RESUMEN
The cellular mechanism of action of tedisamil (KC-8857) (TED), a novel antiarrhythmic/antifibrillatory compound, was studied on transmembrane currents in guinea pig, rabbit and dog ventricular myocytes by applying the patch-clamp and the conventional microelectrode technique. In guinea pig myocytes the rapid component of the delayed rectifier potassium current (IKr) was largely diminished by 1 microM TED (from 0.88+/-0.17 to 0.23+/-0.07 pA/pF, n=5, p<0.05), while its slow component (IKs) was reduced only by 5 microM TED (from 8.1+/-0.3 to 4.23+/-0.07 pA/pF, n=5, p<0.05). TED did not significantly change the IKr and IKs kinetics. In rabbit myocytes 1 microM TED decreased the amplitude of the transient outward current (I(to)) from 20.3+/-4.9 to 13.9+/-2.8 pA/pF (n=5, p<0.05), accelerated its fast inactivation time constant from 8.3+/-0.6 to 3.5+/-0.5 ms (n=5, p<0.05) and reduced the ATP-activated potassium current (IKATP) from 38.2+/-11.8 to 18.4+/-4.7 pA/pF (activator: 50 microM cromakalim; n=5, p<0.05). In dog myocytes 2 microM TED blocked the fast sodium current (INa) with rapid onset and moderately slow offset kinetics, while the inward rectifier potassium (IK1), the inward calcium (ICa) and even the I(to) currents were not affected by TED in concentration as high as 10 microM. The differences in I(to) responsiveness between dog and rabbit are probably due to the different alpha-subunits of I(to) in these species. It is concluded that inhibition of several transmembrane currents, including IKr, IKs, I(to), IKATP and even INa, can contribute to the high antiarrhythmic/antifibrillatory potency of TED, underlying predominant Class III combined with I A/B type antiarrhythmic characteristics.
Asunto(s)
Antiarrítmicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Ciclopropanos/farmacología , Canales Iónicos/fisiología , Miocitos Cardíacos/efectos de los fármacos , Animales , Antiarrítmicos/química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Ciclopropanos/química , Perros , Relación Dosis-Respuesta a Droga , Cobayas , Ventrículos Cardíacos/efectos de los fármacos , Canales Iónicos/agonistas , Canales Iónicos/antagonistas & inhibidores , Potenciales de la Membrana/efectos de los fármacos , Potenciales de la Membrana/fisiología , Miocitos Cardíacos/fisiología , Conejos , Función VentricularRESUMEN
In the present work, the effect of tedisamil on gap junctional conductance (gj) and conduction velocity was investigated in the failing heart of cardiomyopathic hamsters (TO-2 strain). It was found that tedisamil (10(-7) M) increased gj by 53.8+/-1% (n = 23) in cell pairs isolated from 2 months old cardiomyopathic hamsters. The effect of tedisamil was suppressed by intracellular dialysis of an inhibitor of protein kinase A and also by adenosine indicating that the drug increases gj through the activation of adenylcyclase. Tedisamil also increased the conduction velocity and cardiac refractoriness of ventricular muscle from young cardiomyopathic hamsters. At an advanced stage of the disease, however, when the beta-adrenoceptor, adenylcyclase signaling system is impaired, tedisamil was unable to increase gj. The present results indicate that the antiarrhythmic action of tedisamil is in part related to an increase in junctional conductance and conduction velocity.
Asunto(s)
Antiarrítmicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Comunicación Celular/efectos de los fármacos , Ciclopropanos/farmacología , Corazón/efectos de los fármacos , Animales , Antiarrítmicos/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Cricetinae , Ciclopropanos/uso terapéutico , Conductividad Eléctrica , Uniones Comunicantes/efectos de los fármacos , Corazón/fisiopatología , Insuficiencia Cardíaca/prevención & control , Masculino , MesocricetusRESUMEN
BACKGROUND: Tedisamil is a potent bradycardiac/antiischemic drug known to lengthen cadiac repolarization by blocking various potassium channels. Recent in vivo experiments revealed that it is an antiarrhythmic agent. It was therefore of interest to compare the cellular electrophysiologic effects of tedisamil with those of quinidine and sotalol in isolated cardiac preparations. METHODS AND RESULTS: The conventional microelectrode technique was applied in isolated dog cardiac Purkinje and ventricular muscle fibers and in rabbit left atrial muscle. Tedisamil (1 µM) and sotalol (30 µM) lengthened, while quinidine (10 µM) shortened action potential duration in dog Purkinje fibers. The phase 1 repolarization was delayed by tedisamil and quinidine and not changed by sotalol. In dog ventricular muscle and in rabbit atrial muscle, all three drugs studied lengthened repolarization. In dog Purkinje fiber, tedisamil and sotalol lengthened action potential duration more at slow than at high stimulation frequency (reverse use-dependence). In dog ventricular muscle fibers, the effect of the drugs was not clearly frequency dependent. In rabbit atrial muscle fibers, the quinidine-evoked repolarization lengthening was most pronounced at intermediate cycle lengths (500-1000 ms). Tedisamil and quinidine but not sotalol depressed the maximal rate of depolarization (V(max)), which depended on the stimulation frequency (use-dependence). The nature of the use-dependent V(max) block differed between quinidine and tedisamil. Quinidine decreased V(max) at a relatively wide range of stimulation frequencies whle tedisamil. Quinidine decreased V(max) at a relatively wide range of stimulation frequencies while tedisamil decreased V(max) largely at high rate of stimulation. Tedisamil and quiinidine prevented or decreased the pinacidil-evoked action potential shortening in dog ventricular muscle, suggesting block of the ATP-dependent potassium channels (I(KATP)), while with sotalol such effect was not observed. CONCLUSIONS: Although tedisamil, quinidine, and sotalol are known to lengthen the QT interval, their cellular electrophysiologic effects substantially differ. Tedisamil lengthens repolarization and prevents pinacidil-evoked action potential duration shortening, suggesting I(K(ATP)) blockade. Its effect on the V(max) is limited mostly to fast heart rate. These electrophysiologic effects of tedisamil resemble those of chronic amiodarone treatment.
RESUMEN
The cellular electrophysiological effects of 1 microM tedisamil (KC 8857) were studied in human atrial and ventricular fibers. Conventional microelectrode technique was applied to record the transmembrane action potentials at stimulation frequency of 100 per min and 37 degrees C. Tedisamil lengthened action potential duration (APD) more in atrial than in ventricular muscle fibers; prolongation of APD90 was 28.9 +/- 3.3% (n = 6; p < 0.05) for atrial and 13.3 +/- 5.2% (n = 6; P < 0.05) for ventricular tissue. The maximal rate of depolarization was depressed slightly, but significantly by 1 microM tedisamil only in ventricular fibers (12.9 +/- 6.5%, n = 6, P < 0.05). From these cellular electrophysiological data it is concluded that the bradycardic/antiischemic agent tedisamil possesses marked Class III properties not only in cardiac tissues of experimental animals but also those of man.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Antiarrítmicos/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Ciclopropanos/farmacología , Corazón/efectos de los fármacos , Adolescente , Adulto , Niño , Preescolar , Atrios Cardíacos/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Humanos , Técnicas In Vitro , Potenciales de la Membrana/efectos de los fármacos , Persona de Mediana EdadAsunto(s)
Antidepresivos/toxicidad , Electrocardiografía , Sistema de Conducción Cardíaco/efectos de los fármacos , Piperidinas/toxicidad , Antagonistas de la Serotonina/toxicidad , Amitriptilina/toxicidad , Animales , Presión Sanguínea/efectos de los fármacos , Gatos , Perros , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/efectos de los fármacos , ParoxetinaRESUMEN
The effects of intravenous infusions of paroxetine, a novel inhibitor of 5-hydroxytryptamine (5HT) uptake, and of the tricyclic antidepressant, amitriptyline, on the cardiovascular system have been compared in the conscious rabbit and in the anaesthetised cat. As judged by the dose required to produce changes in ECG waveform (including PR and QTc intervals) and disorders of heart rhythm, paroxetine was less cardiotoxic than amitriptyline in both species. Thus, paroxetine has the advantage over amitriptyline of being less toxic to the cardiovascular system which could constitute a considerable advantage in clinical use particularly as other work has shown it to be more potent than amitriptyline in tests for antidepressant activity.
Asunto(s)
Amitriptilina/farmacología , Sistema de Conducción Cardíaco/efectos de los fármacos , Contracción Miocárdica/efectos de los fármacos , Piperidinas/farmacología , Amitriptilina/administración & dosificación , Amitriptilina/toxicidad , Animales , Antidepresivos/farmacología , Gatos , Evaluación Preclínica de Medicamentos , Electrocardiografía , Femenino , Hipotensión/inducido químicamente , Infusiones Parenterales , Masculino , Paroxetina , Piperidinas/administración & dosificación , Conejos , Convulsiones/inducido químicamente , Antagonistas de la Serotonina/farmacología , Taquicardia/inducido químicamenteRESUMEN
Cardiac arrhythmics were induced in conscious rabbits by intracardiac electric stimulation. The arrhythmic threshold remained constant for a period of more than 6 months. The antiarrhythmic drugs ajmaline, prajmalium, disopyramide, quinidine, lidocaine, propranolol and verapamil, given i.v. or orally, were screened for their threshold-raising potency. Particularly the membrane-stabilizing antiarrhythmics showed significant effects. The model may constitute a useful screen for such drugs in the conscious animal.
Asunto(s)
Antiarrítmicos/farmacología , Estimulación Eléctrica , Corazón/fisiología , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Femenino , Inyecciones Intravenosas , Membranas/efectos de los fármacos , Modelos Biológicos , Conejos , Factores de TiempoRESUMEN
The reddening of the ears of guinea pigs following the administration of nicotinic acid and its derivatives is regarded as an animal experiment for the human flush-reaction. In agreement with the observations in humans we found that the reddening effects decreased after repeated administration of xantinol nicotinate (Complamin). The results demonstrate that the reddening of the ears of guinea pigs--and presumably flushing in humans as well--is a complex event. The liberation of prostaglandins, histamine and serotonin, and first of all, cholinergic reactions, seem to be involved.