The Hi-receptor blocker Dimebon is shown to exhibit pronounced antiarrhythmic properties. Its activity and therapeutic action range (toxic/therapeutic ratio) exceed those of quinidine, ethmosine, isoptin, and bonnecor in several animal models of cardiac arrhythmia. The mechanism of its antiarrhythmic action is probably associated with blockade of sodium and particularly calcium channels, prolongation of the effective refractory period, and slowing of impulse traffic in the conduction system of the heart. Dimebon may be recommended for submission to clinical trials as an antiarrhythmic agent.Key Words: Dimebon; antihistamines; antiarrhythmics Dimebon [3,-(2-methyl-pyridyl-5)-ethyl-1,2,3,4-tetrahydro-7-carboline dihydrochloride] is a new Russian-made antihistamine blocking H 1 receptors [5]. The present study was undertaken to test Dimebon for antiarrhythmic activity in view of the evidence that the myocardium contains H 1 receptors and that certain antihistamines are capable of suppressing arrhythmias in experimental animals [4,10]. MATERIALS AND METHODSThe study used 205 male Wistar rats (body weight 0.18-0.22 kg), 48 random-bred rabbits (2.3-3.4 kg), 56 cats (2.6-3.2 kg) and 35 dogs (12-18 kg) of both sexes, as well as 16 and 36 preparations of isolated frog and guinea pig atria (trabeculae and auriculae), respectively.The acute toxicity (median lethal doses, LDs0 ) of Dimebon and other antiarrhythmic drugs tested for comparison was measured in rats.The effects of the drugs on electrocardiographic The ability of the drugs to exert antiarrhythmic activity in mixed atrial/ventricular arrhythmias was assessed using models of arrhythmias induced by aconitine [3], epinephrine [9], and calcium chloride [14] in rats, barium chloride [6] in rabbits, and strophanthin [1] in cats. The end-points used in these experiments were the median effective dose (EDs0), which eliminated arrhythmia in 50% of the test animals, and the LDs0/EDs0 ratio, which gives an indication of the therapeutic (antiarrhythmic) action range of the drug used. In addition, Dirnebon and two other drugs were also tested for effects on atrial [15] and ventricular [13] arrhythmias in dogs. The activity of the drugs in atrial arrhythmia was measured by the method of bio-0007-4888/95/0004-0362512.50 9Plenum Publishing Corporation

The antihistamine drugs (Hi-blockers) dimebone and especially phencarol exhibit antiarrhythmic activity under conditions of neurogenic ventricular fibrillation. The antiarrhythmic activity of phencarol is associated with pronounced vagolytic effect, while that of dimebone is due to both vagolytic and moderate cardiotropic effect. Key Words: phenearol; dimebone; neurogenic ventricular fibrillation; vagolytic effect; cardiotropic effectThe Hi-histamine receptor blockers phencarol (quinuclidyl-3-diphenylcarbinol hydrochloride) and dimebone [3,6 -dimethyl -9-(2-methylpyridyl-5)-ethyl-1,2, 3,4-tetrahydro-3,-carboline dihydrochloride) [2,4] exhibit antiarrhythmic activity in modeled cardiac arrhythmias (CA). For instance, phencarol stops and prevents arrhythmias induced by calcium chloride, adrenalin, and strophanthin without affecting the ECG parameters, heart rate and producing no cardiodepressive effect. The antiarrhythmic activity of phencarol is attributed to its effect not only on Hi-histamine receptors, but also on the cardiomyocyte membrane permeability for calcium ions [9]. Dimebone exerts an antiarrhythmic effect in CA induced not only by chemical agents (adrenalin, strophanthin, calcium and barium chloride), but also by damage to the sinus node (atrial arrhythmia) or by myocardial infarction (ventricular arrhythmias), in some CA being superior or close by its activity and therapeutic range to quinidine, etmozin, bonnecor, and isoptin. The mechanism of this effect includes a primary effect of dimebone on slow calcium channels as well as prolongation of the effective refrac- MATERIALS AND METHODSThe study was performed on 16 cats weighing 2.5-4.5 kg narcotized with Chloralose and Nembutal (75 and 15 mg/kg, respectively) and artificially ventilated; body temperature was controlled automatically (37~ The right vagus nerve was cut at the level of the thyroid cartilage and its peripheral end was pinned on bipolar needle electrodes (the distance between the poles was 2.5 mm) and embedded into medical wax-vaseline oil mixture. Bipolar platinum probes were inserted into the right ventricle through the right femoral and jugular veins and used for recording the intra-atrial ECG (using an intervalograph assembled in our laboratory [7]) and electrical stimulation. The atrium was stimulated (5 msec, 1.5-4.0 threshold voltage) either in a periodic mode or with singe pulses synchronized with the P wave of the ECG using an ESU-2 electrostimulator. The vagus nerve was stimulated in either periodic (2

The dynamics of the Ca-response of cardiomyocytes is studied and the efficiency of befol, verapamil, and amiodarone is compared using various experimental models of stimulation of [Ca2*]r Befol (1-5 I~M) is shown to inhibit the caffeine-and strophanthin G-induced rise of [Ca2"]~. Unlike verapamil and amiodarone, befol exhibits no Ca-blocking activity in modeled K-depolarization. It is concluded that the cardiotropic effect of befol is mediated through its primary action on Na'/Ca 2 § exchange in cardiomyocytes, while the cardioplegic effect of verapamil and amiodarone is due to their ability to block the slow Ca 2. inward current.Key Words: calcium; befok ami/oride; strophanthin; caffeine; cardiomyocytes Calcium ions participate in the coupling between electrical excitation and muscle contraction in cardiomyocytes. In resting cardiomyocytes (CMC) the diastolic concentration of free Ca 2* ions in the cytoplasm ([Ca2~],) does not exceed 150 riM, whereas the Ca 2 § content in the extracellular space is several orders of magnitude higher (1-2 mM). Stimulation of the cells by various agents (electrical pulse, activation of ~1-, J31-, and 132-adrenoreceptors ) leads a rise of [Ca2 § which is directly proportional to the contractile response of CMC and determines the strength of cardiac contractions [10]. The reversible drop of [Ca2*]~ underlies the relaxation process.A positive inotropic effect of pharmacological preparations may be realized through: 1) receptor-mediated (isoproterenol, histamine) or direct (forskolin) activation of adenylate cyclase; 2) elevation of the intracellular concentration of Na § and Ca 2. (cardiac glycosides); and 3) inhibition of K § channels (4-aminopyridines). However, the molecular mechanisms of pharDepartment of Molecular Pharmacology and Radiobiology, Russian State Medical University, Moscow; Department of Pharmacology, Kuban Medical Academy, Krasnodar macological regulation of excitation and contractile activity of the heart have been little studied.Apart from the traditional electrophysiological methods of recording Ca fluxes in the myocardium, a new approach to the measurement of [Ca2 § has recently gained broad acceptance. This method is based on the use of the quin-2, indo-1, and FURA 2-AM fluorescent probes for Ca 2 § ions. This highly sensitive fluorescent technique has helped elucidate the main regularities of Ca homeostasis in isolated CMC [8].The aim of the present study was to investigate the effect of befol, a new Russian-manufactured antidepressant which has recently been found to possess also antiarrhythmic activity [2], on the basal and stimulated [Ca2 § levels in a CMC suspension and to compare this effect with that of verapamil and amiodarone. MATERIALS AND METHODSCMC were isolated from the left ventricle of rat hearts as described previously [9]. The cells were resuspended in a Krebs-Ringer bicarbonate buffer solution (10-15x10 5 cells/ml) and incubated with FURA 2-AM in

Local injection of verapamil into ventrolateral region of the medulla oblongata triggered the release of epinephrine. Verapamil increased the total content of norepinephrine and epinephrine by 560% and decreased the content of serotonin by 46%. Verapamil had no effect on norepinephrine/epinephrine and norepinephrine/(norepinephrine+epinephrine) ratios in normal rats. Blockade of K+-channels in the medulla oblongata by local injection of 0.001 mg amiodarone did not change the levels of epinephrine and norepinephrine and norepinephrine/epinephrine and norepinephrine/(norepinephrine+epinephrine) ratios. In the medulla oblongata, verapamil proportionally increased the levels of norepinephrine, dopamine, and L-DOPA. Similarly, amiodarone increased the levels of L-DOPA and dopamine by 2.6 and 3.2 times, respectively. Amiodarone shifted the ratio of neuroactive amino acids towards inhibitory transmitters.