piperidines and terikalant

The present article presents an overview of the pharmacologic profile of the benzopyran derivative RP 58866, a racemic mixture, and of RP 62719 (terikalant), its active enantiomer. In normal cardiac tissues studied in vitro, both drugs dose-dependently prolonged the atrial and ventricular action potential but affected neither the upstroke of the action potential nor the diastolic potential. Patch-clamp experiments demonstrated that the prolongation of the action potential induced by the drugs is due to a specific blockade of the inward rectifier K+ current. In vivo, intravenous administration to anesthetized dogs of low doses of RP 62719 consistently induced bradycardia and prolonged the atrial, nodal, and ventricular refractory periods, but did not affect the conduction velocity. Because of these properties, RP 58866 and RP 62719 exert potent antiarrhythmic and antifibrillatory actions both at the atrial and ventricular levels in various experimental models of arrhythmia. Our results demonstrate that RP 58866 and RP 62719 are K(+)-channel blockers acting as pure class III antiarrhythmic drugs.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzopyrans; Chromans; Chromones; Electrophysiology; Humans; Models, Cardiovascular; Piperidines; Potassium Channels

The cellular mechanism of action of terikalant, an investigational antiarrhythmic agent known to block the inward rectifier and other potassium currents, has not yet been fully clarified. The aim of the present study was therefore to analyse the in vitro electrophysiological effects of terikalant in canine isolated ventricular muscle and Purkinje fibers by applying the standard microelectrode technique. The effects of terikalant on the duration of action potential at a stimulation cycle length of 1000 ms and on the maximum upstroke velocity of the action potential in right ventricular papillary muscle were examined at 1, 2.5, 10, and 20 microM concentrations. Terikalant significantly prolonged the action potential duration measured both at 50% and 90% of repolarization in concentration-dependent manner. The maximum upstroke velocity of the action potential was unaffected at 1 and 2.5 microM concentrations. However, this parameter was significantly reduced at 10 and 20 microM concentrations of terikalant. In Purkinje fibers terikalant (2.5 microM) also produced a marked action potential lengthening effect. Frequency dependence (cycle length of 300-5000 ms) of the action potential lengthening effect of terikalant was studied at a concentration of 2.5 microM. Prolongation of the duration of action potential occurred in a reverse frequency-dependent manner both in papillary muscle and Purkinje fibers, with a more pronounced frequency-dependence observed in Purkinje fibers. The onset kinetics of the terikalant (10 microM) induced block of the maximum upstroke velocity of the action potential was rapid (0.6+/-0.1 beat(-1), n=6) like that of Class I/B antiarrhythmics, and the offset (recovery) kinetics of the drug (2956+/-696 ms, n=6) best resembled that of Class I/A antiarrhythmic drugs. It was concluded that terikalant, unlike pure Class III antiarrhythmic drugs, has combined mode of action by lengthening repolarization and blocking the inward sodium current in a use-dependent manner.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Chromans; Dogs; Electrophysiology; Female; Heart; In Vitro Techniques; Kinetics; Male; Papillary Muscles; Piperidines; Purkinje Fibers

Contribution of inward rectifier K(+) currents (I(K1)) and ATP-sensitive K(+) currents (I(KATP)) to membrane potential changes of ventricular myocytes appearing during hypotonic challenge is unclear. We used here the whole cell patch clamp technique, voltage and current clamp modes, to record membrane potentials and ionic currents in isolated guinea pig ventricular myocytes under isotonic or hypotonic perfusion. The difference in osmolarity between iso- and hypotonic solutions was about 100 mOsm. Exposure to hypotonic solution for 60 s induced initial prolongation of action potential duration at 90% of repolarization (APD(90)) (from 176 +/- 10 to 189 +/- 11 ms, P<0.05, n = 13). Further perfusion for the next 300 s shorthened APD(90) to 135 +/- 9 ms (P<0.01, in comparison with control values, n = 13) and depolarized resting potential from -79.2 +/- 1.5 to -75.0 +/- 0.9 mV, (P<0.05, n = 13). Neither pretreatment with a blocker of I(K1) channels, terikalant at 10 microM, nor with a blocker of I(KATP) channels, glibenclamide at 1 microM, prevented the above-mentioned changes in membrane potential induced by hypotonic challenge when a pipette solution containing 5 mM ATP was used. Also, glibenclamide and terikalant did not affect the hypotonic-sensitive current, obtained by ramp or voltage-step protocols, respectively. Additionally, the current-voltage relationship (I-V curve) of the whole cell hypotonic-sensitive current shifted from an isotonic I-V curve in a parallel way. Our results indicate that I(K1) and I(KATP) do not participate in membrane potential changes induced by hypotonic solution at least in the guinea pig ventricular myocytes with sufficient intracellular ATP.

Topics: Animals; Chromans; Female; Glyburide; Guinea Pigs; Heart Ventricles; Hypotonic Solutions; Male; Membrane Potentials; Myocytes, Cardiac; Piperidines; Potassium Channels; Ventricular Function

To clarify mechanisms that the antiarrhythmic effects of matrine and berbamine are weaker than those of amiodarone and RP58866.. Experimental arrhythmic models were induced by aconitine, coronary artery ligation and electric stimulation in rats and rabbits. Whole-cell patch-clamp techniques were used to record IK1, IKr, IKs and Ito.. Matrine and berbamine significantly increased the dose of aconitine for induction of ventricular premature and ventricular tachycardia in rats, decreased the number of arrhythmias induced by coronary artery ligation in rats and increased ventricular fibrillation threshold (VFT) induced by electric stimulation in rabbits, but the anti-arrhythmic potency of matrine and berbamine was lower than that of amiodarone and RP58866. The inhibitory actions of matrine and berbamine on IK1, IKr, IKs, Ito were lower than those of amiodarone and RP58866. The IC50 of matrine for IK1, IKr, IKs, Ito were (46 +/- 3), (32.9 +/- 1.2), (37 +/- 8) and (7.6 +/- 0.5) mol x L(-1), respectively. The IC50 of amiodarone for IK1, IKr, IKs, Ito were (21 +/- 5) , (3.7 +/- 0.7), (5.9 +/- 0.9) and (5.9 +/- 0.6) mol x L(-1), respectively.. The inhibitory actions of matrine and berbamine on IK1, IKr, IKs, Ito were lower than those of amiodarone and RP58866, which might be the reason that the antiarrhythmic effects of matrine and berbamine were weaker than those of amiodarone and RP58866.

Topics: Aconitine; Alkaloids; Amiodarone; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzylisoquinolines; Chromans; Dogs; Female; Guinea Pigs; Male; Matrines; Piperidines; Potassium Channels; Quinolizines; Rabbits; Rats

The proarrhythmic activities of the selective I(Kr) blocker erythromycin and the less selective K(+) channel blockers, terikalant and clofilium, have been compared in an alpha(1)-adrenoceptor-stimulated, anaesthetized rabbit model. Terikalant (2.5, 7.5 and 25 nmol kg(-1) min(-1); n = 10), erythromycin (133, 400 and 1330 nmol kg(-1) min(-1); n = 8), clofilium (20, 60 and 200 nmol kg(-1) min(-1); n=10) or vehicle (n = 8) was infused intravenously over 19 min and there was a 15-min interval between each infusion [corrected]. QT and QTc intervals, and epicardial monophasic action potential duration were prolonged significantly (and to a similar extent) only by clofilium and terikalant. The total incidences of torsade de pointes were 60%*, 20%, 0% and 0% in clofilium-, terikalant-, erythromycin- and vehicle-treated animals, respectively (*P < 0.05 compared to vehicle control). In conclusion, terikalant exerted mild proarrhythmic activity though it prolonged repolarisation markedly. Despite being given in high doses, erythromycin neither prolonged repolarisation nor induced proarrhythmia.

Topics: Action Potentials; Adrenergic alpha-1 Receptor Agonists; Animals; Anti-Arrhythmia Agents; Anti-Bacterial Agents; Arrhythmias, Cardiac; Blood Gas Analysis; Blood Pressure; Body Temperature; Chromans; Electrocardiography; Erythromycin; Heart Rate; Male; Piperidines; Quaternary Ammonium Compounds; Rabbits; Torsades de Pointes

The area of vulnerability (AOV) to ventricular fibrillation (VF) induction by high-voltage shocks has been proposed as a measure of vulnerability to VF. Biphasic shocks spanning the T wave and ranging between 50 V and the upper limit of vulnerability (ULV) to VF were delivered before and after terikalant (1 mg/kg) and barium (1.1 mg/kg load followed by 0.05-0.10 mg/kg/min maintenance) or vehicle in dogs. The AOV decreased by 34% and 28% (p < 0.01) after terikalant and barium (n = 8 dogs each), respectively. Mean ULV, defibrillation threshold (DFT), and ventricular vulnerability period (VVP) decreased by 16%, 23%, and 31% (p < 0.01), respectively, after terikalant, and by 25%, 17% (p < 0.01), and 13% (p = 0.08), respectively, after barium. Vehicle (n = 14) did not significantly alter any of these variables. The ULV was correlated with the DFT before and after terikalant (r = 0.78, p < 0.01) and barium (r = 0.83, p < 0.01). Potassium channel blockers of the current reduce the ability to induce VF; this effect may be related to the anti-fibrillatory action of class III anti-arrhythmic drugs and their ability to decrease DFT.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Barium Compounds; Chlorides; Chromans; Dogs; Electric Countershock; Electrocardiography; Female; Infusions, Intravenous; Male; Piperidines; Ventricular Fibrillation; Ventricular Function

Repercussions of cisapride-induced blocking effects on repolarisation of K(+) channels in open and inactivated states investigated in rabbit ventricular myocardium during rest and under stimulation were compared with effects of K(+)-blocking drugs (4-aminopyridine, dofetilide, terikalant). Major lengthening in the first postrest action potential indicates affinity for closed channels. Gradual lengthening during stimulation implies affinity for open channels. Four (control, add-in, steady-state, washout) 20-min rest periods were alternated with regular stimulation (0.5 Hz). Each drug was added during add-in and steady-state periods. Similarly to dofetilide (10 nM) and terikalant (0.3 microM), cisapride (1 microM) increasingly lengthened action potentials during stimulation, whereas 4-aminopyridine (1 mM) prolonged mostly the first postrest action potential. Our results indicate that cisapride induced use-dependent lengthening of repolarisation, compatible with an affinity for open K(+) channels. We also found that in isolated rabbit ventricular myocytes, cisapride (1-10 microM) decreased the inward rectifier K(+) current, an effect contributing to the proarrhythmic potential.

Topics: 4-Aminopyridine; Action Potentials; Animals; Anti-Arrhythmia Agents; Chromans; Cisapride; Dose-Response Relationship, Drug; Electric Stimulation; Heart Ventricles; In Vitro Techniques; Male; Phenethylamines; Piperidines; Rabbits; Sulfonamides; Time Factors; Ventricular Function

The maximal responses (E(max)s) of isolated rat gastric fundus strips to 300 n m porcine galanin (Gal) were decreased in a concentration-dependent manner by terikalant (RP 62719). EC(50)of the agent equalled 4.39 microm (2.35-8.22). On the contrary the action of 30 n m of carbachol were not affected by the modulator in concentrations up to 30 microm. It is concluded that potassium currents may contribute to the modulation of Gal myotropic activity in the gut.

Topics: Animals; Chromans; Dose-Response Relationship, Drug; Female; Galanin; Gastric Fundus; In Vitro Techniques; Male; Muscle Contraction; Piperidines; Potassium Channels; Rats; Rats, Wistar

RP58866 is a potent antiarrhythmic drug that maintains its antiarrhythmic properties during ischemia. Since interstitial concentrations of adenosine increase during ischemia, we examined the properties of the drug with respect to the muscarinic K+ current (IK(ACh)), with a main emphasis on the adenosine (Ado)-induced current (IK(Ado)). Using different Gi-coupled receptors (M2, A1, sphingolipid), we studied the effect of RP58866 in isolated guinea-pig atrial myocytes by the whole-cell voltage clamp technique. Application of 50 microM RP58866 resulted in complete inhibition of the muscarinic K+ current. Inhibition was observed during activation of IK(ACh) by each of the three receptors. IC50 was approximately 2.0 microM. GTP-gamma-S induced IK(ACh) was reduced by RP58866. The drug was active from the outside only, and its intracellular application via the patch pipet had no inhibitory effect. Despite the structural homologies between inward rectifying K+ channels, the adenosine triphosphate-sensitive K+ current (IK(ATP)) was not inhibited by the compound. It is concluded that muscarinic K+ current is inhibited by RP58866, an inhibition not limited to IK1, Ito, and IKr. High interstitial adenosine concentrations during ischemia are expected to increase the participation of IK(Ado) on repolarization. RP58866-induced inhibition of IK(Ado) would, therefore, be of particular relevance during ischemia. The high sensitivity of IK(Ado) to RP58866 may partially explain the unique properties of the drug toward arrhythmias developing in the ischemic myocardium.

Topics: Acetylcholine; Adenosine; Adenosine Triphosphate; Animals; Anti-Arrhythmia Agents; Chromans; Guanosine 5'-O-(3-Thiotriphosphate); Guinea Pigs; Heart Atria; In Vitro Techniques; Membrane Potentials; Muscarinic Antagonists; Myocardium; Patch-Clamp Techniques; Phosphorylcholine; Piperidines; Potassium; Receptor, Muscarinic M2; Receptors, Muscarinic; Sphingosine

The effect of RP62719 on the inward rectifier K(+) current (I(K1)),transient outward K(+) current (I(to)) and delayed outward K(+) current (I(K)) in isolated cardiac myocytes was determined using the whole cell patch clamp technique in guinea pig and dog. RP62719 decreased I(K1) with an inhibitory concentration 50 (IC(50) ) of 5.0+/-1.0 micromol/L at -100 mV in guinea pig ventricular cells. In dog ventricular myocytes, RP62719 inhibited Ito by 84+/-4.4% with an IC(50) of 1.2+/-0.51 micromol/L at +40 mV. In guinea pig ventricular cells, RP62719 decreased I(K): I(Kstep) by 50.0+/-8.3%%and I(Ktail) by 56.0+/-4.9% at +40 mV, respectively. RP62719 inhibited I(Kstep) with an IC(50) of 4.2+/-0.8 micromol/L and I(Ktail) with an IC(50) of 3.3+/-0.75 micromol/L. Thus it is suggested that the ionic mechanism of antiarrhymic effect by RP62719 may be due to its inhibition of I(K1),I(to) and I(K).

Topics: Animals; Anti-Arrhythmia Agents; Cell Separation; Chromans; Dogs; Guinea Pigs; Heart Ventricles; Inhibitory Concentration 50; Myocytes, Cardiac; Patch-Clamp Techniques; Piperidines; Potassium Channels; Potassium Channels, Inwardly Rectifying

1. The kinetics of shortening of action potential duration (APD) following an increase in pacing rate, from 2 to 3.3 Hz, was characterized in guinea-pig ventricular preparations. Terikalant (RP62719), an inhibitor of the inwardly rectifying K+ current (IK1), and dofetilide, a specific inhibitor of the rapidly activating delayed-rectifier current (IKr), were applied to determine the effect of inhibition of these ion currents on slow APD shortening. 2. Action potentials were recorded from isolated guinea-pig ventricular myocytes using the perforated-patch patch-clamp technique, and monophasic action potentials were recorded from Langendorff-perfused guinea-pig ventricles using a contact epicardial probe. 3. Under control conditions, after an increase in pacing rate, APD immediately decreased, and then shortened slowly with an exponential time course. In ventricular myocytes, the time constant of this exponential shortening was 28+/-4 s and the amount of slow shortening was 21.9+/-0.9 ms (n=8) for an increase in rate from 2 to 3.3 Hz. Similar values were observed in Langendorff-perfused ventricles. 4. Terikalant dose-dependently increased APD and the increase was enhanced by rapid pacing ('positive' rate-dependence). The drug dose-dependently decreased the time constant of shortening and amount of slow APD shortening. In contrast, dofetilide, an inhibitor of IKr, which shows 'reverse' rate-dependent APD widening, had no significant effect on the time constant or amount of slow shortening. 5. These observations suggest that IK1 plays a role in rate-dependent shortening of APD. The results appear to support the hypothesis that 'reverse' rate-dependent effects of IKr blockers are due to these drugs not affecting the ion current(s) mediating intrinsic rate-dependent slow shortening of APD.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Chromans; Dose-Response Relationship, Drug; Guinea Pigs; Heart Ventricles; Kinetics; Patch-Clamp Techniques; Phenethylamines; Piperidines; Potassium Channel Blockers; Potassium Channels; Sensitivity and Specificity; Sulfonamides; Time Factors; Ventricular Function

1. RP58866 possesses a unique electrophysiological property: highly effective against various types of arrhythmias including ventricular fibrillation in animal models, noticeably those occurring during ischaemia with depolarized membrane due to elevated extracellular K+ concentrations. To understand the potential ionic mechanisms, we performed detailed studies on the effects of RP58866 on the HERG channels expressed in Xenopus oocytes, which are believed to be important compositions of the rapid component of delayed rectifier K+ current in the hearts. 2. RP58866 significantly inhibited the HERG channels in a concentration-dependent manner, with approximately 50% decrease in the current amplitude at a concentration of 1 microM. RP58866 produced more pronounced inhibition with voltage protocols which favoured inactivation of the HERG channels. It caused substantial negative shift of the inactivation curves but did not alter the activation properties. The inhibition was considerably relieved by elevating [K+]o from 5 - 20 mM, which weakened the channel inactivation. More importantly, the potency was reduced by approximately 100 fold on the mutated HERG channels (S631A) in which the C-type inactivation was substantially weakened. 4. We conclude that blockade of the HERG channels by RP58866 is mainly associated with the binding of the drugs to the inactivated channels. This unique property of HERG blockade might explain some previously reported but unexplained observations: RP58866 maintains its efficacy in APD prolongation with depolarized membrane potential and in arrhythmias during ischaemia with manifested membrane depolarization.

Topics: Animals; Anti-Arrhythmia Agents; Chromans; Dose-Response Relationship, Drug; Heart; Humans; Membrane Potentials; Myocardium; Patch-Clamp Techniques; Piperidines; Potassium Channels; Xenopus

To determine effects of RP58866 on inward rectifier K+ current (IKl), transient outward K+ current (Ito) and delayed outward rectifier K+ current (IK) in isolated cardiac myocytes.. In isolated ventricular myocytes of guinea pig and dog, the effect of RP58866 on IKl, Ito, and IK were observed by the whole cell voltage-clamp technique.. RP58866 decreased IKl in a concentration-dependent manner, with an IC50 of (3.4 +/- 0.8) micromol.L-1 (n = 6) at -100 mV in guinea pig ventricular cells. In dog ventricular myocytes, RP58866 inhibited Ito with IC50 of (2.3 +/- 0.5) micromol.L-1 at +40 mV. In guinea pig ventricular cells, RP58866 at 100 micromol.L-1 decreased IK: IKstep by (58 +/- 13)% at +40 mV, and IKtail by (86 +/- 17)%, respectively. RP58866 inhibited IKstep with an IC50 of (7.5 +/- 0.8) micromol.L-1, and IKtail with an IC50 of (3.5 +/- 0.9) micromol.L-1. The envelope of tail analysis suggested that both IKr and IKs were inhibited.. RP58866 inhibits IKl, Ito, and IK in cardiac myocytes with a similar potency, and is not a specific IKl inhibitor.

Topics: Animals; Anti-Arrhythmia Agents; Cells, Cultured; Chromans; Dogs; Female; Guinea Pigs; Heart Ventricles; Inhibitory Concentration 50; Male; Myocardium; Patch-Clamp Techniques; Piperidines; Potassium Channels

Recent results have shown that the sulfonylurea receptor couples to several types of inward-rectifier potassium (KIR) channels, which suggests that sensitivity to blockade of a pathophysiological phenomenon such as ischemic preconditioning (PC) by glibenclamide may not be the result of this compound selectively blocking the ATP-sensitive potassium (KATP) channel. Therefore, to address this possibility, a role for myocardial KIR v KATP channels in ischemic PC was evaluated in the rat. To test this hypothesis, anesthetized, open-chest, male Wistar rats were assigned to one of seven experimental protocols. Animals assigned to group I (control) received 30 min of occlusion and 2 h of reperfusion. Ischemic PC was produced by 3x5-min occlusion and 2-h reperfusion periods (group II). Terikalant (TK), an inward-rectifier potassium channel blocker, was used to test the role of other K+ channels, most notably the KIR, in the cardioprotective effect of ischemic PC in the rat. TK was given at a dose of 3 mg/kg, i.v., 15 min before the prolonged occlusion and reperfusion periods (group III). In groups IV, V, and VI terikalant (1, 3 and 6 mg/kg, i.v.) was given 15 min before ischemic PC (lowTK+PC, medTK+PC and hiTK+PC, respectively). Group VII consisted of glibenclamide (0.3 mg/kg, i.v.) given 30 min prior to ischemic PC (GLY+PC). Infarct size (IS) as a percent of the area at risk (AAR) was measured using the histochemical stain, 2,3, 5-triphenyltetrazolium chloride. The average IS/AAR for the control was 49.9+/-2.1%. Ischemic PC markedly reduced infarct size (8.6+/-1. 8%; * P<0.05 v control). Terikalant (TK; 1, 3 and 6 mg/kg, i.v.) did not abolish the cardioprotective effect of ischemic PC at any dose (15.5+/-6.4, 16.4+/-5.2 and 8.8+/-1.6%, respectively; * P<0.05 v control). TK itself had no effect on infarct size. GLY completely abolished the cardioprotective effect of ischemic PC (48.2+/-6.4%). In addition, the high dose of TK significantly (P<0.05) increased the action potential duration at 50% repolarization from 48+/-3 to 64+/-4 ms and 30 microM of TK, a concentration which produced a 39% decrease in the inward-rectifier potassium channel current in isolated guinea-pig ventricular myocytes in the whole-cell patch-clamp mode did not block the increase in K ATP current produced by the KATP opener bimakalim (3 microM). These results demonstrate that although the myocardial KATP channel belongs to the K IR superfamily, the endogenous myocardial KIR channel does not m

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; ATP-Binding Cassette Transporters; Cells, Cultured; Chromans; Electrophysiology; Guinea Pigs; Heart; Hemodynamics; Ischemic Preconditioning, Myocardial; KATP Channels; Male; Myocardial Infarction; Piperidines; Potassium Channels; Potassium Channels, Inwardly Rectifying; Rats; Rats, Wistar

The aim of the present study was to compare the influence of terikalant, a blocker of inwardly rectifying K+ channels, galanin, a neuropeptide of 29 aminoacids with a complex mechanism of action including an activation of inwardly rectifying K+ channels and glibenclamide, a blocker of ATP-sensitive K+ channels, on simulated ischaemia-induced changes in contractility and response to phenylephrine of rat-isolated heart muscle. Experiments were performed on isolated rat heart papillary muscles. The following parameters were measured: force of contraction (Fc), velocity of contraction (+dF/dt) and velocity of relaxation (-dF/dt), time to peak contraction (ttp) and relaxation time at 10% of total amplitude of contraction (tt10). In the presence of 1 microM of galanin, as well as terikalant, simulated ischaemia caused a decrease in Fc, +dF/dt and -dF/dt, however, it significantly increased a drop in Fc and -dF/dt. After 60 min of reperfusion, all the measured parameters recovered completely except Fc in the galanin group. Terikalant, but not galanin, prevents the negative inotropic action of phenylephrine observed in the control group. On the other hand, addition of 1 microm of glibenclamide to the no-substrate solution prevented the simulated ischaemia-induced decrease in Fc, +dF/dt and -dF/dt. In this group phenylephrine did not cause the negative inotropic action. The above mentioned data reveal that pretreatment with the inhibitors of ATP-sensitive and inwardly rectifying K+ channels protect rat-isolated papillary muscle against ischaemia-induced disturbances in contractility.

Topics: Animals; Chromans; Female; Galanin; Glyburide; Male; Myocardial Contraction; Myocardial Ischemia; Papillary Muscles; Phenylephrine; Piperidines; Potassium Channels; Rats; Rats, Wistar

1. In the rat hepatic artery, the acetylcholine-induced relaxation mediated by endothelium-derived hyperpolarizing factor (EDHF) is abolished by a combination of apamin and charybdotoxin, inhibitors of small (SKCa) and large (BKCa) conductance calcium-sensitive potassium (K)-channels, respectively, but not by each toxin alone. The selective BKCa inhibitor iberiotoxin cannot replace charybdotoxin in this combination. Since delayed rectifier K-channels (KV) represent another target for charybdotoxin, we explored the possible involvement of KV in EDHF-mediated relaxation in this artery. 2. The KV inhibitors, agitoxin-2 (0.3 microM), kaliotoxin (0.3 microM), beta-dendrotoxin (0.3 microM), dofetilide (1 microM) and terikalant (10 microM), each in combination with apamin (0.3 microM) had no effect on the EDHF-mediated relaxation induced by acetylcholine in the presence of N omega-nitro-L-arginine (0.3 mM) and indomethacin (10 microM), inhibitors of nitric oxide (NO) synthase and cyclo-oxygenase, respectively (n = 2-3). Although the KV inhibitor margatoxin (0.3 microM) was also without effect (n = 5), the combination of margatoxin and apamin produced a small inhibition of the response (pEC50 and Emax values were 7.5 +/- 0.0 and 95 +/- 1% in the absence and 7.0 +/- 0.1 and 81 +/- 6% in the presence of margatoxin plus apamin, respectively; n = 6; P < 0.05). 3. Ciclazindol (10 microM) partially inhibited the EDHF-mediated relaxation by shifting the acetylcholine-concentration-response curve 12 fold to the right (n = 6; P < 0.05) and abolished the response when combined with apamin (0.3 microM; n = 6). This combination did not inhibit acetylcholine-induced relaxations mediated by endothelium-derived NO (n = 5). 4. A 4-aminopyridine-sensitive delayed rectifier current (IK(V)) was identified in freshly-isolated single smooth muscle cells from rat hepatic artery. None of the cells displayed a rapidly-activating and -inactivating A-type current. Neither charybdotoxin (0.3 microM; n = 3) nor ciclazindol (10 microM; n = 5), alone or in combination with apamin (0.3 microM; n = 4-5), had an effect on IK(V). A tenfold higher concentration of ciclazindol (0.1 mM, n = 4) markedly inhibited IK(V), but this effect was not increased in the additional presence of apamin (0.3 microM; n = 2). 5. By use of membranes prepared from rat brain cortex. [125I]-charybdotoxin binding was consistent with an interaction at a single site with a KD of approximately 25 pM. [125I]-charybdotoxin bi

Topics: 4-Aminopyridine; Acetylcholine; Animals; Anti-Arrhythmia Agents; Apamin; Binding, Competitive; Biological Factors; Cerebral Cortex; Charybdotoxin; Chromans; Cyclooxygenase Inhibitors; Drug Interactions; Female; Hepatic Artery; Indoles; Indomethacin; Muscle Relaxation; Muscle, Smooth, Vascular; Nitric Oxide Synthase; Nitroarginine; Patch-Clamp Techniques; Phenethylamines; Piperidines; Potassium Channel Blockers; Potassium Channels; Rats; Rats, Sprague-Dawley; Sulfonamides

We investigated the effects of terikalant, which blocks inward rectifier K+ current, on the sinus rate, atrial and ventricular contractile force in the isolated, blood-perfused right atrial and left ventricular preparations of dogs, and the effects of terikalant on the negative cardiac responses to acetylcholine, adenosine or pinacidil (an ATP-sensitive K+ channel opener) and on the positive cardiac responses to norepinephrine. Terikalant (1-100 nmol) decreased sinus rate and briefly and slightly increased atrial contractile force in isolated atria. However, terikalant did not increase ventricular contractile force in isolated ventricles. Neither propranolol nor atropine inhibited the positive inotropic and negative chronotropic responses to terikalant, respectively. Terikalant (10 or 30 nmol) did not significantly affect the negative cardiac responses to acetylcholine, adenosine nor pinacidil and the positive responses to norepinephrine. These results suggest that terikalant decreases sinus rate with a small changes in myocardial contractile force and does not affect the cardiac responses to muscarinic and adenosine receptor agonists, ATP-sensitive K+ channel openers nor beta-adrenoceptor agonists in the dog heart.

Topics: Acetylcholine; Adenosine; Adrenergic alpha-Agonists; Animals; Anti-Arrhythmia Agents; Atrial Function; Atropine; Chromans; Depression, Chemical; Dogs; Dose-Response Relationship, Drug; Drug Interactions; Female; Guanidines; Heart Rate; Male; Muscle Contraction; Norepinephrine; Pinacidil; Piperidines; Potassium Channels; Propranolol; Vasodilator Agents; Ventricular Function

The class III antiarrhythmic agent RP 58866 and its active enantiomer, terikalant, are reported to selectively block the inward rectifier K+ current, IK1. These drugs have demonstrated efficacy in animal models of cardiac arrhythmias, suggesting that block of IK1 may be a useful antiarrhythmic mechanism. The symmetrical action potential (AP)-prolonging and bradycardic effects of these drugs, however, are inconsistent with a sole effect on IK1.. We studied the effects of RP 58866 and terikalant on AP and outward K+ currents in guinea pig ventricular myocytes. RP 58866 and terikalant potently blocked the rapidly activating delayed rectifier K+ current, IKr, with IC50S of 22 and 31 nmol/L, respectively. Block of IK1 was approximately 250-fold less potent; IC50S were 8 and 6 mumol/L, respectively. No significant block of the slowly activating delayed rectifier, IK1, was observed at < or = 10 mumol/L. The phenotypical IKr currents in mouse AT-1 cells and Xenopus oocytes expressing HERG were also blocked 50% by 200 to 250 nmol/L RP 58866 or terikalant, providing further conclusive evidence for potent block of IKr. RP 58866 < or = 1 mumol/L and dofetilide increased AP duration symmetrically, consistent with selective block of IKr. Only higher concentrations (> or = 10 mumol/L) of RP 58866 slowed the rate of AP repolarization and decreased resting membrane potential, consistent with an additional but substantially less potent block of IK1.. These data demonstrate that RP 58866 and terikalant are potent blockers of IKr and prompt a reinterpretation of previous studies that assumed specific block of IK1 by these drugs.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Cation Transport Proteins; Chromans; DNA-Binding Proteins; Electric Conductivity; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Guinea Pigs; Heart; Mice; Myocardium; Oocytes; Osmolar Concentration; Patch-Clamp Techniques; Piperidines; Potassium; Potassium Channels; Potassium Channels, Voltage-Gated; Reaction Time; Stereoisomerism; Trans-Activators; Xenopus

The putative Class III antiarrhythmic benzopyran compound terikalant (RP62719) has been applied to isolated rat ventricular myocytes. The drug, at extracellular concentrations from 1 to 60 microM, reduced the inactivation time constant of transient outward potassium current (I(to)) with the time constant decreased to 50% of the control value with terikalant at 11 microM. The peak value of I(to) was also diminished with terikalant in excess of 2 microM and analysis of the integral of charge movement showed this quantity to be halved with a drug concentration near 5 microM. The voltage dependence for both activation and inactivation of I(to) were not changed by terikalant and the drug had no effect on the time course of recovery from inactivation. The inhibition of I(to) currents was increased with time during depolarizing pulses suggesting drug interactions with the open channel and analysis of the time dependence of drug block gave estimates of 3.7 x 10(6) M-1 s-1 and 64 s-1 for the respective blocking and unblocking rate constants. At concentrations greater than 5 microM, terikalant also altered the peak amplitudes of inward rectifier K+ currents (IK1) elicited with hyperpolarizing or depolarizing steps from holding potential and diminished IK1 resulting from voltage ramps. The results of this study represent the initial characterization of terikalant actions in a species possessing abundant I(to) in ventricular myocytes.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Calcium Channels; Cells, Cultured; Chromans; Heart; Heart Ventricles; Male; Myocardium; Piperidines; Potassium; Potassium Channels; Rats; Rats, Sprague-Dawley; Ventricular Function

We compared the effects of class I-IV antiarrhythmic agents on the ventricular fibrillation threshold (VFT) induced by electrical stimulation directly on the myocardium in anesthetized, open-chest guinea pigs. VFT was assessed by determining the intensity (mA) of electrical current required to induce ventricular fibrillation (VF) and is expressed as a percentage change of the baseline premedication value. The following antiarrhythmic agents or their solvent were administered intravenously (i.v.) to pentobarbital-anesthetized animals (n = 6-12 per group): class I antiarrhythmic agent encainide (1.5 mg/kg); class II antiarrhythmic agents atenolol (2.5 mg/kg), metoprolol (2.5 mg/kg), and nebivolol (2.5 mg/kg); class III antiarrhythmic agents dofetilide (0.08 mg/kg), terikalant (0.04 mg/kg), and DL-sotalolol (10 mg/kg); and class IV antiarrhythmic agent verapamil (0.16 mg/kg). The antiarrhythmic compounds or their solvents resulted in the following changes in the VFT at 15 min after treatment: saline control, 1 +/- 14% (mean +/- SEM) from its baseline value; 10% hydroxypropyl-beta-cyclodextrine (CD), 4 +/- 13%; encainide, 183 +/- 46% (p < 0.05 vs. saline); atenolol, 66 +/- 23% (p > 0.05 vs. saline); metoprolol, 89 +/- 25% (p > 0.05 vs. saline); nebivolol, 224 +/- 58% (p < 0.05 vs. 10% CD); DL-sotalol, 485 +/- 119% (p < 0.05 vs. saline); dofetilide, 357 +/- 69% (p < 0.05 vs. saline); terikalant, 487 +/- 183% (p < 0.05 vs. saline), and verapamil, -17 +/- 21% (p > 0.05 vs. saline). At the doses used, all compounds significantly reduced heart rate (HR).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenergic beta-Antagonists; Animals; Anti-Arrhythmia Agents; Atenolol; Benzopyrans; Chromans; Disease Models, Animal; Electric Stimulation; Electrocardiography; Encainide; Ethanolamines; Guinea Pigs; Heart; Heart Conduction System; Injections, Intravenous; Male; Metoprolol; Nebivolol; Phenethylamines; Piperidines; Sotalol; Sulfonamides; Ventricular Fibrillation; Verapamil

Saturation binding studies in guinea pig ventricular myocytes with 3H-dofetilide, a radioligand for the cardiac rapidly activating delayed rectifier K+ IKr channel, indicated specific high-affinity binding with a Kd of 83 nM and a Bmax of 0.18 pmol/mg cellular protein (1.36 x 10(6) sites/cell). Using displacement of high-affinity 3H-dofetilide binding as a measure of interaction with the IKr channel, potencies (Ki values) for binding to the IKr channel in guinea pig myocytes for six class III antiarrhythmic agents were characterized and compared to indices of functional electrophysiologic activity in isolated guinea pig papillary muscles [EC25 values, concentration required to increase effective refractory period (ERP) 25% above baseline]. Dofetilide, E-4031, sematilide, and d-sotalol, which have been characterized previously as selective IKr blockers, displayed good agreement between Ki values for displacement of 3H-dofetilide binding (47 +/- 7 nM, 38 +/- 8 nM, 12 +/- 5 microM, and approximately 100 microM, respectively) and EC25 values for increasing ERP in papillary muscles (45.0 nM, 76.9 nM, 20.2 microM and 63.5 microM, respectively). Ibutilide and RP58866, which have been reported to act via mechanisms other than IKr block, had Ki values for displacement of 3H-dofetilide binding (16 +/- 7 nM and 17 +/- 2 nM, respectively) that were approximately 10-fold lower than EC25 values for increasing ERP in papillary muscles (185.8 nM and 223.5 nM, respectively). The potent displacement of high-affinity 3H-dofetilide binding by ibutilide and RP58866 strongly suggest a role for interaction with IKr in their actions.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Arrhythmia Agents; Binding, Competitive; Chromans; Electrophysiology; Guinea Pigs; Heart Ventricles; Papillary Muscles; Phenethylamines; Piperidines; Potassium Channel Blockers; Potassium Channels; Procainamide; Pyridines; Sotalol; Structure-Activity Relationship; Sulfonamides; Tritium

RP58866 (1-[-2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethyl]-4- (3,4-dimethoxyphenyl)-piperidine), a specific blocker of the inwardly rectifying K+ current (IK1), is an extremely effective antiarrhythmic agent in rat, rabbit and primate (marmoset) isolated hearts in the settings of acute ischaemia and reperfusion (Rees and Curtis, 1993a). In the present study we further examined the mechanism of action of RP58866. We used the new dual coronary perfusion cannula that allows left and right sides of the heart to be perfused independently. The model has not previously been used for pharmacological investigations. Isolated rat hearts (n = 112) were randomized to one of four groups: perfusion of the left and right coronary beds with drug-free solution (n = 28), perfusion of the left coronary bed with 3 mumol/l RP58866 (n = 28), perfusion of the right coronary bed with 3 mumol/l RP58866 (n = 28) or perfusion of left and right coronary beds with 3 mumol/l RP58866 (n = 28). After 5 min perfusion, left regional ischaemia was induced and maintained for 30 min. Regional coronary flow was measured by in-line flowmeters. Epicardial monophasic action potentials (MAP) were recorded from the left (n = 15/group) and right (n = 13/group) perfusion regions using a suction electrode. Delivery of RP58866 to the uninvolved zone (right perfusion bed) suppressed ischaemia-induced ventricular fibrillation (VF): incidences (%) of VF were 80, 60, 33 (P < 0.05) and 27% (P < 0.05) in groups with no drug, with RP58866 delivered to the left bed, with RP58866 to the right bed and with RP58866 to the left plus right beds, respectively. Protection correlated with widening of MAP duration in the uninvolved zone which at 100% repolarization was 130.6 +/- 8.0, 129.1 +/- 7.0, 155.8 +/- 6.5 (P < 0.05 versus control) and 155.3 +/- 8.7 (P < 0.05) in the four groups, respectively after 5 min of ischaemia (just prior to the onset of ventricular arrhythmias). Corresponding values recorded from the involved zone (left perfusion bed) were 102.6 +/- 7.8, 131.2 +/- 11.1 (P < 0.05), 138.2 +/- 11.6 (P < 0.05) and 147.1 +/- 8.9 ms (P < 0.05), suggesting that RP58866 may gain access to ischaemic tissue via collatoral flow from the right perfusion bed. In order to suppress ischaemia-induced VF, it appears that the IK1 blocker RP58866 must widen APD in uninvolved tissue. APD widening activity restricted to the involved tissue alone is insufficient to prevent VF. However, caution should be exercised when using the

Topics: Animals; Anti-Arrhythmia Agents; Chromans; Coronary Circulation; Male; Myocardial Ischemia; Perfusion; Piperidines; Potassium; Potassium Channels; Rats; Rats, Wistar; Ventricular Fibrillation

Antiarrhythmic drugs, especially the Class I family, exert a negative inotropic effect on the myocardium which is particularly undesirable in patients with depressed left ventricular function. Therefore, research has been directed to the development of new, more specific molecules of the Class III family. The authors studies the mechanical effects of RP 62719 on guinea pig left ventricular papillary muscle. This new molecule is a pure Class III antiarrhythmic, known to lengthen the duration of the cardiac action potential by selectively blocking the potassium current iK1 (inward rectifier K+ current). The mechanical parameters were determined during the phases of contraction and relaxation under isotonic and isometric conditions. At 0.2 and 2 microM concentrations, RP 62719 improved cardiac contraction under both isotonic and isometric conditions with an increase of about 30% of Vmax (p < 0.001), the maximum unloaded shortening velocity delta 1 (p < 0.001), the peak isometric active force normalized per cross-sectional area [AF/S (p < 0.001)]. At these two concentrations, a positive lusitropic effect (improved relaxation) was demonstrated by an increase in negative peak of derivative per mm2-dF/s and maximum lengthening velocity VR max (p < 0.01). At higher concentrations (20 microM), the inotropic and lusitropic effects were less marked with a bell-shaped form of the dose-effect curve. This study indicates that RP 62719 has moderate but significant positive inotropic and lusitropic effects. These actions could provide significant therapeutic advantages especially in patients cardiac failure.

Topics: Animals; Anti-Arrhythmia Agents; Chromans; Guinea Pigs; Heart Failure; Humans; Isometric Contraction; Isotonic Contraction; Male; Myocardial Contraction; Papillary Muscles; Piperidines; Potassium Channels

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Chromans; Dogs; Guinea Pigs; Humans; Piperidines; Potassium Channels; Rabbits; Rats; Species Specificity

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Chromans; Ion Channel Gating; Piperidines; Potassium Channels; Rats

Simplified models of re-entry may help in our understanding of the electrophysiologic effects of class III drugs. In a model of re-entrant ventricular tachycardia around a ring of epicardium in Langendorff-perfused rabbit hearts, the electrophysiologic effects of class III antiarrhythmic drugs were studied and compared to those of class I drugs. Class III drugs were effective in terminating fast re-entrant ventricular tachycardias. Prolongation of the refractory period without affecting conduction velocity resulted in a closure of the excitable gap and collision of the head of the propagating impulse against its own tail of refractoriness. In slow ventricular tachycardias, despite a similar increase in refractory period, the excitable gap remained large enough to allow perpetuation of the tachycardia.

Topics: Animals; Anti-Arrhythmia Agents; Chromans; Dose-Response Relationship, Drug; Female; Heart Conduction System; Male; Perfusion; Piperidines; Rabbits; Tachycardia, Ventricular

The effectiveness of blockade of the inwardly rectifying K+ current (IK1) in prevention of arrhythmias is unknown. We have examined the antiarrhythmic potential of a new selective IK1 blocker, RP58866, in rat, rabbit, and primate (marmoset) isolated hearts in the settings of acute ischemia and reperfusion.. In concentration-response studies (n = 12 per group), the drug reduced ischemia-induced ventricular fibrillation (VF) in rat from control incidence of 100 to 50%, 17% (p < 0.05), and 0% (p < 0.05) at 1, 3, and 10 mumol/L, respectively. RP58866 produced significant bradycardia at the 3- and 10-mumol/L concentrations and significant QT interval widening at all three concentrations (p < 0.05). When rat hearts (n = 12 per group) were paced (5 Hz) via the left atrium to prevent bradycardia, the antiarrhythmic effects of 10-mumol/L RP58866 were unmodified (ischemia-induced VF incidence was reduced by drug from 83% in control hearts to 8%; p < 0.05). Similarly, pacing did not prevent the drug's QT-widening activity at 90% repolarization (QT90 was 64 +/- 3 msec in control hearts versus 128 +/- 17 msec in the presence of 10 mumol/L of drug after 10 minutes of ischemia; p < 0.05). These values are similar to equivalent values in unpaced hearts (65 +/- 3 msec in control hearts versus 159 +/- 15 msec with 10 mumol/L of drug; p < 0.05). In separate groups of rat hearts (n = 10 per group) subjected to 10 minutes of ischemia, reperfusion-induced VF incidence was reduced from 90% in control hearts to 10% (p < 0.05), 0% (p < 0.05), and 0% (p < 0.05) by 1-, 3-, and 10-mumol/L RP58866. To examine whether drug actions were species-specific, we performed further studies in rabbit and primate using the middle concentration of RP58866 (3 mumol/L). Ischemia-induced VF incidence was too low in these species to assess the effects of the drug. However, RP58866 widened QT interval (p < 0.05), slowed heart rate (p < 0.05), and reduced the incidence of reperfusion-induced VF from 67% to 8% (p < 0.05) in rabbit. Furthermore, in the more clinically relevant primate species (marmoset; n = 9-12 per group), RP58866 (3 mumol/L) abolished ischemia-induced VT (36% incidence in control hearts; p < 0.05) and significantly reduced the incidence of ischemia-induced ventricular premature beats from 91% to 33% (p < 0.05). The drug was also effective against reperfusion VF in primates (incidence reduced from 64% in control hearts to 11%; p < 0.05). As in rat and rabbit, RP58866 significantly widened QT interval in primate and caused bradycardia before and during ischemia. RP58866 had no significant influence on coronary flow in any species. Finally, in further studies on rat, QT widening by RP58866 was found to persist relatively unmodified in nonischemic hearts perfused with solution containing K+. RP58866, a selective IK1 blocker, is a potent and efficacious new antiarrhythmic drug in ischemia and reperfusion in rat, rabbit, and primate. When tested in rat, pharmacological activity was undiminished by cardiac pacing or elevation of extracellular K+.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Callithrix; Cardiac Pacing, Artificial; Chromans; Electrocardiography; Heart; Male; Myocardial Reperfusion Injury; Piperidines; Potassium Channels; Rabbits; Rats; Rats, Wistar; Tachycardia, Ventricular; Ventricular Fibrillation

Outward potassium (K) currents contribute to the repolarization process of cardiac action potentials. There are, however, multiple K currents. Recently, two putatively specific K channel blockers have been developed as potential class III antiarrhythmic agents. E-4031 appears to block specifically a fast component of the delayed rectifier (IK), and RP 58866 is a reported inward rectifier current (IK1) blocker. In the present experiments, we examined the effects of E-4031 and RP 58866 on action potentials recorded from guinea pig papillary muscles to determine whether the properties of IK and IK1 measured in whole-cell experiments would be manifested in distinct effects. Both compounds prolonged the APD50 (action potential duration at 50% repolarization) and APD90 (action potential duration at 90% repolarization). However, RP 58866 did not significantly prolong the action potential at voltages of 0 mV and above, while E-4031 did. The results suggest that preferential IK1 block results in a change in action potential waveform that is distinct from that resulting from block of other outward K currents. This could thus be used as a simple first-pass screening tool in determining a preliminary mechanism of action of class III antiarrhythmics prior to more time-consuming but necessary whole-cell voltage clamp experiments.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Benzopyrans; Chromans; Chromones; Dose-Response Relationship, Drug; Electric Stimulation; Guinea Pigs; Membrane Potentials; Microelectrodes; Papillary Muscles; Piperidines; Potassium Channels; Pyridines

The mechanical effects of RP 62719 [(-)1-[-2-(3,4-dihydro-2H-1- benzopyran-4-yl)ethyl]-4-(3,4-dimethoxyphenyl)-piperidine] were tested in vitro on guinea pig left ventricular papillary muscle. RP 62719 is a novel pure class III antiarrhythmic agent known to prolong the cardiac action potential duration by selectively blocking the inward rectifying K+ current. Mechanical parameters were determined from contraction and relaxation phases under isotonic and isometric conditions. At a concentration of 0.02 microM, RP 62719 did not produce significant effects on inotropy or lusitropy. At 0.2 and 2 microM, the drug improved contraction under both heavy and low loading conditions, as evidenced by a 30% increase in maximum unloaded shortening velocity (Vmax, P < .001), peak amplitude of shortening (delta L, P < .001), peak isometric active force normalized per cross-sectional area (AF/s, P < .001) and positive peak of the force derivative per mm2 (+dF/s, P < .001). At the same concentrations, positive lusitropic effects were evidenced by an increase in maximum lengthening velocity (maxVr) and negative peak of force derivative per mm2 (-dF/s, P < .001). At a higher concentration (20 microM), effects of RP 62719 on inotropy and lusitropy were less marked, thus accounting for the bell-shaped form of the dose-response curve. An increase in the extracellular Ca++ concentration from 2.5 to 3.75 mM improved inotropy to a similar extent (+30-50%) as did 2 microM RP 62719. However, lusitropy and mechanical coupling between contraction and relaxation were not modified in the same proportion under RP 62719 and under 3.75 mM Ca++.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Arrhythmia Agents; Calcium; Chromans; Guinea Pigs; In Vitro Techniques; Male; Myocardial Contraction; Piperidines; Potassium Channels; Stimulation, Chemical

The temperature dependence of drug blockade of a calcium-dependent potassium channel K(Ca) has been studied in cultured CA1 hippocampal neurons. Channel openings from a 70-pS K+ channel were recorded when inside-out patches were exposed to a bath solution containing 140 mM K+ and 0.2 mM Ca2+. The mean open times of channel events were not significantly altered when the bath temperature was lowered from 24 degrees to 14 degrees C (Q10 = 1.2). Introduction of the drug RP-62719 into the bath solution (at 5 microM) resulted in the mean open time of the K(Ca) channel to be diminished by 85% (at 24 degrees C) with no change in the amplitudes of the unitary currents. Over the same temperature range of 24 degrees to 14 degrees C, in the presence of RP-62719, the mean open times were significantly prolonged (Q10 = 2.2). A simple open channel block scheme was used to determine the temperature dependence of the onward- (blocking) and off- (unblocking) rate constants. Thermodynamic analysis, using transition rate theory, showed that the blocking rate constant was associated with a large increase in entropy. The relatively high temperature dependence for channel blockade is not consistent with a rate-limiting process established by simple diffusion of the agent to a channel blocking site. Channel block may involve conformational changes in the channel protein as a consequence of hydrophobic interactions between drug and channel sites.

Topics: Animals; Anti-Arrhythmia Agents; Biophysical Phenomena; Biophysics; Calcium; Cells, Cultured; Chromans; Electrophysiology; Hippocampus; Kinetics; Neurons; Piperidines; Potassium Channels; Temperature; Thermodynamics

By using a Langendorff-perfused ring of anisotropic rabbit epicardium, sustained reentrant ventricular tachycardia with a cycle length of 168 +/- 13 msec (n = 26) was induced by programmed electrical stimulation. Continuous left ventricular epicardial mapping with 256 simultaneously recorded unipolar electrograms demonstrated that the tachycardia was based on circuital movement of the impulse around a fixed obstacle. Because of the anisotropic properties of the myocardium, the circuit consisted of a ring with segments in which the circulating wave propagated slowly (20 +/- 2 cm/sec) or faster (62 +/- 4 cm/sec). This was related to transverse or longitudinal propagation in relation to fiber direction. In six of 26 experiments, sudden acceleration in rate of the tachycardia was observed during programmed electrical stimulation. This acceleration was caused by the occurrence of double-wave reentry (two successive waves traveling in the same direction and using the same circuit). In one of the experiments, induction of double-wave reentry was only possible at basal conditions but not after the administration of a class III antiarrhythmic drug. In a seventh experiment, induction of double-wave reentry became possible after the administration of a class IC antiarrhythmic drug. Because conduction velocity around the ring was depressed during acceleration, the total revolution time of the circuit during double-wave reentry was about 120% of that during single-wave reentry. Ventricular tachycardias in which double-wave reentry could be elicited had longer cycle lengths (197 +/- 11 vs. 156 +/- 8 msec, p less than 0.001) and larger excitable gaps (71 +/- 16 vs. 28 +/- 5 msec, p less than 0.001) than those not showing this phenomenon. Double-wave reentry might have important clinical implications in understanding ventricular tachycardia acceleration during programmed electrical stimulation, proarrhythmic effects of drugs, and pathophysiology of rapid ventricular tachycardias.

Topics: Animals; Anti-Arrhythmia Agents; Chromans; Electric Stimulation; Electrocardiography; Electrophysiology; Female; Heart Ventricles; Male; Myocardium; Piperidines; Rabbits; Tachycardia