Membrane mechanisms of antiarrhythmic effect of quaternidine.

Complex electrophysiological study of the effects of quaternidine carried out on intact hearts from cats, myocardial fragments from rats, and single ionic channels of large edible snail showed that quaternidine demonstrates properties of class 1B antiarrhythmic drug according to Vaughan-Williams nomenclature. This agent did not suppress nomotopic pacemaker automaticity, did not change conduction in ventricles, atria, and atrioventricular junction in hearts with preserved sinus rhythm, did not prolong refractoriness of the atria and atrioventricular junction, but prolonged efficient refractory period of heart ventricles. Quaternidine decelerated rapid depolarization of the action potential, but had no effect on its duration. It did not affect potassium conductance.

[Effect of trimecaine derivatives and lidocaine on hemodynamics]. / Vliianie proizvodnykh trimekaina i lidokaina na gemodinamiku.

The results of experiments on cats showed that quaternidine, a quaternary ammonium derivative of trimecaine, does not induce significant variations in the hemodynamic parameters, being advantageous in this respect to some well-known antiarrhythmic drugs. LKhT-3-00 (dialkylaminophenylacetamide glutaminate)--a tertiary derivative of lidocaine--leads to a slight decrease in the heart rate, an insignificant decrease in the arterial pressure for 10 min, and a pronounced enhancement of the pumping ability of the left ventricle over a time period of 30 min.

[Study of antiarrhythmic activity and duration of action of quaternidine]. / Issledovanie protivoaritmicheskoi activnosti i prodolzhitel'nosti deistviia kvaternidina.

The results of experiments on dogs showed that quaternidine, a quaternary ammonium derivative of trimecaine, produces a significant antiarrhythmogenic effect in cases of rhythm disorders in the late stage of a model myocardial infarction. For drugs administered in a single isotoxic dose, the therapeutic effect of quaternidine in animals with acute myocardial ischemia considerably exceeds the duration of action of lidocaine and trimecaine.

[The antiarrhythmic activity of the trimecain ammonium derivative in myocardial ischemia]. / Protivoaritmicheskaia aktivnost' ammonievogo proizvodnogo trimekaina na fone ishemicheskogo povrezhdeniia serdtsa.

The results of experiments on cats and dogs showed that quaternidine, a quaternary ammonium derivative of trimecaine, exceeds the structural precursors (trimecaine and lidocaine), as well as the reference drugs quinidine and propranolol, in intensity of the antiarrhythmic action upon single administration on the occlusive and reperfusive arrhythmia models. The therapeutic effect of quaternidine in animals with acute myocardial ischemia lasts for about 8 h, which more than 20 times longer as compared to the duration of action of both lidocaine and trimecaine.

[The anti-arrhythmia activity of amino acid-containing trimecaine derivatives on models of early occlusive and reperfusion arrhythmias in cats]. / Protivoaritmicheskaia aktivnost' aminokislotsoderzhashchikh proizvodnykh trimekaina na modeliakh rannikh okkliuzionnykh i reperfuzionnykh aritmii u koshek.

Experiments were conducted on models of early occlusion and reperfusion arrhythmias in cats to study the antiarrhythmic activity of trimecain, its morpholine analogue (MPT), and MPT derivatives containing glycine, magnesium salt of aspartic acid, and N-acetylglutaminic acid. All the compounds were injected in doses of 5% of LD50. A 22.5 mg/kg dose of trimecain prevented cardiac rhythm disorders after occlusion of the coronary arteries as well as after restoration of the coronary blood flow. Replacement of the diethyl group in the structure of trimecain by the morpholine ring led to diminution of antiarrhythmic activity, and MPT in a dose of 28.0 mg/kg, in distinction from the former, had no effect on the frequency of the occurrence of early occlusion arrhythmias and the duration of reperfusion arrhythmias. Introduction of amino acids as an anion into the MPT structure raised the antiarrhythmic activity of the last named.

[The effect of quaternization on local anesthetic effects of trimecaine]. / Vplyv kvarternizácie na lokálnoanestetický úcinok trimekaínu.

Effects of the local anaesthetic trimecaine and its quaternary derivative on the isolated rat sciatic nerves were examined. Trimecaine inhibited action potential propagation in the isolated nerve in vitro at four-times lower concentrations than its quaternary derivative. Despite extracellular application, the quaternary derivative inhibited action potential propagation in the sciatic nerve but with a longer half-life in comparison with trimecaine. With increasing external pH, the blocking effect of trimecaine was profound. The blocking potency of the quaternary compound was not consistently changed with the changes in external medium pH.

[The antiarrhythmic activity of the polymeric forms of quinidine, trimecaine, etatsizin, propranolol and verapamil]. / Antiaritmicheskaia aktivnost' polimernykh form khinidina, trimekaina, étatsizina, propranolola i verapamila.

The antiarrhythmic activity and acute toxicity of polymeric formulations of quinidine, trimecaine, ethacizine, propranolol, verapamil which had been immobilized on a cellulose carrier (monocarboxylcellulose) and low molecular analogues were studied in various experimental animals (rats, mice, dogs). The polymeric formulations of trimecaine and verapamil were found to have a higher antiarrhythmic activity in different arrhythmia models than trimecaine and verapamil. The toxicity of all new compounds was no more than the values of conventional antiarrhythmic drugs.

[Effect of trimecaine and its quaternary derivative G-103 on myocardial action potentials]. / Vliianie trimekaina i ego chetvertichnogo proizvodnogo Zh-103 na potentsial deistviia miokarda.

The conventional microelectrode technique was used to study the effects of trimecaine and its quaternary derivative G-103 on the action potential in the rat myocardium. G-103 suppressed the maximal rate of the action potential depolarization at lower concentrations than trimecaine although its effect developed slower: t 1/2 = 25 and 5 min, respectively. G-103 abolished the tonic component of trimecaine-induced blockade and failed to alter the rate-dependent component.

[Possible mechanism of long-term anti-arrhythmia and local anesthetic effect of quaternary ammonium compounds]. / O vozmozhnom mekhanizme dlitel'nogo antiaritmicheskogo i mestnoanesteziruiushchego deistviia chetvertichnykh ammonievykh soedinenii.

In experiments with dialized neurons of L. stagnalis mollusc the recovery of Na-current (INa) after its depression by local anesthetic trimecaine and its quaternary derivative N-ethyltrimecaine (G-88) was studied. A full recovery of INa within tens of seconds after washing off trimecaine but not G-88 was observed. The half-time for vanishing of INa use-dependent depression by G-88 was 17 minutes, and there was no substantial vanishing of tonic INa block even after an hour of G-88 washing off. A hypothesis is advanced that the long recovery time of INa is one of the mechanisms providing long pharmacological action of quaternary antiarrhythmic and local anesthetic ammonium compounds.

[Pharmacological study of quaternary trimecaine derivatives]. / Farmakologicheskoe izuchenie nekotorykh chetvertichnykh proizvodnykh trimekaina.

It has been demonstrated in experiments on cats, rabbits, white rats and mice that the quaternary derivatives of trimecaine (QDT) produce a protective and antiarrhythmic action in atrial (acetylcholine and aconitine) and ventricular (aconitine and calcium chloride) fibrillation. The relationship has been found between the characteristics of the radical at the quaternary nitrogen atom and the antiarrhythmic activity of the QDT. The effect of the QDT on the electrophysiological parameters of the myocardium not on the hemodynamics have been examined. It has been shown that the QDT might be suggested for use as new antiarrhythmic agents.