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DOI: https://doi.org/10.3897/rrpharmacology.4.28592

2-PHENYL-1-(3-PYRROLIDIN-1-IL-PROPYL)-1 H-INDOLE HYDROCHLORIDE (SS-68): ANTIARRHYTHMIC AND CARDIOPROTECTIVE ACTIVITY AND ITS MOLECULAR MECHANISMS OF ACTION (PART I)

Introduction. The problem of heart rhythm disturbances is one of the most urgent topics of modern cardiology. According to the currently available concepts, 1,2- and 1,3-disubstituted aminoindole derivatives, which compound 2-phenyl-1-(3-pyrrolidin-1-il-propyl)-1H-indole hydrochloride (SS-68) belongs to, are a promising chemical group in terms of their cardio-pharmacological activity.

Materials and methods. To study the anti-arrhythmic activity of SS-68 compound, the following models were used: 1) Models of cardiogenic arrhythmia: aconitine-inducedic, calcium chloride-induced, barium chloride-induced, cesium chloride-induced, adrenaline model of arrhythmia, strophanthine-induced arrhythmias, as well as arrhythmias caused by electrostimulation and acute myocardial ischemia; 2) neurogenic arrhythmias: arrhythmias caused by administration of aconitine, strophanthine K, cesium chloride into the IV ventricle of the brain and also by applying carbachol on the somatosensory cortex. To assess the antianginal activity of SS-68 in various models, the effect of this drug and comparators on the intact and ischemic myocardium was studied.

Results. It was found that with cardiogenic arrhythmias, SS-68 compound exhibits a pronounced antiarrhythmic effect and brings to normal the electrophysiological pattern of the heart, in most cases exceeding the analogous effect of reference drugs (amiodarone, lidocaine, aymaline, ethacizine, etmozine, quinidine anaprilin). In neurogenic arrhythmias, SS-68 also had a stopping effect, and, in addition, reduced the epileptiform activity of the brain in the model with the application of carbachol on the somatosensory cortex. In the study of antianginal and coronary vasolidating activities, SS-68 demonstrated pronounced thrombolytic and anti-ischemic activities, manifested in an increase in the coronary blood flow, a positive effect on ST-segment depression, and a decrease in the area of necrosis in experimental myocardial infarction.

Discussion. The antiarrhythmic and antianginal activities of SS-68 compound create the prerequisites for further study of the pharmacological properties of this molecule. In addition, it seems appropriate to continue studying the pharmacodynamics, pharmacokinetics and molecular mechanisms of SS-68 action.

Conclusions. SS-68 compound is a promising pharmacological agent with a high activity towards various electrophysiological disorders in the heart, and, in addition, it has significant antiischemic and coronary vasolidating properties.

Ключевые слова: arrhythmias, antiarrhythmics, infarction, angina pectoris, SS-68.

Иллюстрации

Figure 1. Comparative activity [according to ED50 in mg/kg (shaded bars) and mM/kg (dark bars)], relative activity (RA), acute toxicity (LD50) and therapeutic window (TW) SS-68, amiodarone (Am) and lidocaine (Li) in the prevention of aconitine-induced arrhythmia in experiments in conscious rats. Note: here and henceforward ED50 – effective dose; LD50 – dose that causes the death of 50% of animals; RA – relative activity; TW – therapeutic window

Figure 2. Comparative activity [according to ED50 in mg/kg (shaded bars) and mM/kg (dark bars)], relative activity (RA), acute toxicity (LD50) and therapeutic window (TW) of SS-68, quinidine (Qu), Aymalin (Ay), amiodarone (Am), and lidocaine (Li) used to arrest aconitine-induced arrhythmia in experiments in anesthetized rats. Note: ED50 – effective dose; LD50 – dose that causes the death of 50% of animals; RA – relative activity; TW – therapeutic window

Figure 3. Comparative activity [according to ED50 in mg/kg (shaded bars) and mM/kg (dark bars)], relative activity (RA), acute toxicity (LD50) and therapeutic window (TW) of SS-68, quinidine (Qu), Aymalin (Ay), amiodarone (Am), and lidocaine (Li) used to arrest aconitine-induced arrhythmia in experiments in anesthetized rats. Note: ED50 – effective dose; LD50 – dose that causes the death of 50% of animals; RA – relative activity; TW – therapeutic window

 

Figure 4. Comparative activity [according to ED50 in mg/kg (shaded bars) and mM/kg (dark bars)], relative activity (RA), acute toxicity (LD50) and therapeutic window (TW) of SS-68, quinidine (Qu) and amiodarone (Am) used to arrest barium chloride-induced arrhythmia in experiments in conscious rabbits. Note: ED50 – effective dose; LD50 – dose that causes the death of 50% of animals; RA – relative activity; TW – therapeutic window

Figure 5. Comparative activity [according to ED50 in mg/kg (shaded bars) and mM/kg (dark bars)], relative activity (RA), acute toxicity (LD50) and therapeutic window (TW) of SS-68 and amiodarone (Am) used to prevent chloride cesium arrhythmia in experiments in anesthetized rats. Note: ED50 – effective dose; LD50 – dose that causes the death of 50% of animals; RA – relative activity; TW – therapeutic window

Figure 6. Comparative activity [according to ED50 in mg/kg (shaded bars) and mM/kg (dark bars)], relative activity (RA), acute toxicity (LD50) and therapeutic window (TW) of SS-68 and amiodarone (Am) used to treat cesium chloride-induced arrhythmia in experiments in anesthetized rats. Note: ED50 – effective dose; LD50 – dose that causes the death of 50% of animals; RA – relative activity; TW – therapeutic window

Figure 7. Comparative activity [according to ED50 in mg/kg (shaded bars) and mM/kg (dark bars)], relative activity (RA), acute toxicity (LD50) and therapeutic window (TW) of SS-68, amiodarone (Am), atenolol (At), and anaprilin (An) used to prevent adrenal-induced arrhythmia in experiments in anesthetized rats. Note: ED50 – effective dose; LD50– dose that causes the death of 50% of animals; RA – relative activity; TW – therapeutic window

Figure 8. Comparative activity [according to ED50 in mg/kg (shaded bars) and mM/kg (dark bars)], relative activity (RA), acute toxicity (LD50) and therapeutic window (TW) of SS-68, quinidine (Qu), aymalin (Ay), lidocaine (Li), and verapamil (Ve) used to arrest strophanthine-induced arrhythmia in experiments in anesthetized cats. Note: ED50 – effective dose; LD50 – dose that causes the death of 50% of animals; RA – relative activity; TW – therapeutic window

Figure 9. Comparative activity (according to TAD) of SS-68 and lidocaine (Li) in ventricular arrhythmias caused by a two-stage coronary artery litigation in dogs. Note: TAD – threshold antiarrhythmic dose, EVC – ectopic ventricular contractions, MAE – maximum antiarrhythmic effect, DAE50 – decrease in antiarrhythmic effect by 50%, BPM – beats per minute (heart rate). * – the differences are statistically significant at p<0.01 compared with lidocaine.

Figure 10. Comparative antifibrillatory activity (A) and duration of action (B) of SS-68 (5 mg/kg) and amiodarone (Am; 10 mg/kg) under conditions of intact (IntM) and infarcted myocardium (InfM) in cats. Note: IVFT – increased ventricular fibrillation threshold, DAE – duration of antifibrillatory effect.

Figure 11. Comparative activity of SS-68 (5 mg/kg), lidocaine (L; 7 mg/kg) and amiodarone (A; 10 mg/kg) in early occlusive (EOA) and reperfusion arrhythmias (ERA) in cats. Note: C – control, HRD – heart rhythm disturbance, VF – ventricular fibrillation of the heart. The figures in the light part of the bar charts are the number of animals without either arrhythmia or VF, in the dark part – the number of animals with arrhythmia and VF. * – the differences are statistically significant (p<0.05) compared with the control

Figure 12. Comparative activity (according to EC15) of SS-68, ethacizine, quinidine, lidocaine and amiodarone in their effect on the effective refractory period of the isolated atrial appendage of a guinea pig. Note: EC15 – effective concentration of the substance, increasing the refractory period by 15%.

Figure 13. Comparative activity of SS-68, quinidine (Qu), etmozine (Et) and amiodarone (Am) in dogs with atrial flutter. Note: bar charts: shaded bars – doses in mg/kg, dark bars – doses in mM/kg; figures above the bars: in the numerator – doses in mg/kg, in the denominator – doses in mM/kg. The data characterizing quinidine and etmozine are given according to (Senova et al. 1973), amiodarone – according to (Dolskaya 2010).

Figure 14. Influence of SS-68 on the EF (in blue) in the cat’s SAN. Note: a – the initial state, b – with stimulating VN, c –45 minutes after the administration of SS-68; g – in 45 minutes with vagal-cardiac synchronization (VCS).

Figure 15. EF migration (blue against black background) of SAN in a cat. Note: A – the localization scheme for the cat’s SAN. B – localization of the EF in the SAN: a – the initial EF localization; b – EF localization in case of bradycardia caused by stimulatng VN with electrical pulses in a batch mode; c – localization of the EF 45 minutes after the administration of SS-68. C – the morphological structure of the SAN (left) and the localization of the EF in the depth of the SAN (right).

Figure 16. Comparative activity [according to ED50 in mg/kg (shaded bars) and mM/kg (dark bars)], relative activity (RA), acute toxicity (LD50) and therapeutic window (TW) SS-68, etmozine (Etm), ethacizine (Eth), anaprilin (An), lidocaine (Li) and amiodarone (Am) used to arrest aconitine-induced arrhythmia of the central origin in experiments in anesthetized cats. Note: ED50 – effective dose; LD50 – dose that causes the death of 50% of animals; RA –relative activity; TW - therapeutic window

Figure 17. Comparative activity [according to ED50 in mg/kg (shaded bars) and mM/kg (dark bars)], relative activity (RA), acute toxicity (LD50) and therapeutic window (TW) of SS-68, lidocaine (Li), etmozine (Etm), ethacizine (Eth), anaprilin (An), verapamil (Ve) and amiodarone (Am) used to treat strophantine-induced arrhythmia of the central origin in experiments in anesthetized cats. Note: ED50 – effective dose; LD50 – dose that causes the death of 50% of animals; RA – relative activity; TW – therapeutic window

Figure 18. Comparative activity [according to ED50 in mg/kg (shaded bars) and mM/kg (dark bars)], relative activity (RA), acute toxicity (LD50) and therapeutic window (TW) of SS-68 and amiodarone (Am) used to arrest cesium chloride- induced arrhythmia of central origin in experiments in anesthetized cats. Note: ED50 – effective dose; LD50 – dose that causes the death of 50% of animals; RA – relative activity; TW - therapeutic window

Figure 19. Oppressive effect of SS-68 compound (29.3 μM) on the epileptiform activity caused by the preliminary exposure to CCh (12.5 mM). Note: K1 and K2 – the upper (400 μm immersion depth) and the lower (1200 μm) layers of the cortex column, respectively, in which the microapplication of SS-68 was made. (up to 1 μl). The arrows mark the time of administration of SS-68.

Figure 20. Antiarrhythmic effect of SS-68 in conditions of HRD induced by microapplication of CCh on the somatosensory cortex of the rat’s brain. Note: K1 and K2 – the upper (400 μm immersion depth) and the lower (1200 μm) layers of the experimental cortical column, respectively, in which the microapplication was made (up to 1 μl) KX and the SS-68; K3 and K4 – upper (400 microns) and lower (1500 microns) layers of the control column located at a distance of 1200 microns from the experimental one; K5 – the electrocardiogram.

Figure 21. Influence of SS-68 (2 mg/kg intravenously) on the blood supply of the heart in cats. Note: curves from top to bottom: CAFV – coronary artery flow velocity, OR – oxygen reserve, BP – blood pressure, MOD – myocardial oxygen demand. * – significance in comparison with the initial data (p<0.05).

Figure 22. Influence of SS-68 (0.05 mg, intracoronarily) on the phasic coronary blood flow (PCBF) in dogs Note: Columns: 1, 2 and 3 – peak of reactive hyperemia (RH) (% of the initial data), peak of the action of SS-68 (% of the initial data) and the expansion reserve (% of RH), respectively. CBFed – coronary blood flow (CBF) at end diastole; CBFds – CBF diastolic stroke; CBF min – diastolic CBF per minute; CBFb. – CBF per beat; BP – blood pressure; LVP – left ventricular pressure; PPCVed – perfusion pressure in the coronary vessels at end diastole; RCVed – resistance of coronary vessels at end diastole; CBFss – CBF systolic stroke; PPCVs – perfusion pressure in the coronary vessels systolic; CBFI – CBF index; BPM – beats per minute (heart rate). * – the differences are statistically significant (p<0.05) compared to the baseline data.

Figure 23. Influence of SS-68 (2 mg/kg, intravenously) on the coronary artery blood flow velocity (CAFV) in conditions of myocardial ischemia induced by occlusion of the coronary artery (CAO) in dogs.

Figure 24. Influence of SS-68 compound (2 mg/kg, intravenously) on the blood supply of the myocardial ischemia focus in dogs. Note: VVRF – volume velocity of the retrograde blood flow; MOD (DP) – double product [index of myocardial oxygen demand (MOD)]; BP – blood pressure; OR – oxygen reserve; BPM – beats per minute (heart rate); * – the differences are statistically significant (p<0.05).

Figure 25. Changes in indices in relation to the baseline data 5 min after pituitrin-induced coronary spasm along with administration of SS-68 compound (2 mg/kg, intravenously) in cats. Note: CAFV – coronary artery blood flow velocity, MOD – myocardium oxygen demand, BP – blood pressure, OR – oxygen reserve. * – the differences are statistically significant (p<0.05).

Figure 26. Antianginal activity of SS-68 compound (1 mg/kg, intravenously) in experiments in cats. Note: * – the differences are statistically significant (p<0.05).

Figure 27. Antianginal effect of SS-68 comound (2 mg/kg, intravenously) in experiments in cats. Note: * – the differences are statistically significant (p<0.05).

Figure 28. Influence of a double intravenous administration of SS-68 compound at a dose of 2 mg/kg (the total dose of 4 mg/kg) on the size of the necrotic zone (in %) 24 hours after the experimental myocardial infarction in cats. Note: A – control, B – after administration of SS-68. TA – total amount ; I, II, III, IV, V – levels of sections (blocks) of the heart.

Figure 29. Average mass of necrotic myocardium: in control (C) and under the influence of SS-68 compound (bar chart); total index of necrosis (in %) (pie chart, necrosis – darker sector).

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