Slow Response Action Potentials Research Articles

Electrophysiological effects of ischemia/reperfusion (I/R) on pacemaker cells in guinea-pig left ventricular outflow tract and the effects of antiarrhythmic drugs treatment

To investigate the electrophysiological effects of ischemia/reperfusion (I/R) on the spontaneous slow response action potentials in guinea-pig left ventricular outflow tract and the effects of antiarrhythmic drugs onI/R. The action potentials of pacemaker cells in guinea-pig left ventricular outflow tract were recorded by conventional intracellular microelectrode technique. The influences of ischemia(I) 10 min, reperfusion(R) 2 min, and R 15min on the spontaneous slow response potentials were investigated. The effects of lidocaine, propafenone, amiodarone, verapamil, adenosine, and sodium nitroprusside (SNP) on I/R were also studied. Electrophysiological parameters were examined:velocity of diastolic depolarization(VDD), rate of pacemaker firing(RPF), maximal diastolic potential(MDP), maximal rate of depolarization(Vmax), amplitude of action potential(APA), 50% and 90% of duration of action potential(APD50 and APD90). ①In I 10 min group, the values of VDD, RPF, Vmax and APA were decreased markedly compared with control group (P<0.05, P<0.01).In R 2 min group, VDD and RPF were increased significantly(P<0.01), MDP was increased notably(P<0.05), APD50 and APD90 were shortened significantly compared with I 10 min and control group. Vmax was increased markedly vs control group(P<0.05). APA was decreased notably vs I 10 min group (P<0.05), but was increased markedly vs control group(P<0.05). In R 15 min group, the action potentials recovered gradually to the levels of control group. ② Compared with I 10 min/R 2 min group, 1 μmol/L lidocaine, 10 μmol/L propafenone, 1 μmol/L amiodarone, 1 μmol/L verapamil, 50 μmol/L adenosine, and 10 μmol/L SNP decreased VDD and RPF significantly. I/R injury can trigger abnormal spontaneous activities of guinea-pig left ventricular outflow tract.The electrophysiological effects of I/R injury on left ventricular outflow tract can be treated by antiarrhythmic drugs.

Antiarrhythmic effects of dehydroevodiamine in isolated human myocardium and cardiomyocytes

Ethnopharmacological relevanceDehydroevodiamine alkaloid (DeHE), a bioactive component of the Chinese herbal medicine Wu-Chu-Yu (Evodiae frutus), exerted antiarrhythmic effect in guinea-pig ventricular myocytes. We further characterize the electromechanical effects of DeHE in the human atrial and ventricular tissues obtained from hearts of patients undergoing corrective cardiac surgery or heart transplantation. Materials and methodsThe transmembrane potentials of human myocardia were recorded with a traditional microelectrode technique while sarcolemmal Na+ and Ca2+ currents in single human cardiomyocytes were measured by a whole-cell patch-clamp technique. The intracellular pH (pHi) and Na+–H+ exchanger (NHE) activity were determined using BCECF-fluorescence in human atria. ResultsIn human atria, DeHE (0.1–0.3μM) depressed upstroke velocity, amplitude of action potential, and contractile force, both in slow and fast response action potential. Moreover, the similar depressant effects of DeHE were found in human ventricular myocardium. Both in isolated human atrial and ventricular myocytes, DeHE (0.1–1μM) reversibly, concentration-dependently decreased the Na+ and Ca2+currents. Moreover, DeHE (0.1 and 0.3μM) suppressed delayed afterdepolarizations and aftercontractions, induced by epinephrine and high [Ca2+]o in atria. In human ventricular myocardium, the strophanthidin-induced triggered activities were attenuated by pretreating DeHE (0.3μM). The resting pHi and NHE activity were also significantly increased by DeHE (0.1–0.3μM). ConclusionsWe concluded for the first time that, in the human hearts, DeHE could antagonize triggered arrhythmias induced by cardiotonic agents through a general reduction of the Na+ and Ca2+ inward currents, while increase of resting pHi and NHE activity.

ORM‐10103, a novel specific inhibitor of the Na+/Ca2+ exchanger, decreases early and delayed afterdepolarizations in the canine heart

At present there are no small molecule inhibitors that show strong selectivity for the Na(+) /Ca(2+) exchanger (NCX). Hence, we studied the electrophysiological effects of acute administration of ORM-10103, a new NCX inhibitor, on the NCX and L-type Ca(2+) currents and on the formation of early and delayed afterdepolarizations. Ion currents were recorded by using a voltage clamp technique in canine single ventricular cells, and action potentials were obtained from canine and guinea pig ventricular preparations with the use of microelectrodes. ORM-10103 significantly reduced both the inward and outward NCX currents. Even at a high concentration (10 μM), ORM-10103 did not significantly change the L-type Ca(2+) current or the maximum rate of depolarization (dV/dtmax ), indicative of the fast inward Na(+) current. At 10 μM ORM-10103 did not affect the amplitude or the dV/dtmax of the slow response action potentials recorded from guinea pig papillary muscles, which suggests it had no effect on the L-type Ca(2+) current. ORM-10103 did not influence the Na(+) /K(+) pump or the main K(+) currents of canine ventricular myocytes, except the rapid delayed rectifier K(+) current, which was slightly diminished by the drug at 3 μM. The amplitudes of pharmacologically- induced early and delayed afterdepolarizations were significantly decreased by ORM-10103 (3 and 10 μM) in a concentration-dependent manner. ORM-10103 is a selective inhibitor of the NCX current and can abolish triggered arrhythmias. Hence, it has the potential to be used to prevent arrhythmogenic events.

Electrophysiological mechanisms of sophocarpine as a potential antiarrhythmic agent

To examine the electrophysiological effects of sophocarpine on action potentials (AP) and ionic currents of cardiac myocytes and to compare some of these effects with those of amiodarone. Langendorff perfusion set-up was used in isolated guinea pig heart, and responses to sophocarpine were monitored using electrocardiograph. Conventional microelectrode, voltage clamp technique and perforated patch were employed to record fast response AP (fAP), slow response AP (sAP) and ionic currents in guinea pig papillary muscle or rabbit sinus node cells. Tachyarrhythmia produced by isoprenaline (15 μmol/L) could be reversed by sophocarpine (300 μmol/L). Sophocarpine (10 μmol/L) decreased the amplitude by 4.0%, maximal depolarization velocity (V(max)) of the fAP by 24.4%, and Na(+) current (I(Na)) by 18.0%, while it prolonged the effective refractory period (ERP) by 21.1%. The same concentration of sophocarpine could also decrease the amplitude and V(max) of the sAP, by 26.8% and 25.7%, respectively, and attenuated the Ca(2+) current (I(CaL)) and the K(+) tail current substantially. Comparison of sophocarpine with amiodarone demonstrated that both prolonged the duration and the ERP of fAP and sAP, both decreased the amplitude and V(max) of the fAP and sAP, and both slowed the automatic heart rate. Sophocarpine could reverse isoprenaline-induced arrhythmia and inhibit I(Na), I(CaL), and I(Kr) currents. The electrophysiological effects of sophocarpine are similar to those of amiodarone, which might be regarded as a prospective antiarrhythmic agent.

Possible arrhythmiogenic mechanism produced by ibuprofen

The aim of the present study was to investigate the electrophysiological effect of ibuprofen on the cardiac action potentials (AP) and electrocardiograms (ECG), and to identify its arrhythmiogenic mechanism. The intracellular microelectrode recording technique was employed to record the fast- and slowresponse AP in guinea pig papillary muscles. The cardiac responses of ibuprofen were monitored by ECG, both in in vivo and in vitro studies. The ECG recording revealed that ibuprofen could induce arrhythmias, both in vitro and in vivo. Fatal ventricular fibrillations are readily produced in in vitro experiments by ibuprofen. Our results show that ibuprofen could dose dependently shorten the duration of AP and the effective refractory period (ERP), and it could also decrease the maximum depolarization velocity of phase 0 (V(max)) in both the fast- and slow-response AP. The duration of the QRS complex wave (QRS duration) in ECG was prolonged. Although the heart rate was depressed by ibuprofen, the corrected QT interval duration (QTc) decreased. Ibuprofen could inhibit cardiac Na+ and Ca2+ channels as it slows V(max) in both fast- and slowresponse AP. Furthermore, ibuprofen shortens the ERP and decreases the excitation propagation within the heart, which might provide a substrate for an arrhythmiogenic re-entry circuit. Taken together, we conclude that ibuprofen, when used improperly, may impose a potential hazard in inducing cardiac arrhythmias in patients with existing heart diseases.

The characteristics of action potential and nonselective cation current of cardiomyocytes in rabbit superior vena cava

As a special focus in initiating and maintaining atrial fibrillation (AF), cardiomyocytes in superior vena cava (SVC) have distinctive electrophysiological characters. In this study, we found that comparing with the right atrial (RA) cardiomyocytes, the SVC cardiomyocytes had longer APD90 at the different basic cycle lengths; the conduction block could be observed on both RA and SVC cardiomyocytes. A few of SVC cardiomyocytes showed slow response action potentials with automatic activity and some others showed early after depolarization (EAD) spontaneously. Further more, we found that there are nonselective cation current (INs) in both SVC and RA cardiomyocytes. The peak density of I Ns in SVC cardiomyocytes was smaller than that in RA cardiomyocytes. Removal of extracellular divalent cation and glucose could increase INs in SVC cardiomyocytes. The agonist or the antagonist of INs may increase or decrease APD. To sum up, some SVC cardiomyocytes possess the ability of spontaneous activity; the difference of transmembrane action potentials between SVC and RA cardiomyocytes is partly because of the different density of INs between them; the agonist or the antagonist of INs can increase or decrease APD leading to the enhancement or reduction of EAD genesis in SVC cardiomyocytes. INs in rabbit myocytes is fairly similar to TRPC3 current in electrophysiological property, which might play an important role in the mechanisms of AF.

Calcium transient dynamics and the mechanisms of ventricular vulnerability to single premature electrical stimulation in Langendorff-perfused rabbit ventricles

Single strong premature electrical stimulation (S(2)) may induce figure-eight reentry. We hypothesize that Ca current-mediated slow-response action potentials (APs) play a key role in the propagation in the central common pathway (CCP) of the reentry. We simultaneously mapped optical membrane potential (V(m)) and intracellular Ca (Ca(i)) transients in isolated Langendorff-perfused rabbit ventricles. Baseline pacing (S(1)) and a cathodal S(2) (40-80 mA) were given at different epicardial sites with a coupling interval of 135 +/- 20 ms. In all 6 hearts, S(2) induced graded responses around the S(2) site. These graded responses propagated locally toward the S(1) site and initiated fast APs from recovered tissues. The wavefront then circled around the refractory tissue near the site of S(2). At the side of S(2) opposite to the S(1), the graded responses prolonged AP duration while the Ca(i) continued to decline, resulting in a Ca(i) sinkhole (an area of low Ca(i)). The Ca(i) in the sinkhole then spontaneously increased, followed by a slow V(m) depolarization with a take-off potential of -40 +/- 3.9 mV, which was confirmed with microelectrode recordings in 3 hearts. These slow-response APs then propagated through CCP to complete a figure-eight reentry. We conclude that a strong premature stimulus can induce a Ca(i) sinkhole at the entrance of the CCP. Spontaneous Ca(i) elevation in the Ca(i) sinkhole precedes the V(m) depolarization, leading to Ca current-mediated slow propagation in the CCP. The slow propagation allows more time for tissues at the other side of CCP to recover and be excited to complete figure-eight reentry.

Electromechanical properties of Purkinje fiber strands isolated from human ventricular endocardium

Background Abnormalities in the regulation of intracellular Ca 2+ were observed in cardiac cells obtained from failing human hearts. However, the electromechanical properties and pharmacologic responses of human ventricular Purkinje fibers have not been well characterized. Methods Strands of free-running Purkinje fibers and/or trabecular muscle fibers with a diameter of around 1.5 mm were removed from the endocardial surface of ventricles obtained from 16 transplant recipient hearts. Action potential (AP) was detected by conventional microelectrode techniques and twitch force by a force-displacement transducer. Results The human Purkinje fiber strands as revealed by histologic examination were composed of Purkinje cells and the surrounding ventricular muscle cells. In well-polarized Purkinje fibers (mean ± SE of maximum diastolic potential [MDP] = −85 ± 1 mV) showing fast-response AP (Phase 0 V̇ max >100 V/sec), the cardiotonic agents isoproterenol and strophanthidin (1 to 2 μmol/liter) accelerated the slope of diastolic depolarization and induced delayed afterdepolarization but not spontaneous APs. Steady-state contraction and the post-rest potentiation of contraction (PRPC) were similar in both Purkinje fibers and ventricular muscles, but inotropic agents induced tachyarrhythmia only in Purkinje fibers. In partially depolarized Purkinje fibers (MDP <−70 mV) with slow-response AP, isoproterenol and/or strophanthidin readily induced automatic and triggered rhythms. Conclusions Accumulation of excessive cytosolic Ca 2+ in the presence of cardiotonic agents could lead to tachyarrhythmias in Purkinje fibers, but rarely in ventricular muscles of failing human hearts.

Electrical interactions between a rabbit atrial cell and a nodal cell model.

Atrial activation involves interactions between cells with automaticity and slow-response action potentials with cells that are intrinsically quiescent with fast-response action potentials. Understanding normal and abnormal atrial activity requires an understanding of this process. We studied interactions of a cell with spontaneous activity, represented by a "real-time" simulation of a model of the rabbit sinoatrial (SA) node cell, simultaneously being electrically coupled via our "coupling clamp" circuit to a real, isolated atrial myocyte with variations in coupling conductance (Gc) or stimulus frequency. The atrial cells were able to be driven at a regular rate by a single SA node model (SAN model) cell. Critical Gc for entrainment of the SAN model cell to a nonstimulated atrial cell was 0.55 +/- 0.05 nS (n = 7), and the critical Gc that allowed entrainment when the atrial cell was directly paced at a basic cycle length of 300 ms was 0.32 +/- 0.01 nS (n = 7). For each atrial cell we found periodic phenomena of synchronization other than 1:1 entrainment when Gc was between 0.1 and 0.3 nS, below the value required for frequency entrainment, when the atrial cell was directly driven at a basic cycle length of either 300 or 600 ms. In conclusion, the high input resistance of the atrial cells allows successful entrainment of nodal and atrial cells at low values of Gc, but further uncoupling produces arrhythmic interactions.

Changes in electrophysiological and mechanical responses of the rat papillary muscle to α- and β-agonist in streptozotocin-induced diabetes

To clarify the changes occurring in diabetic animals in the responsiveness of the myocardium to alpha 1- and beta-adrenoceptor agonists, we examined both alpha- and beta-adrenoceptor-mediated electrophysiological and mechanical responses in the depolarized right ventricular papillary muscle of streptozotocin (STZ) induced diabetic rats and age-matched controls. Both methoxamine (10(-7)-10(-4) M) and isoproterenol (10(-9)-10(-6) M) enhanced the slow response action potential in a concentration-department manner. The amplitude and the APD50 (time required for 50% repolarization) of the methoxamine-induced slow response action potential were both markedly increased in STZ-induced diabetic rats in comparison with control rats, whereas those of the isoproterenol-induced slow response were significantly decreased. The methoxamine-induced contraction in depolarized muscle was slightly but not significantly increased in STZ-induced diabetic rats, whereas the isoproterenol-induced contractile response was significantly attenuated. The maximum number of binding sites (Bmax) for [3H]dihydroalprenolol and for [3H]prazosin were both significantly decreased in diabetic rats, compared with age-matched control rats, without any change in the affinity constants. The slow response action potential induced by methoxamine but not isoproterenol was attenuated by IAP (islet-activating factor) treatment (50 micrograms/kg, i.v. for 3 days). These results suggest that an alpha-adrenoceptor-mediated electrophysiological response is unmasked when the beta-adrenoceptor-mediated response is desensitized in the papillary muscle of STZ-induced diabetic rats.

Reversibility of Electrophysiological Abnormalities in Subacute Ischemia

Twenty-four hours after occlusion of the left anterior descending coronary artery in the dog, ventricular tachycardia is the predominant rhythm. At this time, records of transmembrane potentials from the subendocardial Purkinje fibers adjacent to the infarct show a low maximum diastolic potential, prominent phase 4 depolarization, and slow response action potentials. Exposure of the fibers to pinacidil, 25-100 microM, increases resting potential to the estimated value of EK, abolishes the phase 4 depolarization, and restores action potential amplitude and Vmax toward normal. Perfusion of the bed of the occluded coronary artery with Tyrode's solution prior to isolation of the subendocardial tissues results in similar normalization of transmembrane potentials. These findings indicate: (a) that the major cause of the abnormal transmembrane potentials of the subendocardial tissues is the loss of resting potential; and (b) that abnormalities of the transmembrane potentials are caused by some substance that can be washed out by perfusion and not by a direct effect of ischemia.

Myocardial action potential prolongation by calcium channel activation under calcium-free EGTA condition in guinea pigs and rats

1. 1. Prolongation of action potentials upon the addition of isoproterenol or dbcAMP under Ca-free EGTA condition were observed in isolated myocardial preparations from both the guinea pig and the rat, whose action potential configuration greatly differ. The degree of prolongation was greater in the rat than in the guinea pig. 2. 2. The prolongation of the action potential was rapidly reversed upon the addition of calcium ion and was dose-dependently suppressed by the addition of calcium antagonists. The sensitivity to nicardipine of this action potential was tenfold higher than of the so-called slow response action potentials. The duration of the prolonged action potential was dependent on the external sodium concentration, but was not affected by tetrodotoxin. 3. 3. Thus, it was demonstrated in intact myocardia that sodium ion may persistently pass through the calcium channel to prolong the action potential when it is activated under the condition where the calcium-mediated inactivation of calcium channels is removed. 4. 4. Contribution of calcium-mediated inactivation of calcium channels to the repolarization of normal myocardium may be larger in the rat than in the guinea pig.

Depressant Effects of Prostacyclin in Human Atrial Fibers and Cardiomyocytes.

The aim of this study was to characterize the electropharmacological effects of prostacyclin (PGI(2)) in human atrial fibers and cardiomyocytes. Atrial tissues obtained from the hearts of 28 patients undergoing corrective cardiac surgery were used. Transmembrane action potentials were recorded using a conventional microelectrode technique, and twitch force by a transducer. Effects of PGI(2) (1 nM-10 &mgr;M) on action potential characteristics and contraction of atrial fibers were evaluated in normal [K](o) (4 mM) and high [K](o) (27 mM) in the absence and presence of cardiotonic agents. In addition, atrial and ventricular myocytes were isolated enzymatically from atrial tissues and hearts of 4 patients undergoing cardiac transplant. The effects of PGI(2) on Na- and Ca-dependent inward currents (I(Na) and I(Ca)) of cardiomyocytes were tested. In 9 human atrial fibers showing fast-response action potentials (mean dV/dt(max) = 101 +/- 15 Vs(-1)) in 4 mM [K](o), PGI(2) did not influence dV/dt(max) of phase 0 depolarization even at 1 &mgr;M. However, at a concentration as low as 10 nM, PGI(2) depressed spontaneous rhythms or slow-response action potentials in high-K-depolarized fibers. PGI(2) also depressed delayed afterdepolarizations and aftercontractions induced by cardiotonic agents. In isolated cardiomyocytes, PGI(2) reduced I(Ca) but not I(Na). The present findings show that, in human atrial fibers and cardiomyocytes, PGI(2) induces greater depressant effects on the slow-response action potential, I(Ca) and triggered activity than on the fast-response action potential. It is suggested that PGI(2) may act through a selective reduction of transmembrane Ca influx. Copyright 1994 S. Karger AG, Basel

Inhibitory Effects of Tiamulin on Contractile and Electrical Responses in Isolated Thoracic Aorta and Cardiac Muscle of Guinea-pigs

The inhibitory effect of tiamulin, an antibiotic produced by Pleurotus mutilis, on contractile and electrical responses in isolated thoracic aorta and cardiac muscle of guinea-pigs was studied. In the thoracic aorta, tiamulin with an IC50 of 9.7 x 10(-6) M inhibited sustained contractions induced by isosmotically added 60 mM KCl. The inhibitory effect of tiamulin on a Ca(2+)-induced contraction in a depolarized muscle was competitively antagonized by raising external Ca2+ concentration. Bay K 8644 (10(-7) M) antagonized tiamulin's inhibition of the Ca(2+)-induced contraction. Tiamulin (2 x 10(-5) M) decreased the elevated cytoplasmic Ca2+ level measured by the fura 2 AM method in the depolarized muscle. In high K(+)-isoprenaline-treated left atria, tiamulin (2 x 10(-5)-2 x 10(-4) M) produced negative inotropic effects. On the other hand in the membrane action potential of papillary muscles, tiamulin (2 x 10(-6)-2 x 10(-4) M) produced decreases in action potential and durations and 2 x 10(-4) M tiamulin depressed the slow response action potential in depolarized muscles. Tiamulin produced prolongations of the PR interval in ECG, negative chrono- and inotropic effects, and an increase in perfusion flow in guinea-pig isolated and perfused hearts. These effects of tiamulin on the aorta or cardiac muscle were similar to those of verapamil and nifedipine. These results suggest that both the inhibitory action of tiamulin on the high K(+)-induced contraction in the aorta and the negative inotropic effect of tiamulin on the cardiac muscle are due to an inhibition of Ca2+ entry through the voltage-dependent Ca2+ channels of cells of both these muscles.

Ionic mechanisms responsible for the antiarrhythmic action of dehydroevodiamine in guinea‐pig isolated cardiomyocytes

1. Dehydroevodiamine alkaloid (DeHE), an active ingredient of a Chinese herbal medicine Wu-Chu-Yu (Evodiae frutus), has been shown to decrease aterial blood pressure in experimental animals and prolong action potential duration in cardiac cells. The aim of the present study was to explore the ionic basis of its possible antiarrhythmic effects. 2. Guinea-pig atrial and ventricular myocytes were isolated enzymatically and the ionic currents were recorded under whole-cell patch-clamp with single suction pipettes. 3. DeHE at a concentration of 0.1 microM inhibited reversibly the time-dependent outward K current (delayed rectifier, Ik) and the Na-dependent inward current (INa). 4. In low-K (1 mM) and high-Ca (9 mM) solution, DeHE also depressed the delayed afterdepolarizations (DAD) and the transient inward current (Iti) induced by 2 microM strophanthidin. On the other hand, DeHE occasionally induced early afterdepolarizations and slow response action potentials at a depolarized level. 5. At higher concentrations (1 microM and above), the L-type Ca current (ICa,L) was moderately inhibited. 6. The present findings indicate that DeHE may depress triggered arrhythmias in Ca-overloaded guinea-pig cardiac myocytes through its inhibitory actions on INa, Iti and, to a smaller extent, ICa. DeHE may also exert class III antiarrhythmic effect through a reduction of outward K currents (Ik) across the sarcolemma.

Effects of Ritanserin on Transmembrane Action Potentials in Canine Purkinje Fibers

Ritanserin has been reported to be a potential antiarrhythmic. We studied the cellular electrophysiologic effects of ritanserin in canine Purkinje fibers. Ritanserin produced significant depressant effects on transmembrane action potentials elicited in canine Purkinje fibers. At concentrations of 10 and 40 mg/liter, ritanserin decreased Vmax (the upstroke velocity) of action potential in a dose-dependent fashion and shortened the duration of fast response action potential. These concentrations of ritanserin also reduced the amplitude and duration of the slow response action potentials induced in Purkinje fibers treated with isoproterenol (10(-5) M) and high K+ (22 mM). These in vitro results suggest that the cellular electrophysiologic actions of ritanserin may be due to its direct actions on cardiac sodium and calcium channels, which, in turn, may account for its antiarrhythmic effects.

Cardiac Electrophysiologic Effects of 9-Deoxydoxorubicin

Electrophysiology of 9-Deoxydoxorubicin.Introduction: The purpose of this investigation was to use standard microelectrode techniques to study the actions of the anthracycline antibiotic, 9-deoxydoxorubicin (9-DOD), on cellular electrophysiologic properties of canine Purkinje fibers and on ouabain-induced ventricular tachycardia (VT) in intact dogs. Methods and Results: 9-DOD, 1-5 μM, suppressed delayed afterdepolarizations and prolonged repolarization and the effective refractory period in Purkinje fibers. It had no effect on maximum diastolic potential, Vmax of phase 0, or action potential overshoot through a 10 μM concentration. Although 9-DOD did augment early afterdepolarizations (EAD) induced by cesium, it did not induce EAD. In six of eight intact dogs with ouabain-induced VT, 9-DOD, 0.32-1.28 mg/m2 IV, brought conversion to sinus or junctional rhythm. In its cellular and intact animal antiarrhythmic actions, 9-DOD is about 50 times more potent than the parent compound, doxorubicin. Like doxorubicin, it is highly selective for delayed afterdepolarization-induced rhythms, suppressing these at concentrations lower than those required to reduce the rate of automatic rhythms. Moreover, it has a greater Class III action than doxorubicin and prolongs the duration of normal and calcium-induced (slow response) action potentials. Hence, this subtle variation on the doxorubicin molecule adds greatly to the antiarrhythmic action of the drug. Conclusions: Although useful as an investigative tool, clinical development of 9-DOD as an antiarrhythmic is not possible because the antitumor activity of the parent compound, which results in lipid peroxidation and cardiotoxicity, persists.

Investigation of Electrophysiologic Mechanisms for the Antiarrhythmic Actions of R 56865 in Cardiac Glycoside Toxicity

R 56865 is an experimental compound that has been shown to ameliorate the effects of cardiac glycoside toxicity and myocardial ischemia. We evaluated the direct electrophysiological effects of R 56865 and its effects on the electrophysiological sequelae of ouabain toxicity in vivo and in vitro. In normal anesthetized dogs, R 56865 alone at doses of 0.04 to 0.16 mg/kg i.v. had no effect on atrial, AV nodal, or ventricular conduction times and refractoriness, but at doses of 0.64 to 2.5 mg/kg it tended to increase these parameters. In ouabain-pretreated dogs, R 56865 (0.08 to 0.32 mg/kg i.v.) dose-relatedly reduced ouabain-induced ventricular arrhythmias. In normal isolated canine Purkinje fibers, R 56865 (1-10 microM) reduced Vmax at short pacing cycle lengths and decreased the action potential duration at concentrations of 0.1 to 10 microM. R 56865 at concentrations through 10 microM had no significant effect on normal action potentials of canine ventricular muscle and slow response action potentials in guinea pig papillary muscles. In Purkinje fibers exposed to toxic concentrations of ouabain, R 56865 (1 microM) reduced the delayed after depolarization (DAD) amplitude and inhibited triggered activity. R 56865 had no effect on normal automaticity in canine Purkinje fibers at 1 microM, but 10 microM significantly slowed it. R 56865 at 10 microM did not affect isoproterenol-enhanced automaticity and only slightly reduced barium-induced abnormal automaticity that occurred at reduced membrane potentials. These results demonstrate that R 56865 reverses cardiac glycoside-induced arrhythmias in anesthetized dogs at doses that do not significantly affect conduction or refractoriness. Suppression of ouabain-induced DAD and triggered activity in isolated Purkinje fibers, at concentrations not affecting normal or abnormal automaticity, may be the mechanism of R 56865's antiarrhythmic actions in vivo. Suppression of DAD does not appear to be associated with blockade of voltage-dependent calcium channels, but R 56865 may prevent intracellular sodium overload by limiting excessive sodium entry during ouabain intoxication.

Depressant effect of adenosine in isolated human and canine atrial fibres

STUDY OBJECTIVE0--he aim was to explore the cellular mechanisms responsible for the depressant effects of adenosine in human atrial tissues. Conventional microelectrode technique was used to record transmembrane action potential of human atrial tissues obtained at cardiac surgery. Effects of adenosine (0.1-100 microM) on action potential characteristics and contractile force of human atrial fibres in the absence and presence of an adenosine receptor antagonist (DPSPX) were evaluated. Results were then compared with those obtained from the canine atrial tissues. Atrial tissues obtained from hearts of 25 patients undergoing corrective cardiac surgery were used. Seven mongrel dogs were anaesthetised and strands of atrial muscle were removed and used for comparison. In human atrial fibres showing fast response action potential (mean dV/dtmax around 100 V.s-1) in normal [K]o (4 mM) Tyrode solution, adenosine (1 nM-10 microM) did not induce consistent effects on the action potential characteristics. When the fibres were depolarised in high [K]o (27 mM) or in atrial fibres showing slow response action potential (dV/dtmax less than 50 V.s-1), however, 10 microM adenosine reduced the upstroke velocity and the amplitude of action potential significantly and markedly depressed the contractile force. In atrial fibres spontaneously active in normal Tyrode solution (maximum diastolic potential around -50 mV), adenosine inhibited rate of spontaneous discharge in a concentration dependent manner. Delayed afterdepolarisation and aftercontraction induced by adrenaline or/and high [Ca]o were also suppressed. The depressant effects of adenosine were blocked after pretreatment with 50 microM DPSPX, a specific antagonist for adenosine receptor. These findings show that adenosine may abolish abnormal automatic rhythms and triggered activity in human atria.

Influence of N‐ethylmaleimide on action potential and force of contraction of guinea‐pig papillary muscles

1. Standard microelectrode techniques were used to investigate the influence of N-ethylmaleimide on the action potential, slow response action potential and force of contraction of guinea-pig papillary muscles. 2. N-ethylmaleimide, 3 x 10(-5) to 10(-4) mol l-1, concentration-dependently increased the force of contraction. The positive inotropic effect developed quickly and, with the largest drug concentration, was followed by a progressive decline of the contractile force. The action potential duration was progressively shortened by N-ethylmaleimide. 3. The effects of N-ethylmaleimide were not prevented in the presence of tetrodotoxin 3 x 10(-8) mol l-1 and propranolol 4 x 10(-6) mol l-1 or by a reduction of the Na(+)-concentration to 70 mmol l-1. 4. Verapamil, 10(-6) mol l-1, reduced the positive inotropic, but not the action potential shortening effect of N-ethylmaleimide. 5. In K(+)-depolarized muscles in the presence of propranolol and tetrodotoxin, N-ethylmaleimide 10(-4) mol l-1 increased the maximum depolarization velocity and the duration of the slow response action potential. The latter effect was transient and was followed by a progressive reduction of the action potential duration. 6. The most likely explanation for the action potential shortening effect of N-ethylmaleimide seems to be an increase of an outward potassium current while the transient inotropic effect of the drug may be caused, at least in part, by an increase of the slow inward calcium current.