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J G Papp

Publications and source records attributed to J G Papp.

At least 55 records · Page 3Linked to original sources
PubMed1997

Does the opening of ATP-sensitive K+ channels modify ischaemia-induced ventricular arrhythmias in anaesthetised dogs?

These experiments were designed to determine whether there is any change in the severity of ventricular arrhythmias resulting from coronary artery occlusion in anaesthetised mongrel dogs if ATP-sensitive potassium channels were already open at the time of coronary occlusion. To achieve this we locally infused the K(ATP) channel opener levcromakalim, in a total dose of 3 microg/kg, and given by slow infusion over a 30 min period directly into a side branch of the left anterior descending coronary artery. This dose increased blood flow in that main artery by 30% (and by 7% in the adjacent left circumflex artery). The degree of inhomogeneity of electrical activation, measured from the left ventricular wall distal to the occlusion site, was unaffected by levcromakalim administration but there was significant epicardial ST-elevation, perhaps indicating K+ egression from cells. Following coronary artery occlusion there was no marked difference in the severity of arrhythmias between control and levcromakalim-treated dogs, except for an increased number of episodes of ventricular tachycardia due entirely to effects in two of the nine treated dogs. We conclude that opening cardiac K(ATP) channels with levcromakalim, at this one dose level, and administered directly to the left ventricular wall, does not significantly modify arrhythmia severity during ischaemia. These results cannot be extrapolated to studies in which such drugs markedly reduce coronary perfusion pressure.

Adenosine Triphosphate↗
PubMed1997

Bradykinin and endothelial-cardiac myocyte interactions in ischemic preconditioning.

Myocardial ischemia results in the release of a variety of vasoactive substances from coronary vascular endothelial cells and/or from cardiac myocytes. Some of these substances appear to be protective and include nitric oxide and bradykinin. One hypothesis for the pronounced antiarrhythmic effects of preconditioning involves the early generation of bradykinin and, subsequently, nitric oxide. Evidence for early bradykinin release has come from clinical studies involving patients undergoing coronary angioplasty where, in 4 of 5 patients, there was evidence for elevated kinin levels in coronary sinus blood either during balloon inflation (i.e., ischemia) or deflation (reperfusion). The levels reached are sometimes considerable (increases 10-20 fold). The second piece of evidence comes from dogs subjected to a preconditioning stimulus (2 x 5 min periods of ischemia), followed 20 min later by occlusion of the same artery for a 25-min period. This preconditioning procedure markedly reduces ischemia-induced ventricular arrhythmias and, although under resting conditions there was little difference between arterial and coronary sinus bradykinin levels (125 +/- 22 and 157 +/- 41 pg/mL, respectively), there was a marked increase in coronary sinus levels in preconditioned dogs before the prolonged occlusion (637 +/- 293 pg/mL compared with 114 +/- 18 pg/mL in nonpreconditioned dogs); levels at the end of the prolonged occlusion in the preconditioned dogs were also higher (577 +/- 305 pg/mL compared with 162 +/- 34 pg/mL in control dogs). Other evidence for the involvement of bradykinin and nitric oxide comes from studies in which the generation, or effects, of these mediators have been suppressed (e.g., with the bradykinin B2 receptor blocking agent icatibant, with inhibitors of the L-arginine-nitric oxide pathway, and by methylene blue). The conclusion is that early bradykinin release is protective under conditions of ischemia, is presumably enhanced during therapy with angiotensin-converting enzyme (ACE) inhibitors and is suppressed under conditions of endothelial dysfunction.

Animals↗
PubMed1997

Modification by bradykinin B2 receptor blockade of protection by pacing against ischaemia-induced arrhythmias.

In dogs, rapid cardiac pacing, by way of a pacing electrode in the right ventricle, protects against ventricular arrhythmias when a coronary artery is occluded immediately after cessation of the pacing period. This represents a form of ischaemic preconditioning. The role of bradykinin in mediating the protective effects of rapid cardiac pacing in this model was investigated using a selective antagonist of bradykinin at B2 receptors (icatibant; HOE 140). In the presence of icatibant cardiac pacing (220 beats min(-1)) resulted in more severe ischaemia (as assessed by ST-segment elevation from the pacing electrode at the end of the stimulus) and to a higher incidence of ventricular arrhythmias during the pacing protocol. When the coronary artery was occluded under such conditions the antiarrhythmic protection afforded by cardiac pacing was not seen although other indices of reduced ischaemia severity (epicardial ST-segment mapping; changes in the degree of inhomogeneity of electrical activation within the ischaemic area) were not affected by icatibant treatment. These results suggest that bradykinin is an important trigger mediator involved in the protective effects of cardiac pacing. Whether this is due to the generation of endothelium-derived protective substances (such as nitric oxide and prostacyclin) or whether it results from a direct effect on B2 receptors in cardiac myocytes is unclear.

Adrenergic beta-Antagonists↗
PubMed1997

KATP channel modulators increase survival rate during coronary occlusion-reperfusion in anaesthetized rats.

We investigated the effect of ATP-sensitive K+ channel (KATP) openers (pinacidil and cromakalim), and a KATP blocker (glibenclamide) on reperfusion-induced arrhythmias in pentobarbitone-anaesthetized rats. Arrhythmias were induced by reperfusion following a 6 min ligation of the left main coronary artery. Rats were pretreated with pinacidil (0.1 or 0.3 mg/kg), or cromakalim (28 or 56 micrograms/kg), or glibenclamide (5 mg/kg), or vehicle. Pinacidil and cromakalim produced dose-related reductions in blood pressure. Pinacidil (0.1 mg/kg) and cromakalim (56 micrograms/kg) significantly decreased the incidence of reperfusion-induced ventricular fibrillation and increased survival. Glibenclamide did not decrease ventricular fibrillation incidence, yet improved survival by increasing the possibility of recovery from ventricular fibrillation. The present study suggests that both opening and blocking KATP channels may increase survival during coronary occlusion and reperfusion in anaesthetized rats.

Action Potentials↗
PubMed1997

Increased cardiac workload by adrenoceptor agonists for the estimation of potential antiischemic activity in a conscious rabbit model.

The antiischemic effect of drugs can be detected at a lower dose range if the cardiac workload is increased. A brief period of frequency-loading (ventricular overpacing = VOP) results in well-defined, reproducible changes in cardiac parameters in the conscious, chronically instrumented rabbit; however, rapid pacing frequently evoked ventricular tachycardia or even fatal ventricular fibrillation. Therefore, cardiac workload has been increased by i.v. administration of adrenoceptor agonists, such as isoproterenol (ISO), phenylephrine (PHE), and their combination, respectively. The doses applied (especially the combination of 2 micrograms/kg ISO and 16 micrograms/kg PHE, giving optimal changes) were sufficient to produce a marked elevation of both the ST segment in the intracavital electrogram and the left ventricular end-diastolic pressure, without evoking cardiac arrhythmias. We compared the effect of this adrenergic "test" stimulus with that of VOP on hemodynamic and electrophysiological parameters of the heart, and furthermore, on the modification of responses to both "test" stimuli by oral administration of the coronary vasodilator: Isosorbide-5-mononitrate (IS-5-N), given in a dose of 40 mg/kg. Both VOP- and ISO+PHE-induced changes were significantly attenuated by IS-5-N, and a temporal coincidence of the maximal effects was found as well. We reached the following conclusion: The combined administration of ISO and PHE not evoking fatal arrhythmias in the dose range applied can replace the more risky VOP as a "test" workload in the estimation of antiischemic action.

Adrenergic alpha-Agonists↗
PubMed1997

Influence of anesthetics on the incidence of reperfusion-induced arrhythmias and sudden death in rats.

PURPOSE: We compared the influence of pentobarbital (P, 60 mg/kg), urethane (U, 1.8 g/kg), and a contribution of diazepam with ketamine hydrochloride (D+K, 10 + 100 mg/kg) anesthesia on the incidence of ischemia/ reperfusion-induced arrhythmias in rats. In anesthetized rats, myocardial ischemia was produced by a 6-min ligation of the left main coronary artery, followed by 5 min of reperfusion. The incidence of reperfusion-induced ventricular fibrillation (VF) and ventricular tachycardia (VT) was markedly decreased in the D+K-anesthetized animals compared with the P-anesthetized group (VF, 46 vs. 89%; VT, 64 vs. 94%). The mean blood pressure (MBP) before coronary ligation was significantly lower in U-anesthetized animals (72 +/- 3.5 vs. 102 +/- 4.1 and 108 +/- 5.9 mm Hg in P and D+K, respectively). The MBP recovery was the best in the D+K-anesthetized group. In experimental work, pentobarbitone anesthesia may be recommended for studying arrhythmias, while the combination of diazepam and ketamine may be useful for hemodynamic investigations.

Anesthetics↗
PubMed1996

Nicorandil suppressed ventricular arrhythmias in a canine model of myocardial ischaemia.

These experiments were designed to explore the possibility that a K+ channel opener which also donates nitric oxide to the myocardium (nicorandil) may modify ischaemia-induced ventricular arrhythmias in a large animal model. In mongrel dogs anaesthetised with chloralose-urethane and thoracotomised, a side branch of the left anterior descending artery was catheterised for the local intracoronary infusion of nicorandil (2.5 micrograms kg-1 min-1 for 20 min prior to coronary artery occlusion and then continuing throughout the 25 min occlusion period). In this dose, nicorandil had no haemodynamic effects, increased coronary blood flow by up to 16% and significantly reduced the severity of ischaemia-induced arrhythmias (e.g. from nearly 500 ventricular premature beats in the controls to 160 +/- 60 in the nicorandil group). There was a significant reduction in the number of episodes of ventricular tachycardia during the ischaemic period and a reduced incidence of ventricular fibrillation following reperfusion resulting in a 42% survival from the combined ischaemia-reperfusion insult (cf. 0% in the control; P < 0.05). The marked changes that occurred in ST-segment elevation (mapped with epicardial electrodes) and in the inhomogeneity of electrical activation within the ischaemic area in control dogs was markedly reduced in those dogs administered nicorandil. We conclude that the local intracoronary administration of nicorandil reduces the severity of both ischaemia and the life-threatening arrhythmias that result from an abrupt reduction in coronary blood flow in this canine model. Possible mechanisms include an increase in coronary blood flow, a reduction in the severity of myocardial ischaemia and an ability of the compound to "donate' nitric oxide to the ischaemic area.

Animals↗
PubMed1996

Haemodynamic and other effects of sulphonylurea drugs on the heart.

Antidiabetic sulphonylureas have attracted a great deal of interest in experimental cardiology to evaluate the role of ATP-sensitive potassium channels in the cardiovascular system. It is well established that KATP channels are present in cardiac cells and also in vascular smooth muscle cells and are implicated in the regulation of myocardial and vascular function. It follows that drugs which open, or inhibit the opening of these channels, might profoundly modify cardiovascular function both under physiological and pathophysiological conditions. This paper reviews the evidence for the role of KATP channels in the cardiovascular system and discusses how the different generations of sulphonylurea drugs interfere with cardiac function. We will particularly concentrate on the haemodynamic effects of different sulphonylureas and shortly discuss how these drugs modify ischaemia-reperfusion arrhythmias.

Adenosine Triphosphate↗
PubMed1996

Cardiac electrophysiological effects of levosimendan, a new calcium sensitizer.

1. The conventional microelectrode and the patch-clamp techniques were used to study the electrophysiological effects of levosimendan, a new calcium-sensitizing cardiotonic drug, in cardiac ventricular muscle. 2. Levosimendan (5 microM) did not change the main repolarizing currents, such as the inward rectifier potassium, transient outward and the delayed rectifier outward potassium current, in rabbit ventricular myocytes. 3. In rabbit ventricular muscle, levosimendan, at relatively low concentrations (0.1-1 microM), did not change significantly the amplitude of the inward calcium current but increased the amplitude of the twitch tension. 4. In guinea pig ventricular muscle, levosimendan, at higher concentrations (1-5 microM), significantly increased the amplitude of the inward calcium current and the slow-response action potential parameters. 5. It is concluded that levosimendan, in addition to its calcium sensitizing properties characterized by "silent electrophysiology," exhibits cardiac electrophysiological effects similar to those of phosphodies-terase inhibitors.

Action Potentials↗
PubMed1996

Electrical restitution in rat ventricular muscle.

The mechanism of electrical restitution was studied in isolated rat ventricular muscle using drugs that inhibit specific ion currents. The effect of transient changes in cytosolic Ca concentration and Na/Ca exchange in relation to the restitution process was also studied in single ventricular cardiomyocytes. Conventional microelectrode techniques were applied to record action potentials having gradually increasing coupling intervals, each evoked following a train of stimuli with a frequency of 1 Hz. Ion currents were recorded from enzymatically isolated cells using the whole cell patch clamp technique. Ca transients were monitored in myocytes loaded with the fluorescent dye, indo-1. The electrical restitution process in multicellular rat ventricular preparations at 37 degrees C was described as a sum of three exponential components: an early positive component, a subsequent fast negative component and a late negative component, having time constants of 21.9 +/- 1.9, 73.1 +/- 6.0 and 1053 +/- 61 ms, respectively (n = 9). Inhibition of the transient outward K current, the delayed rectifier K current, or the chloride current did not substantially alter these time constants. The early positive and fast negative components were fully abolished by nifedipine or MnCl2. In the presence of caffeine, the fast negative component was absent, while the time constant of the early positive component increased to 39.5 +/- 5.8 ms (n = 5). In single myocytes loaded with indo-1, the Ca transients decayed with a time constant of 151 +/- 12 ms at room temperature (n = 5). These Ca transients were accompanied by inward current tails, identified as a Na/Ca exchange current, having a decay time constant of 140 +/- 4.5 ms. It is concluded that electrical restitution in rat ventricular muscle is relatively little affected by recovery from voltage-dependent inactivation of ion channels, it is rather governed by transient changes in cytosolic Ca concentration possible via Ca-dependent inactivation of the L-type Ca current and activation of the Na/Ca exchange current.

Action Potentials↗
PubMed1996

Cardiovascular effects of conventional sulfonylureas and glimepiride.

Sulfonylureas have, in the past, been reported to have adverse cardiovascular effects. Glimepiride is a new sulfonylurea. In spite of stimulating less insulin secretion, it has, depending on the species, equal or higher blood glucose decreasing activity and according to preliminary studies less cardiovascular activity than glibenclamide. Further studies were performed to confirm the lower cardiovascular activity of glimepiride. The IC50 for inhibition of rilmakalim-activated KATP channel currents in isolated ventricular myocytes was 31.6 nM for glimepiride and 6.8 nM for glibenclamide. In endotoxin shock-rats at a dose of 1 x 2 mg/kg i.v., glibenclamide induced a significantly higher blood pressure increase than glimepiride. At two i.v. doses of 20 mg/kg 4 min apart, in normal rats, glibenclamide produced signs of ischemia in the ECG in nearly all animals, glimepiride almost none, in diabetic rats, glibenclamide produced in all animals a lethal cardiogenic shock preceeded by serious ECG changes, glimepiride only in one fifth of the animals. In open-chest dogs, on intracoronary infusion of equieffective blood glucose-lowering doses, glibenclamide, gliclazide and glimepiride all reduced coronary blood flow, increased coronary resistance, depressed the mechanical activity of the heart, enhanced myocardial O2-extraction, reduced the serum potassium level and induced a moderate endocardial ST-segment elevation, but glimepiride to a significantly less extent than glibenclamide and gliclazide. The presented data confirm that glimepiride at equivalent blood glucose decreasing doses has less cardiovascular activity than conventional sulfonylureas.

Animals↗
PubMed1996

Pharmacology of moxonidine, an I1-imidazoline receptor agonist.

Moxonidine is a second-generation, centrally acting antihypertensive drug with a distinctive mode of action. Moxonidine activates I1-imidazoline receptors (I1-receptors) in the rostroventrolateral medulla (RVLM), thereby reducing the activity of the sympathetic nervous system. Moxonidine leads to a pronounced and long-lasting blood pressure reduction in different animal models of hypertension, e.g., spontaneously hypertensive rats, renal hypertensive rats, and renal hypertensive dogs. Blood pressure reduction with moxonidine is usually accompanied by a reduction in heart rate which, however, in most studies is of shorter duration and lesser magnitude than the fall in blood pressure. Chronic administration of moxonidine to SHRs with established hypertension causes normalization of myocardial fibrosis, capillarization, and regressive changes in myocytes, in parallel with the reduction of blood pressure. Left ventricular hypertrophy and renal glomerulosclerosis are also significantly reduced. After withdrawal of chronic moxonidine treatment, blood pressure gradually rises to pretreatment values. Direct injection of moxonidine into the vertebral artery of cats elicits a more pronounced fall in blood pressure compared with i.v. injection of an equivalent dose. This observation and others clearly indicate that moxonidine's antihypertensive activity is centrally mediated. The RVLM is the site of action within the CNS that mediates pronounced blood pressure reduction after direct administration of moxonidine into the RVLM of anesthetized SHRs. Selective I1-receptor antagonists introduced into this area abolish the action of systemic moxonidine. Receptor binding studies have shown high and selective affinity of moxonidine for I1-receptors vs. alpha(2)-adrenergic receptors. In vivo studies using a variety of selective I1 or alpha(2)-adrenergic agonists and antagonists have confirmed the primary role of I1-receptors in blood pressure regulation by moxonidine. In addition to lowering blood pressure, moxonidine possesses further properties that appear likely to be relevant in its therapeutic application in the hypertensive syndrome. Moxonidine increases urine flow rate and sodium excretion after central and direct intrarenal administration. It is active against ventricular arrhythmias in a variety of experimental settings. It lacks the respiratory depressant effect attributed to central alpha 2 activation. It exerts beneficial effects on glucose metabolism and blood lipids in genetically hypertensive obese rats. It exhibits anti-ulcer activity. And, finally, moxonidine lowers intraocular pressure, suggesting a possible benefit in glaucoma. Therefore, moxonidine, by its novel mode of action, represents a new therapeutic principle in the treatment of hypertension. Because of its unique profile, moxonidine may prove to be effective in slowing progression of the disease by providing protective effects beyond merely blood pressure reduction. Further studies are needed to verify this potential.

Animals↗
PubMed1996

Comparison of the chronic and acute effects of amiodarone on the calcium and potassium currents in rabbit isolated cardiac myocytes.

1. The acute and chronic effects of amiodarone were studied on the transmembrane ionic currents in rabbit single ventricular myocytes at 35 degrees C by applying the whole-cell configuration of the patch-clamp technique. 2. Acute exposure to 1 and 5 microM amiodarone significantly reduced the amplitude (-53.9 +/- 3.9%, n = 5 and -64.0 +/- 2.0%, n = 3, P < 0.01), but chronic amiodarone treatment (i.p. 50 mg kg-1 day-1 for 3-4 weeks) changed neither the amplitude nor the kinetics of the inward calcium current. 3. Both acute superfusion with amiodarone (1 and 5 microM) and chronic amiodarone treatment significantly decreased the amplitude of the delayed rectifier outward potassium current (IK). 4. Acute application of amiodarone (1 and 5 microM) did not alter but chronic amiodarone treatment moderately depressed the transient outward current (Ito). 5. Neither the acute (1 and 5 microM) nor the chronic amiodarone treatment changed the magnitude of the inward rectifier potassium current (Ik1). 6. It is concluded that acute amiodarone application and chronic amiodarone treatment alter transmembrane ionic currents of ventricular myocytes differently. This may explain, at least in part, the marked differences in the cardiac electrophysiological effects observed after acute and chronic amiodarone treatment in patients.

Amiodarone↗
PubMed1996

ATP-sensitive potassium channel modulators: both pinacidil and glibenclamide produce antiarrhythmic activity during acute myocardial infarction in conscious rats.

We investigated the effects of pinacidil, an ATP-sensitive potassium channel opener, and of glibenclamide, an ATP-sensitive potassium channel inhibitor, on the incidence of arrhythmias and sudden cardiac death after coronary artery ligation in conscious rats. Occlusion of the left main coronary artery was produced by tightening a previously placed loose silk ligature. In the control group (n = 25) only 40% and 24% of the animals survived for 15 min and 16 hr after coronary artery ligation, respectively. Intravenous pretreatment with 0.1, 0.3 or 1 mg/kg pinacidil increased the survival rate to 67% (n = 15), 70% (n = 20) and 67% (n = 12) in the first 15 min and to 60%, 55% and 67% in the first 16 hr, respectively. Glibenclamide pretreatment (5.0 mg/kg i.p.) improved the survival rate at both time-points to 87% (n = 16). Both types of pretreatment significantly decreased the incidence of life-threatening arrhythmias and increased the number of animals that survived without developing any arrhythmia. In conclusion, the present findings demonstrate that in conscious rats, pretreatment with pinacidil and pretreatment with glibenclamide, although they obviously have different mechanisms of action, may result in a very similar final outcome with respect to arrhythmias and sudden cardiac death during the acute phase of experimental myocardial infarction.

Adenosine Triphosphate↗
PubMed1996

The cellular electrophysiological effects of tedisamil in human atrial and ventricular fibers.

The cellular electrophysiological effects of 1 microM tedisamil (KC 8857) were studied in human atrial and ventricular fibers. Conventional microelectrode technique was applied to record the transmembrane action potentials at stimulation frequency of 100 per min and 37 degrees C. Tedisamil lengthened action potential duration (APD) more in atrial than in ventricular muscle fibers; prolongation of APD90 was 28.9 +/- 3.3% (n = 6; p < 0.05) for atrial and 13.3 +/- 5.2% (n = 6; P < 0.05) for ventricular tissue. The maximal rate of depolarization was depressed slightly, but significantly by 1 microM tedisamil only in ventricular fibers (12.9 +/- 6.5%, n = 6, P < 0.05). From these cellular electrophysiological data it is concluded that the bradycardic/antiischemic agent tedisamil possesses marked Class III properties not only in cardiac tissues of experimental animals but also those of man.

Action Potentials↗