12+

ON MECHANISM OF ANTIARRHYTHMIC ACTION OF SOME DIMETHYLPHENYLACETAMIDE DERIVATIVES

Abbreviations: AC – acetylcholyne; AF – atrial fibrillation; AP – action potential; BLM – bi-lipid membrane; DPA – Dimethylphenylacetamide; VA – ventricular arrhythmia

Introduction: The study aim was to identify essential elements of the antiarrhythmic action mechanism of tertiary and quaternary derivatives of Dimethylphenylacetamide.

Materials and Methods: The study was conducted in albino rats and mice of both sexes; isolated neurons of mollusc Limnea stagnalis ; and strips of rats’ right ventricle myocardium. Two compounds of Dimethylphenylacetamide LKhT-3-00 and LKhT-12-02 were studied. The cholynolytic property of the compounds was investigated by using a Schallek method in the authors’ modification. The adrenotropic activity of the derivatives was explored by Moore and Spear ( 1984 ), as well a by the method of catecholamine level detection in heart tissue. The permeability of derivatives through BLM was evaluated experimentally and theoretically. The derivatives’ influence on Na + -current was studied directly and indirectly.

Results and Discussion: Neither tertiary nor quaternary derivatives possess the cholynolytic property. LKhT-3-00 prevented an increase in the adrenaline concentration in the left ventricle myocardium. The compounds prevent catecholamine arrhythmia and conductivity disorders. LKhT-3-00 like Lidocaine passes through the BLM of the cardiac cell in an ionised form, whereas the quaternary derivative permeates cardiac cell membrane in an electro-neutral form. Lidocaine derivatives restrain acute ischemia-induced oxidative process growth in the cardiac muscle. Simultaneously, the LKhT-3-00 compound can activate antioxidant mechanisms and prevent acidosis and optimise the balance between [O 2 ] and [CO 2 ] concentrations in coronary dark blood. At a concentration of 10 mg/ml, although the derivatives reduce the amplitude of the leading edge of AP and its rate of increase, they do not, however, affect the duration of AP .

Conclusions: The compounds possess the Na + -blocking and cell-protecting properties. They do not affect K + -current through Kv4.3-channels.

Иллюстрации

Figure 1. Chemical structures of DPA compounds

Table 1. Evaluation of Anti-adrenergic Effect of Tertiary and Quaternary DPA derivatives in experiments on anaesthetised mice

Note : VA - ventricular arrhythmia, CCD - cardiac conduction disease.

# - differences when comparing the results with the “Control group” results are significant at p <0.05, Fisher’s exact test.

* - differences when comparing the results with “Control group” results are significant at p <0.05;

а - when compa ring with the “Propranolol”group, the differences are statistically significant at p <0.05 (analysis of the survival curves using the Gehan criterion with Yates’ correction).

Table 2. Determination of Epinephrine and Norepinephrine in Myocardium of Rats’ hearts during Experimental Ischemia with Administration of DPA derivatives

Note : LV - left ventricle, LA - left atrium, RZ - remote zone, IZ – ischemic zone

* - statistical significance of the differences when compared with the “ LV group” at p <0.05 is determined using a one-dimensional analysis of variance and the subsequent application of the Newman-Keuls criterion.

# - statistical significance of the differences when compared with the “Control” group at p <0.05 is determined using a one-dimensional analysis of variance and the subsequent application of the Newman-Keuls criterion

Figure 2.  Average duration of AC -induced AF with preventative ( 1 ) and controlling ( 2 ) iv administration of atropine sulphate (A), compound LKhT-3-00 (B), compound LKhT-12-02 (С); D - control group of animals

Figure 3. Relative increase in the refractivity of the ventricular heart tissue of the rat (in % of the original value) affected by: 15 μM lidocaine (n = 5), 50 μM trimecaine (n = 4), 5 μM LHT-12-02 (n = 6) and 30 μM LHT-3-00 (n = 5). Note : mean refractivity in the control: 92 ± 3 (lidocaine), 90 ± 7 (trimecaine), 94 ± 8 (LKhT-12-02) and 96 ± 4 ms (LKhT-3-00). The average values and root-mean-square deviations are provided. On the abscissa - the time of registration of parameters in min. * - according to O.G. Agenosova

Table 3. Correlation of Pro-oxidant / antioxidant Potential of Cardiomyocyte Membranes of Rat’s Hearts with Acute Myocardial Infarction, with Dimethylphenylacetamide (Lidocaine), Derivatives Being Preventatively Administered.

Note : LA - left atrium, LV - left ventricle, RZ - remote zone, IZ - ischemic zone

* - when compared with the control group, the results are statistically significant at p <0.05 (single-factor analysis of variance, Newman-Keuls criterion);

q - In comparison with the control group, the “Lidocaine” and “LKhT-12-02” groups, the results are statistically significant at p <0.05 (single-factor analysis of variance, Newman- Keuls criterion).

Figure 4. Effect of dimethylphenylacetamide derivatives (at a concentration of 10.0 mg/l) on AP (upper curve) and V max (bottom curve) of the papillary muscle of the rat’s right heart ventricle.

Figure 5. Records of currents through potassium channels of the neuron of the Limnea stagnalis mollusc in a “whole-cell” configuration.

DOI: https://doi.org/10.3897/rrpharmacology.4.25112
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