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1.
Papp JG Németh M Krassói I Mester L Hála O Varró A 《Journal of cardiovascular pharmacology and therapeutics》1996,1(4):287-296
BACKGROUND: Acute and chronic treatment with amiodarone has been reported to cause different electrocardiographic changes in patients. The cellular electrophysiologic effects of chronic administration (50 mg/kg/day orally for 6 weeks) and acute superfusion (5 μM in the tissue bath) of amiodarone were therefore studied in dog cardiac ventricular muscle and Purkinje fibers using conventional microelectrode techniques. METHODS AND RESULTS: During stimulation at 1 Hz, chronic amiodarone treatment lengthened the ventricular muscle action potential duration (APD) from 227.8 +/- 6.3 ms (n = 20) to 262.3 +/- 5.2 ms (n = 21; P <.01), but shortened that of Purkinje fibers from 337.6 +/- 9.2 (n = 21) to 308.3 +/- 7.1 (n = 19; P <.05). Acute superfusion of 5 μM amiodarone in cardiac tissue obtained from chronically treated dogs did not change ventricular muscle APD but shortened Purkinje fiber AP from 309.7 +/- 13.6 ms to 281.9 +/- 11.9 ms (n = 8; P <.05). Neither the chronic nor the acute amiodarone exposure prevented the APD shortening in ventricular muscle evoked by 10 μM pinacidil, suggesting that amiodarone does not interfere with the ATP-dependent potassium channels. The normal difference in APD between ventricular muscle and Purkinje fibers in untreated, control preparations was 110 ms but decreased to 46 ms in fibers obtained from dogs chronically treated with amiodarone and increased to 185 ms in fibers obtained from dogs chronically treated with amiodarone and increased to 185 ms in the presence of 30 μM sotalol, a class III antiarrhythmic drug used for comparison. Amiodarone (5 μM) applied directly abolished early afterdepolarizations (EADs) (induced by 1 μM dofetilide + 20 μM BaCl(2) + 2 mM CsCl) in 5 of 6 experiments and caused strong use-dependent V(max) block with relatively fast onset kinetics (rate constant = 1.23 +/- 0.13 AP(-1), n = 5) and offset (time constant = 364 +/- 62.5 ms, n = 5). After chronic amiodarone treatment, in contrast with acute sotalol application (30 μM), no reverse use-dependent effect was observed on the APD in Purkinje fibers. CONCLUSIONS: These results provide further evidence that amiodarone differs from other recognized class III antiarrhythmic drugs (ie, it is a mixed type agent with acute fast kinetic class I [type B] and a unique class III antiarrhythmic action characterized by decreased dispersion of APDs between ventricular muscle and Purkinje fibers). Amiodarone can abolish EADs unlike other class III agents that are usually associated to induction of EADs. These features might be responsible not only for the antiarrhythmic efficacy, but also for the relative safety (low incidence of torsade de pointes) of amiodarone in clinical settings. 相似文献
2.
Friedrichs GS Abreu JN Cousins GR Chi L Borlak J Lucchesi BR 《Journal of cardiovascular pharmacology and therapeutics》1996,1(4):313-324
BACKGROUND: The electrophysiologic and antifibrillatory properties of tedisamil (KC-8857;3,7-di-(cyclopropylmethyl)-9,9-tetramethylene-3,7-diazabicyclo[3.3.1]-nonane dihydrochloride) were studied in a conscious canine model of sudden cardiac death. METHODS AND RESULTS: Three to five days after surgically induced myocardial infarction (2-hour occlusion of the left anterior descending coronary artery), animals were subjected to programmed electrical stimulation to identify those at risk for ischemia-induced ventricular fibrillation. Sixty minutes after tedisamil (10 mg/kg, administered orally) PES was repeated. Tedisamil increased the ventricular effective refractory period from 106 +/- 6 to 134 +/- 7 ms (P <.05) compared to placebo treatment, which did not alter the ERP (123 +/- 6 to 116 +/- 5 ms). Tedisamil prolonged the QTc interval, from a predrug value of 308 +/- 14 to 327 +/- 14 ms, postdrug. The extent of the surgically induced anterior wall myocardial infarct did not differ between groups, tedisamil, 29 +/- 2%, and placebo, 28 +/- 2% of the left ventricle. CONCLUSIONS: Tedisamil conferred protection against ischemia induced ventricular fibrillation; 7 of 10 tedisamil-treated dogs survived, compared to 4 of 14 surviving in the vehicle treated group (P <.05). Although we observed instances of vomiting and/or diarrhea in several dogs after a single oral administration of tedisamil, the data indicate that oral administration of tedisamil provides protection from ischemia-induced ventricular fibrillation in the postinfarcted conscious canine. The mechanism by which tedisamil achieves its antifibrillatory effect may be related to its ability to prolong the ERP of the ventricular myocardium without altering ventricular conduction velocity. 相似文献
3.
Frequency-dependent interactions of mexiletine and quinidine on depolarization and repolarization in canine Purkinje fibers 总被引:1,自引:0,他引:1
D M Roden D H Iansmith R L Woosley 《The Journal of pharmacology and experimental therapeutics》1987,243(3):1218-1224
The use of the antiarrhythmic agents mexiletine and quinidine in combination can be clinically beneficial when single agent therapy is ineffective in ventricular tachyarrhythmias. We therefore compared the effects of mexiletine (10 microM), quinidine (10 microM) and a series of their combinations (total concentration 10 microM) in canine cardiac Purkinje fibers driven at a wide range of stimulation frequencies. All treatments depressed Vmax in tissues driven rapidly (cycle length 300 msec), but only with greater than or equal to 5 microM quinidine was Vmax depressed at longer cycle lengths. Moreover, the time constants for development of and recovery from frequency-dependent block were different: short (200-500 msec) for mexiletine, long (3-5 sec) for quinidine and intermediate or biexponential for the combination. Although both drugs depressed Vmax (albeit with different time dependencies), action potential duration at all cycle lengths from 300 to 8000 msec was shortened by mexiletine, lengthened by quinidine and largely unaltered by combinations. Fibers treated with quinidine in low Ko and driven at slow rates developed marked action potential prolongation and abnormal automaticity in the form of early afterdepolarizations; the addition of mexiletine was sufficient to reverse this effect. In summary, mexiletine and quinidine produced different and frequency-dependent effects on depolarization and repolarization. The effects of their combinations reflected these actions, with opposing actions on repolarization at any stimulation rate but additive frequency-dependent depression of Vmax. We conclude that the clinically beneficial effects of this combination may reflect additive frequency-dependent effects on cardiac sodium channels in the face of unaltered repolarization time. 相似文献
4.
Tedisamil blocks the transient and delayed rectifier K+ currents in mammalian cardiac and glial cells 总被引:13,自引:0,他引:13
I D Dukes L Cleemann M Morad 《The Journal of pharmacology and experimental therapeutics》1990,254(2):560-569
The potassium currents in rat and guinea pig ventricular myocytes and mouse astrocytes were studied using tedisamil, a novel antiarrhythmic agent. A 1 to 20 microM dosage of tedisamil caused marked prolongation of the action potential in isolated rat ventricular myocytes, mimicking its reported effects on multicellular rat heart preparations. Under voltage clamp conditions, tedisamil caused a dose-dependent increase in the speed of inactivation of the transient outward K+ current (Ito), the predominant outward current in rat ventricular myocytes. In cardiac myocytes, the tedisamil block was neither use- nor voltage-dependent. The slow reversibility of drug action when applied from the outside, and its effectiveness when applied intracellularly, suggested an internal site of drug action. In guinea pig ventricular myocytes, tedisamil blocked the slowly developing time-dependent delayed rectifier K+ current (IK) over the same concentration range as that found for Ito in the rat myocytes. Tedisamil reduced this current without changing the characteristics of its slow (tau approximately 1 sec) activation. The effects of tedisamil on Ito and IK were independent of the phosphorylation state of the channel, as assessed by the equal effectiveness of the drug in the presence or absence of isoproterenol. Tedisamil also blocked the transient K+ current and the delayed rectifier current (IK) in mouse astrocytes over the same concentration range as that found in the cardiac myocytes and by a process that accelerated (transient K+ current) or mimicked (IK) inactivation. At concentrations of up to 50 microM, tedisamil had little effect on the time-dependent inward rectifier K+ current, or inward calcium current in rat or guinea pig ventricular myocytes.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
5.
Opie LH 《Journal of cardiovascular pharmacology and therapeutics》2003,8(Z1):S33-S37
Atrial fibrillation has recently come into clinical and research focus. In particular, ventricular rate control has been carefully compared with atrial rhythm control. Additionally, the recent discovery of atrial stunning has initiated clinical and research interest in atrial remodeling. Atrial fibrillation is more likely to occur when the atria are damaged by increased fibrosis. The ideal way to prevent atrial fibrillation and the risk of repetition is by tackling the root causes, such as ischemic heart disease, heart failure, and left ventricular hypertrophy. Tedisamil is an unusual antifibrillatory compound that has a novel mechanism of action by inhibiting the transient outward current (Ito) and the repolarizing potassium currents in the sinoatrial node. Tedisamil works acutely against atrial fibrillation. Importantly, atrial fibrillation is often caused by or related to cardiac ischemia, and conversely, ischemia is caused by the increased oxygen demand of atrial fibrillation. Hence, the double properties of tedisamil as a drug that both inhibits atrial fibrillation and acts in an anti-ischemic mode are an attractive basis for future clinical research. 相似文献
6.
This investigation was aimed at increasing both accuracy and performance of systems used to obtain and measure V(max) (dV/dt(max)), an important yet underevaluated physiological parameter. A method is presented to correct measured V(max) (V(mes)) based on an algorythm adapted to 2 tested systems: IOX and DataPac. We also investigated 89 rabbit Purkinje fibres (before and 30 min following drugs effective on ventricular repolarization) to derive experimental electrophysiological correlations. In fact, no method may be reliable without knowing its accuracy over a large scale of representative physiological values. This is why it is essential to estimate accuracy, precision and fidelity of systems aimed at action potential recording before pharmacological or pathophysiological investigations are performed, even more if therapeutical consequences might ensue. A formula is presented to obtain real V(max), based on V(mes) [V(max)=V(mes)/1 - (tau.V(mes)/APA)(2.p)], where tau=49.64 μs, p=0.72 and APA=action potential amplitude. This formula is reliable up to V(max) values of 1000 V/s which may be seen in rabbit Purkinje fibres, a classical model for in vitro studies. Using this formula may have practical implications in cellular electrophysiology which may impact on safety pharmacology and therapeutics. 相似文献
7.
BACKGROUND: The effects of sotalol on refractoriness in human ventricular and atrial muscles have been well established, but the drug's effect on the electrical properties of the His-Purkinje system in humans is not known, especially whether sotalol's effect is due solely to its action on prolonging repolarization or in combination with its beta-blocking properties. We studied the electrophysiologic effects of intravenous sotalol and propranolol in patients undergoing electrophysiologic studies of cardiac arrhythmias. METHODS AND RESULTS: We studied 22 patients (19 men, 3 women; mean age, 60 +/- 6 years) who had coronary artery disease and assessable anterograde, retrograde, or both, His-Purkinje system function. Fifteen patients underwent electrophysiologic studies before and after intravenous sotalol (1.5 mg/kg), and 7 patients underwent electrophysiologic studies before and after intravenous propranolol (0.15 mg/kg). Both sotalol and propranolol had no significant effect on the H-V interval, but sotalol significantly increased ventricular refractoriness and His-Purkinje refractoriness, both in anterograde and retrograde conduction, whereas propranolol did not, Sotalol's effect on His-Purkinge refractoriness also caused atrioventricular block distal to the His bundle during atrial pacing at a moderately fast rate. Sotalol was not effective in preventing bundle branch re-entry tachycardia, nevertheless, it increased cycle length of bundle branch re-entry tachycardia by increasing refractoriness. CONCLUSIONS: Sotalol increased His-Purkinje refractoriness in humans but had no effect on His-Purkinje conduction. The drug must be used judiciously in patients with a diseased His-Purkinje system because it may cause atrioventricular block distal to His at fast heart rates. Sotalol had no effect on macrore-entry utilizing bundle branches. 相似文献
8.
Effect of lidocaine on the electrophysiological properties of ventricular muscle and Purkinje fibers 总被引:7,自引:4,他引:7
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Preparations of right ventricular papillary muscle and false tendon (Purkinje fiber) were obtained from dog hearts, placed in a bath perfused with Tyrode solution, and observed both under control conditions and during exposure to lidocaine in concentrations from 1 x 10(-7) to 5 x 10(-4) mole/liter. Transmembrane voltages were recorded from both ventricular muscle (VM) and Purkinje fibers (PF) of spontaneously beating and electrically driven preparations. Low concentrations (1 x 10(-6) and 1 x 10(-5) mole/liter) attenuated or abolished phase 4 (diastolic) depolarization and spontaneous firing in PF without decreasing their diastolic excitability. Concentrations of 1 x 10(-5) mole/liter produced maximal shortening of both action potential duration (APD) and effective refractory period (ERP) and made the ERP long relative to APD; the latter alteration was more prominent in VM. At concentrations = 1 x 10(-5) mole/liter, lidocaine either caused a slight increase or no change in peak maximum rate of phase 0 depolarization (V(max)) and membrane responsiveness, the relationship between transmembrane activation voltage (MAV) and V(max) of the resultant action potential; these concentrations had no significant effect on resting potential (RP) in VM, maximal diastolic transmembrane voltage (DTMV(max)) in PF, or action potential amplitude in either fiber type.High (toxic) concentrations (>/= 1 x 10(-4) mole/liter) did not cause further shortening of APD or ERP in either VM or PF but did produce a decrease in peak V(max) of phase 0 and membrane responsiveness. In most cases, these concentrations also caused a decrease in RP or DTMV(max) and action potential amplitude, with progression to bizarre action potential depolarization and inexcitability. These properties of lidocaine are strikingly different from those of quinidine or procaine amide. The mechanisms responsible for lidocaine's in vivo antiarrhythmic action are discussed. 相似文献
9.
J R Berlin T Akera T M Brody 《The Journal of pharmacology and experimental therapeutics》1986,238(2):632-641
Quinidine has been reported to have no effect on the positive inotropic action of digoxin observed in isolated cardiac muscle preparations. This is surprising because quinidine has been shown to reduce Na+ influx in cardiac muscle. The conditions which increase Na+ influx stimulate the glycoside binding to Na+- and K+-activated Mg++-dependent ATP phosphohydrolase (Na+,K+-ATPase), and therefore quinidine may be expected to have an opposite effect. Thus, the effects of quinidine on cardiac muscle and its possible interactions with digoxin were re-evaluated using electrically paced left atrial muscle preparations of guinea pig heart. Quinidine caused a frequency- and concentration-dependent decrease in maximal upstroke velocity and amplitude of the action potential without altering resting membrane potential. In addition, quinidine prolonged action potential duration markedly in a frequency-dependent manner. Despite action potential prolongation, the alkaloid reduced net Na+ influx as determined by a decrease in steady-state ouabain-sensitive 86Rb+ uptake. Under these conditions, however, quinidine failed to reduce the rate of onset or the maximal positive inotropic effect of digoxin; or did it reduce digoxin binding to Na+,K+- ATPase in beating atrial muscle preparations. Benzocaine, which reduced net Na+ influx without increasing the action potential duration, also failed to affect the peak inotropic effect of digoxin or the glycoside binding. Quinidine had no direct effects on glycoside binding to isolated cardiac Na+,K+-ATPase. Moreover, [3H]ouabain binding to isolated enzyme was relatively insensitive to changes in Na+ concentrations between 1 and 8 mM although binding was stimulated clearly by Na+ above 8 mM. These results indicate that quinidine, at therapeutic concentrations, does not interact pharmacodynamically with digoxin in isolated cardiac muscle. 相似文献
10.
Cardiac electrophysiologic action of a new beta-adrenergic blocking agent carteolol hydrochloride, or OPC-1085, was studied in either isolated, perfused rabbit hearts or in atrial, ventricular or Purkinje fibers of dogs and rabbits superfused in the tissue bath. Transmembrane potentials were recorded with intracellular microelectrodes and atrioventricular conduction was studied by recording a His bundle electrogram. OPC-1085 at a concentration of 0.1 mg/L shortened the sinus node recovery time, while propranolol at a comparable concentration prolonged it. Isoproterenol-enhanced canine Purkinje automaticity was more markedly depressed by OPC-1085 than by propranolol. In rabbit atrial and ventricular muscle, OPC-1085 up to the concentration of 2 mg/L did not alter the action potential characteristics but tended to shorten the conduction time. At 20 mg/L, OPC-1085 significantly decreased the maximal rate of depolarization and maximal following frequency, and prolonged the action potential duration and conduction time in non-reserpinized as well as reserpinized preparations. On atrioventricular conduction, 0.1 mg/l to 5mg/L of this drug prolonged the St-A and H-V intervals but tended to shorten the A-H interval. All these intervals were prolonged at 20 mg/L. The action potential duration of canine Purkinje-ventricular block developed at higher frequencies of stimulation. In view of the clinical dosage levels, it is sugg ested that the antiarrhythmic effects of OPC-1085 depend predominantly on its beta blocking action. At higher concentrations, OPC-1085 may exert some beta stimulating action, whereas still higher and possibly toxic concentrations could depress conduction through a direct membrane effect. 相似文献
11.
Contribution of quinidine metabolites to electrophysiologic responses in human subjects 总被引:1,自引:0,他引:1
K M Kavanagh D G Wyse L B Mitchell T Gilhooly A M Gillis H J Duff 《Clinical pharmacology and therapeutics》1989,46(3):352-358
The quinidine metabolites 3-hydroxyquinidine, 2'-oxoquinidione, and quinidine-N-oxide and the contaminant dihydroquinidine have been shown to have electrophysiologic activity. This study investigated the time-dependent contributions of quinidine, dihydroquinidine, and the quinidine metabolites to the electrophysiologic effects of a prolonged quinidine infusion in 14 patients referred for management of symptomatic ventricular tachyarrhythmias. Electrophysiologic testing and blood sampling were done at baseline and every 5 minutes throughout a 110-minute quinidine infusion. Changes in ventricular effective refractory periods correlated significantly with serum concentrations of quinidine-N-oxide (r = 0.54; p less than 0.001), 3-hydroxyquinidine (r = 0.50; p less than 0.001), and time (r = 0.52; p less than 0.001) but did not correlate with the quinidine concentrations (r = 0.19). Multiple linear regression revealed that only 3-hydroxyquinidine and time contributed independently to changes in the ventricular effective refractory period. Quinidine concentration was the only variable that contributed independently to changes in ventricular tachycardiac cycle lengths. Time was the only variable that correlated independently with changes in QRS and QTc durations. These data indicate that active metabolites accumulate during an intravenous infusion that attains therapeutic quinidine levels and that quinidine and its metabolites may have different electrophysiologic effects. 相似文献
12.
ROBERT M. CAMPBELL RAYMOND L. WOOSLEY DAVID H.S. IANSMITH DAN M. RODEN 《Pacing and clinical electrophysiology : PACE》1990,13(1):30-36
Bepridil and lidoflazine are calcium channel antagonists that also prolong action potential duration, produce QT interval prolongation on the surface ECG, and have been associated with the distinctive form of ventricular tachycardia, torsade de pointes. It has been demonstrated that quinidine, which also prolongs QT interval and induces torsade de pointes, produces early afterdepolarizations and triggered activity in canine Purkinje fibers driven at slow rates. The effects of bepridil (1-10 microM) and of lidoflazine (5-15 microM) on the transmembrane action potential from canine Purkinje fibers were therefore studied. At long cycle lengths, unlike with quinidine, triggered activity arising during phase 3 was rare; phase 3 secondary plateaus (early afterdepolarizations) were, however, common. Arrest of transmembrane potential between -50 and -60 mV during stimulation at long cycle lengths was also frequently observed (7/20 of bepridil and 3/15 of lidoflazine-treated fibers). In preparations with prominent phase 3 secondary plateaus, addition of epinephrine resulted in triggered activity; similarly, epinephrine caused automaticity from a depolarized membrane potential in 8/9 fibers quiescent at -50 to -60 mV. Thus, the calcium channel blocking drugs bepridil and lidoflazine produced striking repolarization changes at slow stimulation rates, but unlike quinidine, triggered activity was rare. The effect of epinephrine on these drug-treated fibers suggests that the slow inward calcium current plays a role in the generation of triggered activity in the presence of prolonged repolarization. 相似文献
13.
We used standard microelectrode techniques to study developmental changes in the actions of quinidine on the transmembrane potentials of Purkinje fibers obtained from the hearts of adult dogs and of dogs less than 1 month old. Quinidine had no major effect on resting membrane potential and action potential overshoot at either age. It reduced Vmax significantly at a basic cycle length of 500 msec, the magnitude of effect not differing with age. When frequency-dependent effects on Vmax were studied at basic cycle lengths of 1500 and 500 msec, the magnitude of the effect was not age-related nor were the time or number of beats to steady state effect and the recovery from quinidine effect. However, in its actions on repolarization, quinidine did demonstrate age dependence: the magnitude of change was greater in young than in adult fibers. Our results with quinidine are different from those of previous studies in which we showed age dependence of the effects of lidocaine on Vmax and repolarization, with greater effects occurring in the adult than in the neonate. This difference in the ability of lidocaine and of quinidine to modify transmembrane potential characteristics with age emphasizes the differences that exist in the effects of individual antiarrhythmic drugs on the determinants of cardiac electric activity. 相似文献
14.
J W Mason R A Winkle A K Rider E B Stinson D C Harrison 《The Journal of clinical investigation》1977,59(3):481-489
Using His bundle recording techniques, we examined direct and autonomically mediated conduction system effects of quinidine in five cardiac transplant recipients who have anatomically denervated hearts. We made control conduction interval and refractory period measurements, and then infused 10 mg/kg quinidine gluconate over a 20-min period. At 30 min, we determined the electrophysiologic changes induced by quinidine. Quinidine significantly increased the atrial-His (AH) interval (from 97+/-9 [SEM] to 108+/-7 ms, P less than 0.001), the His-ventricular (HV) inteval (from 43.9 +/- 1 to 52.8 +/- 3 ms, P less than 0.01), the donor heart sinus cycle length (from 599 +/- 38 to 630 +/- 56 ms, P less than 0.08), and the atrial effective refractory period (from 214 +/- 14 to 241 +/- 11 ms, P less than 0.01). Quinidine significantly decreased the innervated, remnant atrial sinus cycle length (from 847 +/- 104 to 660 +/- 96 ms, P less than 0.01) and the blood pressure. The mean plasma concentration of quinidine at the time that electrophysiologic measurements were repeated was 4.37 +/- 0.449 micrograms/ml. We conclude that quinidine's predominant sinus nodal and atrioventricular nodal effects in man are autonomically mediated and opposite to its direct actions upon these structures. On the other hand, quinidine's prevailing effect on atrial refractoriness and His-Purkinje conduction in man is direct. 相似文献
15.
Lathrop DA Nánási PP Varró A Schwartz A 《Journal of cardiovascular pharmacology and therapeutics》1996,1(2):133-140
BACKGROUND: Conventional microelectrode techniques were used to compare the concentration-dependent effects of vesnarinone (0.1-100 μM) and amrinone (1 μM-1 mM) on action potential duration (APD) and developed force in both isolated dog ventricular trabeculae and Purkinje strands. METHODS AND RESULTS: Both drugs increased contractility of trabecular muscle preparations, while, in Purkinje strands, vesnarinone failed to increase developed force during continuous pacing at 2 Hz. Vesnarinone lengthened APD in both preparations; although this effect was more marked in Purkinje strands. Ventricular muscle APD was not affected by amrinone (1 μM to 1 mM), while, in Purkinje strands, amrinone produced a biphasic effect on APD. Low concentrations (1-100 μM) of amrinone shortened Purkinje fiber APD, while only the highest concentration (1 mM) used lengthened APD. In addition, in Purkinje strand preparations the effects of vesnarinone (10 μM) on APD and developed force were proportional to pacing cycle length at frequencies slower than 2 Hz; however, at frequencies faster than 2 Hz vesnarinone decreased developed force while APD was lengthened. In ventricular trabecular muscle preparations, the effects of vesnarinone were not affected by frequency. CONCLUSIONS: These results indicate clear differences between the effects of vesnarinone and amrinone in isolated cardiac preparations. These differences in experimental effects in isolated cardiac preparations may help provide an explanation for the disappointing clinical response of patients in heart failure to amrinone, while vesnarinone has appeared to be beneficial. 相似文献
16.
Lars Eckardt Günter Breithardt Wilhelm Haverkamp 《The Journal of pharmacology and experimental therapeutics》2002,300(1):64-71
There is growing concern that antipsychotic drugs that prolong the QT interval almost always increase the risk for patients to develop life-threatening ventricular tachyarrhythmias (VTs) of the torsade de pointes type. We therefore sought to compare the electrophysiologic effects of the psychotropic agent sertindole, which prolongs cardiac repolarization by inhibiting the rapid component of the delayed rectifier potassium current (I(Kr)) but has a low torsadogenic potential to the antiarrhythmic agent dl-sotalol. In 18 Langendorff-perfused rabbit hearts, sotalol (10 microM, n = 8) and sertindole (0.5, 1.0, and 1.5 microM; n = 10) led to significant and comparable QT prolongation. In the presence of sotalol, torsade de pointes reproducibly occurred in atrioventricular node-blocked hearts after lowering the potassium concentration to 1.5 mM. High doses of sertindole (1.5 microM) only caused monomorphic VT (n = 4) and nonsustained polymorphic VT (n = 2) in the presence of QRS prolongation. Multiple simultaneous epi- and endocardial monophasic action potentials and a volume-conducted ECG demonstrated widening of the T/U wave, early afterdepolarizations, and increased dispersion of repolarization in the presence of dl-sotalol. In contrast to sotalol, QT and monophasic action potential prolongation were cycle length-independent in the presence of sertindole. Sertindole had no significant effect on transmural or interventricular dispersion of repolarization. Early afterdepolarizations did not occur. Despite comparable QT prolongation, sertindole did not display the proarrhythmic profile typical of other blockers of I(Kr) such as dl-sotalol. It is likely that a different mode of interaction between sertindole and the channel and/or additional pharmacological effects of sertindole, e.g., its ability to inhibit I(Na) and/or its ability to block alpha(1)-receptors, play a role. 相似文献
17.
J K Gibson H Gelband A L Bassett 《The Journal of pharmacology and experimental therapeutics》1977,202(3):702-710
Effects of nadolol, a new beta adrenergic antagonist, were determined on transmembrane potentials of canine Purkinje fibers and ventricular and atrial muscle. Significant alterations in Purkinje fiber potentials occurred only with nadolol concentrations of 10(-4) M or greater. After 1 hour exposure to 10(-4) M, resting potential and action potential amplitude were reduced; at 3 hours, action potential rate of rise, phase 2 duration and action potential duration at 75% repolarization also were decreased. 10(-3) M nadolol also was depressant and, additionally, consistently reduced membrane responsiveness. Nadolol (10(-8)-10(-4) M) had no significant effects on effective refractory period. Ventricular and atrial muscle were less sensitive to all drug concentrations. Nadolol (10(-8)-10(-4) M) had little action on automaticity in normal, ouabain-treated or stretched Purkinje fibers but markedly decreased catecholamine-enhanced automaticity. In isoproterenol-treated Purkinje fibers, pA2 for nadolol was 8.2 and 7.7 for propranolol. Nadolol (10(-3) M or less) did not affect isometric force developed by isolated canine atrial trabeculae. We suggest that direct membrane depressant effects of nadolol do not contribute to its antiarrhythmic activity and that its beta adrenergic blocking ability is beneficial in catecholamine-related cardiac ectopia. 相似文献
18.
Experimental models of torsades de pointes 总被引:1,自引:0,他引:1
Summary— Torsades de pointes is the most typical ventricular tachycardia involving QT-interval prolongation. It is a rather unusual but potentially lethal ventricular tachycardia with a distinctive morphology favored by bradycardia, antiarrhythmic drugs and hypokalemia and requires specific treatment. Torsades de pointes has been shown to be related to bradycardia-dependent early afterdepolarizations (EAD) and/or increased dispersion of repolarization. However, although EAD can be obtained relatively easily in vitro with quinidine or sotalol, torsades de pointes are very difficult to reproduce in animal models. The models of torsades de pointes which have been proposed can be categorized as morphological, EAD-related or pharmacological models. The purpose of the ‘morphological’ models was to reproduce the twisting of QRS axis typical of torsades de pointes, with no consideration of other aspects such as long QT or bradycardia. These models were produced by epicardial electrical or chemical (aconitine) stimulation at two distant ventricular sites or by overdosing of quinidine in dogs with acute myocardial infarction. The second type of model focused on the conditions producing EAD in vitro. Ventricular tachycardias were obtained in anesthetized dogs using toxics such as cesium or anthopleurine, both producing EAD in vitro. These ventricular tachycardias were shown to be sensitive to magnesium, heart rate and autonomic tone, but torsades de pointes remained rare, at least after cesium injections. The pharmacological models that could be used to study the QT-dependent proarrhythmic effects of drugs are the anesthetized rabbit with alpha-adrenergic stimulation, and the conscious dog model with chronic AV-block and diuretic-induced hypokalemia. Methoxamine-treated anesthetized rabbits develop ventricular tachycardias during clofilium infusions. These ventricular tachycardias, although appearing at very high heart rates, have typical torsades de pointes aspects and are often associated with giant QT waves. The specificity of the model remains to be tested. In our conscious bradycardic and hypokalemic dogs, quinidine and sotalol but not flecainide, propranolol or lidocaine induced QT-dependent arrhythmogenic effects and torsades de pointes. Efficacy of high rate stimulations and magnesium were repeatedly observed. This demanding model, especially designed for qualitative drug comparisons, is also well suited to studies on the mechanisms of initiation of torsades de pointes. The pertinence of these models for estimating the risk of QT-dependent proarrhythmias associated with non-antiarrhythmic agents remains to be tested. 相似文献
19.
Electrophysiologic and voltage clamp analysis of the effects of sotalol on isolated cardiac muscle and Purkinje fibers 总被引:6,自引:0,他引:6
E Carmeliet 《The Journal of pharmacology and experimental therapeutics》1985,232(3):817-825
The effect of dl-, d- and I-sotalol on electrophysiologic characteristics of guinea-pig papillary muscles, sheep and rabbit Purkinje fibers was studied. Standard electrophysiologic and voltage clamp techniques were used. At concentrations between 10(-6) and 10(-4) M, the main effect of sotalol consisted of prolongation of the action potential duration. In voltage clamp experiments this effect correlated with a substantial reduction of the time-dependent K current activated during the plateau of the action potential and a small reduction of the background K current. At concentrations above 10(-4) M, a secondary shortening of the action potential concomitant with a fall in maximal rate of depolarization was seen. In voltage clamp experiments this effect correlated with a decrease of a slowly inactivating Na current. In the absence of catecholamines d- and I-sotalol exerted identical effects on action potentials and voltage clamp currents. 相似文献
20.
J Weissenburger J M Davy F Chézalviel O Ertzbischoff J M Poirier F Engel P Lainée E Penin G Motté G Cheymol 《The Journal of pharmacology and experimental therapeutics》1991,259(2):871-883
In order to create and evaluate a model sensitive to QT-dependent proarrhythmic effects of drugs, a long QT syndrome was produced in chronically instrumented dogs with bradycardia and hypokalemia. Bradycardia (mean cycle length: 1495 +/- 78 msec) was provided by permanent atrioventricular block and hypokalemia (K+ = 2.6 +/- 0.05 mmol/l) by high doses of diuretics. To evaluate that model, six of these conscious dogs were subjected to quinidine, flecainide, lidocaine, propranolol and sotalol infusions. In crossover design, drugs were infused i.v. at rates allowing stable and nontoxic drug plasma levels during the experiment. Four-lead ECGs were recorded for arrhythmias for 30 min before (base line) and 75 min after onset of infusion. Ventricular cycle length was increased dramatically by sotalol, lidocaine and propranolol (+618 +/- 192, +388 +/- 125 and +329 +/- 114 msec, respectively) and QT interval was increased by sotalol, quinidine and flecainide (+56 +/- 8, +31 +/- 7.9 and +20 +/- 5.7 msec, respectively). Quinidine and sotalol, but not flecainide, propranolol or lidocaine, exhibited significant arrhythmogenic activities. During quinidine infusion, most dogs exhibited some ventricular arrhythmias whose most severe forms were runs of ventricular tachycardia. These arrhythmias were suppressed by pacing at high rates. During sotalol infusion, five out of six dogs exhibited typical "torsades de pointes." This incidence was not related to the slowing effects of sotalol on idioventricular pacemakers, because a similar incidence was obtained in five complementary dogs paced at 40 bpm. It could be related to dose, because torsades de pointes occurred only once in another group of five dogs receiving half the dose used in the controlled study. Only quinidine and sotalol, but not propranolol, flecainide or lidocaine, are clinically associated to torsades de pointes. They were also the only drugs associated with proarrhythmic events in the present study, a fact suggesting that QT-dependent arrhythmogenic effects of drugs can be reliably evaluated in conscious hypokalemic dogs with complete atrioventricular block. 相似文献