Csaba Pankucsi

Comparative study of cardiac electrophysiological effects of atrial natriuretic peptide

The effects of atrial natriuretic peptide (ANP) on action potential characteristics were studied in various (human, rabbit, guinea-pig) atrial and guinea-pig right ventricular papillary muscles. ANP (1–100 nM) did not modify the resting membrane potential nor the maximum rate of depolarization phase (Vmax). Up to 10 nM, ANP dose-dependently decreased the action potential amplitude both in guinea-pig atrial and ventricular muscles, but it did not affect this parameter in the other atrial preparations. ANP caused a dose-dependent, marked decrease of action potential duration (APD) in practically every cardiac preparation studied (exception of guinea-pig left atrium). The strongest effect on APD can be observed in human atrial and guinea-pig ventricular fibers. The K+ channel blocker 4-aminopyridine (1 mM) and the ATP-dependent K+ channel inhibitor glibenclamide (10μNl) prevented the effect of ANP on APD in both ventricular atrial preparations. ANP prevented the appearance of isoprenaline (0.5 μM) induced slow AP in K+ depolarized myocardium. The present data suggest that ANP may inhibit the slow inward Ca2+ channel activity and facilitate the K+ channel activity.

Action potential duration and force-frequency relationship in isolated rabbit, guinea pig and rat cardiac muscle

The effect of action potential duration and elevated cytosolic sodium concentration on the forcefrequency relationship in isolated rabbit, guinea pig and rat papillary muscle preparations was studied. Shortening of action potential duration in guinea pig and rabbit from 150–200 ms to values characteristic of rat (20–40 ms), using the K(ATP) channel activator levkromakalim (15 μmol·l−1), markedly reduced the force of contraction and converted the positive force-frequency relationship into negative one at longer pacing cycle lengths. This conversion was greatly enhanced in the presence of acetylstrophanthidin (0.2–1 μmol·l−1), an inhibitor of the Na-K pump. Acetylstrophanthidin (1 μmol·l−1) alone, however, had no effect on the forcefrequency relationship. Prolongation of action potential duration in rat with inhibitors of cardiac K channels (4-aminopyridine [10 mmol·l−1] plus tetraethylammonium [2 mmol·l−1) increased the force of contraction and abolished the negative force-frequency relationship observed in rat at longer pacing-cycle lengths. It is concluded that both action potential duration and cytosolic sodium concentration are major determinants of the force-frequency relationship in mammalian myocardium.

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

Abstract 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 μmol/l) selectively lengthened action potential duration (both APD50 and APD90) in all preparations. The effect of higher concentrations (30–100 μmol/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 μmol/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 μmol/l), unchanged at 30 μmol/l and shortened at 100 μmol/l. The ratio of ERP/APD90, however, was significantly increased at concentrations higher than 3 μmol/l.In canine Purkinje fiber, when the delayed rectifier K current (IK) was blocked by d-sotalol (60 μmol/l) and APD was shortened back to its control value by additional application of nicorandil (15 μmol/l), APD was not affected by 3 μmol/l but was shortened by 30 μmol/l of EGIS-7229. 100 μmol/l EGIS-7229 shortened APD in guinea pig papillary muscle. This effect of EGIS-7229 was effectively prevented by nifedipine pretreatment (10 μmol/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.

Meal-induced enhancement in insulin sensitivity is not triggered by hyperinsulinemia in rats

Several reports confirmed the phenomenon of postprandial increase in whole-body insulin sensitivity. Although the initial step of this process is unknown, the pivotal role of postprandial hyperinsulinemia has strongly been suggested. The aim of the present study was to determine whether hyperinsulinemia per se induces insulin sensitization in healthy male Wistar rats. Rapid insulin sensitivity test (RIST) were performed in fasted, anesthetized rats before and during stable hyperinsulinemia achieved by hyperinsulinemic euglycemic glucose clamping (HEGC) with insulin infused either through the jugular vein (systemic HEGC) or into the portal circulation (portal HEGC) at a rate of 3 mU/(kg min). Insulin sensitivity expressed by the rapid insulin sensitivity (RIST) index (in milligrams per kilogram) was characterized by the total amount of glucose needed to maintain prestudy blood glucose level succeeding an intravenous bolus infusion of 50 mU/kg insulin over 5 minutes. In fasted animals, the RIST index was 37.4 +/- 3.1 mg/kg. When hyperinsulinemia mimicking the postprandial state was achieved by systemic HEGC, the RIST index (39.7 +/- 10.6 mg/kg) showed no significant changes as compared with the pre-HEGC values. Hyperinsulinemia achieved by portal insulin infusion also failed to modify the RIST index (35.7 +/- 4.3 mg/kg). The results demonstrate that acute hyperinsulinemia, no matter how induced, does not yield any sensitization to the hypoglycemic effect of insulin.

Electrophysiological effects of EGIS-7229, a new antiarrhythmic agent, in isolated guinea pig papillary muscle☆

1. The cellular electrphysiological effects of EGIS-7229, a novel antiarrhythmic agent, were studied in guinea pig papillary muscles with the use of conventional microelectrode techniques. 2. The drug had a concentration-dependent biphasic effect on action potential duration (APD). APD was significantly lengthened at low concentration (3 mumol/1), whereas it was shortened at concentrations higher than 10 mumol/l. 3. At concentrations higher than 10 mumol/l, the drug decreased the maximum velocity of action potential upstroke (Vmax), the force contraction, and altered the restitution kinetics of APD. 4. The effect of EGIS-7229 on Vmax was frequently dependent; it was most prominent at short pacing cycle lengths (use-dependent block). 5. On the basis of present results, EGIS-7229 appears to carry mixed class I and class III characteristics. Class III properties are present at low concentrations, whereas, at higher concentrations, class I actions may be predominant.

Differences in the Effects of d- and dl-Sotalol on Isolated Human Ventricular Muscle: Electromechanical Activity After Beta-Adrenoceptor Stimulation

Background: The racemate of sotalol (dl-sotalol) and its dextrorotatory isomer ( d-sotalol) are equally effective in increasing isolated cardiac action potential durations. dl-Sotalol, however, is reported to be more effective than d-sotalol in increasing ventricular effective refractoriness following coronary artery occlusion. These differences are attributed to the beta-adrenergic blocking properties of dl-sotalol. We wished to determine if in isolated human ventricular muscle preparations the effects of 30 μM d- and dl-sotalol could be modified by preexposure to 1 μM isoproterenol. Methods and Results: Microelectrodes were used to record action potential duration (APD) in the presence and absence of isoproterenol during continuous pacing. Preparations were obtained from explanted hearts of transplant recipients suffering idiopathic cardiomyopathies. Without isoproterenol, APD measured at 90% of repolarization (APD90) was signiticantly increased by both d- and dl-sotalol (352.0 ± 17.7 to 418.0 ± 23.8 ms, P < .05; and 339.2 ± 17.0 to 405.0 ± 25.3 ms, P < .05; respectively). Isoproterenol alone, prior to sotalol exposure, tended to shorten APD90 in the two groups first exposed to this beta-aclenoceptor agonist and subsequently exposed to either d-sotalol or dl-sotalol (317.5 ± 16.5 to 286.2 ± 28.8 ms and 288.0 ± 16.2 to 254.0 ± 15.0 ms, respectively). dl-Sotalol signiticantly increased APD90 from its baseline value after isoproterenol (288.0 ± 16.2 to 359.0 ± 25.1 ms, P < .005) while d-sotalol did not (317.5 ± 16.5 to 316.2 ± 28.5 ms, NS). Conclusions: The beta-adrenergic blocking properties of dl-sotalol may be important in determining antiarrhythmic efficacy when tonic sympathetic nervous activity is high.

Nitrate tolerance-induced deterioration of the ischemic adaptability of the heart

Methods Male rabbits made tolerant to the hypotensive response to 30 μg/kg intravenous nitroglycerin (NG) by a preceding one-week exposure to transdermal NG (0.07 mg/kg/h) were subjected to 35 min coronary occlusion (test ischemia) followed by 3 h of reperfusion with the following additional interventions: no intervention (NI); postconditioning pacing (PPC): five cycles of 5 min periods of rapid ventricular pacing (500 b.p.m.), or postconditioning coronary occlusion (PCO): five cycles of 5 min coronary occlusion with 10 min interpacing/interocclusion intervals, applied after the end of the test ischemia. These protocols were applied in both nitrate-tolerant and nontolerant animals. Infarct size expressed as a percentage of area at risk (I/R) was determined by triphenyltetrazolium chloride staining, left ventricular cyclic nucleotides were determined by radioimmunoassay from samples out of the area at risk, 75 min after the test ischemia. Results In non-tolerant animals both PPC and PCO reduced the I/R compared to the NI group. When animals had been made nitrate-tolerant, the I/R was significantly higher in the NI group compared with non-tolerant animals and the beneficial effect of the PPC or PCO on the I/R disappeared.

The possible link between insulin resistance and increased cardiovascular mortality

Methods Chronically instrumented conscious rabbits were equipped with a right ventricular electrode catheter for pacing and recording the intracavitary electrogram as well as with arterial and venous catheters for blood sampling, blood pressure monitoring and for insulin and glucose infusions, respectively. Hyperinsulinaemia was produced by 2-step hyperinsulinaemic (35.7 ± 7.4 and 103.2 ± 10.5 μU/ml) euglycaemic (5.5 ± 0.5 μU/ml) glucose clamping. Programmed electrical stimulation (PES) was applied for ventricular effective refractory period (VERP) determination and arrhythmia generation.

Electrophysiological effects of dridocainide on isolated canine, guinea-pig and human cardiac tissues

The cellular electrophysiological effects of dridocainide (EGIS-3966), a novel class I antiarrhythmic agent, was studied using conventional microelectrode techniques in canine cardiac Purkinje fibres and papillary muscle preparations obtained from humans and guinea-pigs. In each preparation, dridocainide (0.6–2 μmol/l) decreased the maximum velocity of action potential upstroke (Vmax) in a frequency-dependent manner, although marked differences were observed in its effects in Purkinje fibre and ventricular muscle preparations. In canine Purkinje fibres, action potential duration measured at 50% and 90% of repolarization was decreased, while action potential duration measured at 10% of repolarization was increased by dridocainide. In addition, the plateau of the action potential was depressed by the drug. These changes in action potential configuration were not observed in guinea pig or human papillary muscles. The offset kinetics of the dridocainide-induced Vmax block were different in Purkinje fibres and in ventricular muscle: the slow time constant of recovery of Vmax was estimated to be 2.5 s in dog Purkinje fibre and 5–6 s in human and guinea-pig papillary muscle. In guinea-pig papillary muscle, the rate of onset of the Vmax block was 0.15 and 0.2 per action potential in the presence of 0.6 and 2 μmol/l dridocainide, respectively. Dridocainide also decreased the force of contraction in this preparation. On the basis of the present results, dridocainide appears to posess mixed class LC and LA properties, with LC predominance in human and guinea-pig ventricular muscle. Present results also indicate that results of conventional classification of class I drugs may depend on the parameters chosen, as well as on the preparation selected.