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 Dimebon, which is an Hi-receptor blocker, is shown to act as a moderate coronary vasodilator without exerting a marked effect on myocardial contractility. Key Words: Dimebon; coronary blood flow; myocardial contractilityA major problem in cardiology is sudden cardiac death, which is often preceded by ventricular arrhythmias due to inadequate coronary circulation [7]. Recently, we reported evidence that the Russianmade antihistamine Dimebon (Hi-receptor blocker) exhibits, in various animal models, an antiarrhythmic activity superior to that of quinidine, Ethmosine, Bonnecor, and verapamil [2]. Our present study is the first in which Dimebon was tested for its effects on coronary blood flow (CBF) and myocardial contractility. MATERIALS AND METHODSPhasic changes in CBF were examined in five dogs with open chest [4] after an intravenous injection of Dimebon at 2.5 mg/kg body weight. The following parameters were measured: heart rate, left ventricular and aortic pressures, perfusion pressure in coronary vessels at the end of diastole, stroke systolic CBF, stroke diastolic CBF, coronary index (ratio of the stroke diastolic CBF to the stroke systolic CBF), stroke CBF, minute CBF, and resistance of coronary vessels at the end of diastole. Myocardial contractility was evaluated from the level of intraventricular pressure and the rate of its change (AP/Atox) and also by measuring the acceleration developed by the myocardium [5]. Department of Pharmacology, Kuban Medical Academy, KrasnodarThe effect of intravenous Dimebon (2.5 mg/kg) on myocardial contractility was tested on seven artificially ventilated cats with [3-adrenoceptors blocked by Obsidan (1 mg/kg intravenously). In these cats we additionally determined the phasic structure of the cardiac cycle by measuring the lengths of the asynchronous contraction phase, isometric contraction phase, tension period, ejection period, total systole, and left ventricular diastole [3].The effect of Dimebon on the electrical and contractile properties of coronary vessels was examined in vitro using 12 isolated segments of porcine coronary arteries [6] exposed to a hyperpotassic solution or to serotonin.The data were statistically analyzed as described by Belen'kii [1]. RESULTSDimebon administration to dogs led to significant rises in the heart rate by 3.7%, stroke systolic CBF by 68.8%, stroke diastolic CBF by 42.2%, stroke CBF by 49.5%, and minute CBF by 52.6%, and to a 48.6% increase in the acceleration developed by the myocardium; the aortic and perfusion pressures significantly decreased by 6.9% and 12.3%, respectively (Fig. 1).Variations in the other two parameters (coronary index and AP/At ) in response to Dimebon were insignificant, which should be interpreted as an indication of its beneficial cardiotropic action. It is
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