piperidines and tedisamil

The modulation of the protein kinase A-activated chloride current (PKA-I[Cl]) may lead to modification of the cardiac action potential shape. The purpose of this study was to evaluate the effects of glibenclamide, tedisamil, dofetilide, E-4031, and BRL-32872 on the PKA-I(Cl). Experiments were conducted by using the patch-clamp technique in guinea pig ventricular myocytes. PKA-I(Cl) was activated by application of 1 microM isoproterenol and was inhibited by 1 microM propranolol, 10 microM acetylcholine, or 1 mM 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS). The sulfonylurea receptor inhibitor, glibenclamide, inhibited PKA-I(Cl) at micromolar concentration. Among class III antiarrhythmic agents, tedisamil induced a dose-dependent inhibition of PKA-I(Cl) with a half effective concentration (EC50) of 7.15 microM (Hill coefficient, 0.54). This effect may contribute to action potential widening induced by tedisamil. In contrast, the selective inhibitors of the rapid component of the delayed rectifier K current (I[Kr]), dofetilide, and E-4031, as well as BRL-32872, that blocks I(Kr) and the L-type calcium current, did not significantly affect the amplitude of PKA-I(Cl), even at high concentrations (10-30 microM). These results demonstrate that compounds such as glibenclamide and tedisamil that are known to block the adenosine triphosphate (ATP)-sensitive K current also affect PKA-I(Cl). Furthermore it appears that blockade of PKA-I(Cl) is not a common feature for all class III antiarrhythmic agents.

Topics: 4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; Acetylcholine; Animals; Anti-Arrhythmia Agents; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Cardiotonic Agents; Chlorides; Cyclic AMP-Dependent Protein Kinases; Cyclopropanes; Glyburide; Guinea Pigs; Heart Ventricles; Hypoglycemic Agents; Ion Transport; Isoproterenol; Male; Myocardium; Patch-Clamp Techniques; Phenethylamines; Piperidines; Potassium Channels; Propranolol; Pyridines; Sulfonamides

The new antiarrhythmic compounds E-4031 (1-[2-(6-methyl-2-pyridyl)ethyl]-4-(4-methylsulfonyl- aminobenzoyl)piperidine), almokalant and tedisamil prolonged the action potential duration (APD) of human right ventricular papillary muscle. In order to investigate whether drug-channel interaction takes place during rest, regular stimulation (0.5 Hz) was interrupted by three 30-min periods of quiescence. Drug was added at the beginning of the second period of rest, the third period was interposed at equilibrium of drug action. Under predrug control conditions, the first action potential after rest was longer than with regular stimulation, steady state was reached again with a monotonic time course. With E-4031 the first action potential after 30 min of drug exposure during quiescence was similar to predrug control, but drug-induced prolongation of APD developed during further stimulation, indicating drug interaction with open channels. After the third period of quiescence, the first APD remained significantly increased compared to predrug values suggesting that E-4031 may be trapped within the resting channel. With almokalant, however, the first APD after wash-in was already prolonged and APD increased further with regular pacing. The effect was partially reversed during the third period of rest. These findings are compatible with open-channel block or no evidence for trapping. On the other hand, tedisamil prolonged APD but did not change the monophasic time course neither when added during quiescence nor at equilibrium of drug action. It is concluded that changes in APD after quiescence indicate differences among these drugs in their interactions with channel subtypes controlling repolarization.

Topics: Action Potentials; Adult; Aged; Anti-Arrhythmia Agents; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cyclopropanes; Female; Heart; Humans; In Vitro Techniques; Ion Channels; Male; Middle Aged; Piperidines; Propanolamines; Pyridines

The effects of the Ito blocker, tedisamil (0.1, 1.0, and 3.0 mg/kg, IV), and the IK blocker, E-4031 (0.1, 1.0, and 3.0 mg/kg, IV), on the incidence and duration of reperfusion-induced arrhythmias were compared in the anesthetized rat (n = 12 per group). Reperfusion arrhythmias were evaluated after a 5 minute occlusion period of the left main coronary artery. In the absence of any pronounced effect on blood pressure, tedisamil and E-4031 reduced heart rate in a dose-dependent manner. During the preischemic period, QTc interval was increased by tedisamil but was not changed by E-4031. Both compounds increased the QTc interval during the ischemic period and also during the reperfusion. E-4031 was unable to reduce the incidence and duration of reperfusion-induced ventricular arrhythmias after 5 minutes of coronary artery occlusion. Tedisamil dose-dependently reduced the duration of reperfusion arrhythmias and their incidence. In a second set of experiments, the combination of tedisamil (1.0 mg/kg) with E-4031 (1.0 mg/kg) was administered. The electrocardiographic action of this combination was similar to that observed with tedisamil given alone. However, with the combination the incidence of fibrillation was reduced from 83% in the control group to 8% in the treated group (p < 0.001), and the mortality was reduced from 67% to 0% (p < 0.001), that is, to a greater extent than with tedisamil (1.0 mg/kg) alone. The results show that the blockade of Ito by tedisamil allows a reduction of reperfusion-induced mortality and that a specific IK blocker (E-4031) is devoid of antifibrillatory action in the anesthetized rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cyclopropanes; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Electrocardiography; Heart Rate; Male; Piperidines; Pyridines; Rats; Rats, Wistar; Reperfusion Injury