or cholesterol-enriched diet for 24 weeks. Plasma lipids and changes in the endothelin content of plasma and vascular tissue were measured in the superior mesenteric artery and in the thoracic aorta. The functional severity of atherosclerosis was determined by examining vascular responses in the isolated thoracic aorta. The blood flow in the superior mesenteric artery was measured by transit-time flowmetry and drugs were injected through an intra-abdominal aortic catheter. Acetylcholine (5, 10, 20 microg kg(-1)) elicited dose-dependent, mesenteric vasodilation in normocholesterolaemic rabbits. In hypercholesterolaemic animals the response to acetylcholine was completely abolished and even became a vasoconstriction. Endothelin levels in plasma and in the vascular tissue were significantly elevated in hypercholesterolaemic animals compared with controls. Cromakalim at a dose of 3 microg kg(-1), elicited similar mesenteric vasodilation in hypercholesterolaemic and normocholesterolaemic animals. These experiments show that the endothelium-dependent responses of the superior mesenteric artery to acetylcholine are functionally impaired by prolonged hypercholesterolaemia, that this altered vascular reactivity is associated with the elevation of endothelin levels in the circulation and in vascular tissues, and that in hypercholesterolaemia the mesenteric vasodilator effect of the K+-channel opener cromakalim is entirely preserved, suggesting that severe hypercholesterolaemia does not depress the function of ATP-sensitive potassium channels in mesenteric vascular smooth muscle.

Acetylcholine↗