Antithrombotic Activity of the Antiplatelet Agent Angipur on the Model of Arterial Thrombosis in Rats with Isoproterenol-Induced Myocardial Infarction.

We studied the effect of Angipur on the process of experimental thrombosis induced by damage to the carotid artery wall by surface application of 50% ferric chloride (III) solution in rats without comorbidities and with isoproterenol-induced myocardial infarction. In animals without comorbidities, Angipur administered intravenously was 1.2 times less effective, in terms of ED50, than the well-known inhibitor of GPIIb/IIIa platelet receptors tirofiban. However, under conditions of non-coronary myocardial infarction, Angipur significantly prolonged the time of thrombus formation and exhibited 1.4-fold higher activity than the reference drug tirofiban.

Effects of Zoniporide and BMA-1321 Compound on the Rate of Oxygen Absorption by Cardiomyocyte Mitochondria in Rats with Experimental Chronic Heart Failure.

Uncoupling of respiration and ATP production by myocardial mitochondria was observed in rats with chronic isoproterenol intoxication (L-isoproterenol subcutaneously, 1 mg/kg, for 10 days) in comparison with controls (injected with the solvent). Inhibitors of NHE-1 zoniporide (1 mg/kg intraperitoneally, 13 days) and BMA-1321 compound (0.92 mg/kg intraperitoneally, 13 days) improved the mitochondrial function in rats with isoproterenol-induced cardiac failure: respiratory control coefficients increased, more so for the respiratory chain complex II, the main source of ROS in heart failure. The effect of BMA-1321 was more manifest (53%; p<0.05) in comparison with zoniporide (35%; p<0.05).

NEUROPROTECTIVE PROPERTIES OF A NEW INHIBITOR OF NA+/H+ EXCHANGER (COMPOUND RU-1355) ON THE MODEL OF FOCAL ISCHEMIA IN RATS.

Primary neuroprotective properties of new inhibitor of Na⁺/⁺ exchanger (compound RU-1355) were established on the model of 60-min focal ischemia of the left middle cerebral artery followed by 24-h reperfusion in rats. Compound RU-1355 significantly (by 34%) decreased neurological symptoms, reduced (1.67 times) the growth of neuron-specific enolase level in serum, decreased (2.3 times) the size of the necrotic zone, and reduced by 59% (p <0.05) the degree of cerebral edema According to the results of morphometric, immunoassay, and neurological assessments of brain damage, compound RU-1355 is superior on ave- rage by 43.5% (p < 0.05) in comparison to selective NHE1 inhibitor zoniporide.

[Structure and physiological role of NHE1 and pharmacological regulation of its activity].

This article summarizes results of preclinical and clinical trials concerning the effects of NHE1 inhibitors and prospects for their clinical application. NHE1 has been identified as the most abundant isoform of Na+/H+ exchanger in the heart of mammals. NHE1 regulates pH homeostasis, cell proliferation, migration, adhesion, and apoptosis. Ischemic activation of the NHE1 in myocardium results in intracellular calcium overload, which aggravates ischemic/reperfusion injury. In accordance with results of preclinical experimental studies, selective inhibition of the sarcolemmal NHE1 can delay progression of injury during ischemia, thereby reducing myocardial necrosis and improving recovery of ventricular function upon reperfusion. Inhibitors of NHE1, which can provide beneficial effect in the clinical treatment of these conditions, are currently under preclinical and clinical tests. At present, there are 481 NHE inhibitors known according to the Thomson Reuters Integrity database.

[Cardioprotective properties of zoniporide studied on experimental ischemia and reperfusion models in rat myocardium].

Using the experimental model of rat heart ischemia/reperfusion, it is established that zoniporide (inhibitor of Na+/H+ exchanger) produces a significant (1.4-fold) decrease in the area of myocardial necrosis, 2.1-fold decrease in the serum troponin I level, and 2-fold decrease in the severity of post-reperfusion arrhythmias.

[Functional reserves of the heart under conditions of alimentary magnesium deficit].

Aim of the study was to assess functional reserves of myocardium in animals with deficit of magnesium during stress tests. Magnesium deficit was modeled by 10 week long magnesium deficient diet. After 54% lowering of magnesium level in erythrocytes we registered left ventricular pressure, myocardial contraction and relaxation rates, heart rate, systolic and diastolic arterial pressure, intensity of structures functioning. Than we subjected hearts of these animals to volume load, graded stimulation of cardiac adrenoreceptors, maximal isometric load by clamping ascending aorta. In animals with magnesium deficit we noted smaller increases of left ventricular pressure, myocardial contraction and relaxation rates under conditions of all functional tests, and of systolic arterial pressure during loading with volume and adrenaline. Lowering of myocardial reactivity under conditions of volume and adrenaline loading as well as isometric work load could constitute a basis of genesis of heart failure in magnesium deficit.

[Clinical and functional characteristics of chronic obstructive pulmonary disease in association with pathology of the cardiovascular system in persons of advanced age].

The study was aimed at clinic-functional features of chronic obstructive pulmonary disease (COPD) in association with an arterial hypertension and an ischemic heart disease in persons of advanced age. 69 women and 82 men have been examined through clinic-laboratory, functional and tool methods of inspection. Distinctions in frequency of combined pathologies in the group of women of advanced age have been revealed in comparison with men. Presence of combined pathologies in women of advanced age with chronic obstructive illness of lungs aggravates its clinical current. The accompanying ischemic heart trouble influences the clinical picture of COPD in a greater extent.

[Comparative study of the antiarrhythmic activity of L-, D-and DL-stereoisomers of potassium magnesium aspartate].

Injection forms of potassium (K) and magnesium (Mg) aspartate (Asp) were compared in preventing cardiac disorders caused by electrolytic disturbances, primarily low K and Mg levels (e.g. caused by the treatment with cardiac glycosides and diuretic drugs). Widely used K- and Mg-Asp preparations (asparkam, panangin, pamaton) are synthesized from aspartic acid representing a racemic mixture of L- and D-stereoisomers. Differences in metabolism and utilization of D- and L-amino acids probably influence the pharmacological properties of K and Mg L- and D-aspartates. Moreover, the pharmacologically effective doses of Mg and K salts can induce toxicity, which depends on the nature of anions. The aim of this study was to compare of antiarrhythmic action of K and Mg L-, D-, and DL-Asp stereoisomers using calcium chloride (CaCl2) and aconitine induced arrhythmia models in rats and strophanthin-K induced arrhythmia model in guinea pigs. It was found that intravenously administered K- and Mg-L-Asp exhibited higher activity compared to K- and Mg-D- and DL-Asp on the strophanthin-K, CaCl2, and aconitine induced arrhythmia models. Indeed, K- and Mg-L-Asp more effectively decreased the incidence of arrhythmias, increased the time to onset of the first arrhythmia, decreased percentage loss of rats, and increased the survival life of animals after the first arrhythmia onset in rats with arrhythmias induced by strophanthin-K and CaCl2 as compared to K and Mg-D- and DL-Asp. At the same time K- and Mg-L-Asp was better than D- and DL-Asp with respect to acute toxicity (LD50), effective dose (ED50) and antiarrhythmic (therapeutic) ratio (LD50/ED50) in rats with aconitine-induced arrhythmia model.

[Comparative evaluation of the effects of carnitine stereoisomers and racemate on the cardio- and hemodynamics of rats on a carnitine-deficient diet].

L-carnitine (L-beta-hydroxy-gamma-N,N,N-trimethylaminobutyric acid) is conditionally necessary for mitochondrial transport and metabolism of long-chain fatty acids, and thus for myocardial energetic metabolism. D-carnitine is not biologically active and might interfere with proper utilization of the L isomer, and so there are claims that the racemic mixture (DL-carnitine) should be avoided. The pharmacological effects of carnitine are stereospecific: L-carnitine was effective in various animal and clinical studies, while D- and DL-carnitine was found to be ineffective or even toxic to some cells and tissues, such as muscle cells and the myocardium. DL-carnitine caused symptoms of myasthenia and cardiac arrhythmias, which disappeared after L-carnitine administration. Therefore, the purposes of this work were (1) to study the effect of L-carnitine vs. that of D- and DL-stereoisomers on carnitine restoration rate in blood plasma of carnitine-deficient rats and (2) to evaluate the effect of stereoisomers and racemate of carnitine on the cardio- and hemodynamics of rats on carnitine-deficient diet. To induce carnitine deficiency, 60 rats were placed on a carnitine-deficient diet containing 1 g of N-trimethyl-hydrazine-3-propionate (mildronate) per a kilogram of the diet. The controls, 15 rats, received a basal control diet of the same duration. After 80 days, L-, D-, and DL-carnitine were administered in a dose of 200 mg/kg per os for 30 days, together with the carnitine-deficiency diet. To investigate the effect of L-, D-, and DL-carnitine on the abnormalities of the myocardial function of the carnitine-deficiency rats, various hemodynamic variables including left ventricular pressure, indices of contractility and relaxation, heart rate, systolic and diastolic blood pressure in response to volume loading test, adrenoreactivity test, and maximal isometric loading test, were measured. In this study, the carnitine-deficient diet with mildronate caused a substantial loss of carnitine in blood plasma by 56.49% (19.70 +/- 4.97 vs. 45.27 +/- 6.97 micromol/ 1, p < 0.001), which was accompanied by myocardial malfunctioning. After 30 days of L-carnitine administration, the plasma level of carnitine was significantly higher by an average of 118.55% (p < 0.001) compared with carnitine-deficient controls, while after administration of D- and DL-stereoisomers the carnitine content did not change or increased insignificantly. L-carnitine administration to carnitine-deficient rats led to normalization in myocardial function including indices of contractility and relaxation, systolic and diastolic blood pressure in response to volume loading test, adrenoreactivity test, and maximal isometric loading test. Chronic administration of D- and DL-carnitine did not change an altered cardio- and hemodynamics of carnitine-deficient rats compared with L-carnitine.

[The cardiotoxic properties of anti-arrhythmia agents]. / Kardiotoksicheskie svoistva antiaritmicheskikh sredstv.

Experiments were conducted on cats to study the cardiotoxic and arrhythmogenic properties of some antiarrhythmic agents in continuous intravenous infusion in doses multiple of the dose which causes an antiarrhythmic effect on an acontic model of arrhythmia in rats in 50% of cases. Novocainamide, cordarone, bonnecor, and quinidine possessed the most marked cardiotoxicity. A less marked cardiodepressive activity was encountered in the case of ethmosine and ethacysin. The appearance of the cardiodepressive properties of the agents depended on the rate of their injection. The results of the study testify to the possibility of prognosticating the arrhythmogenic and cardiodepressive effects in experimental investigation of new antiarrhythmic agents.

[The cardiotoxic properties of kordaron in acute myocardial ischemia and infarct]. / Kardiotoksicheskie svoistva kordarona v usloviiakh ostroi ishemii i infarkta miokarda.

Cardiodepressive and arrhythmogenic properties of cordarone were studied on cat in conditions of experimental acute ischemia and myocardial infarction upon intravenous infusion. The obtained results showed an increase cordarone cardiotoxicity and arrhythmogenic properties in conditions of myocardial infarction. No reliable difference was observed in dynamics of cordarone-induced changes in ECG parameters in animals with myocardial ischemia of various duration and intact animals.

Arrhythmogenic threshold of the myocardium under conditions of magnesium deficiency.

We studied the arrhythmogenic threshold of the myocardium after injection of CaCl2 to magnesium-deficient rats receiving Mg2+ L-aspartate, MgCl2, their combination with vitamin B6, and reference preparations Magne B6 and MgSO4 until complete compensation of magnesium level in the plasma and erythrocytes. Magnesium-deficient diet and deionized water were used for inducing alimentary Mg2+ deficiency and modeling pathological changes in rats. After reducing Mg2+ level to 0.7 mmol/liter in the plasma and to 1.5 mmol/liter in erythrocytes, Mg L-aspartate, MgCl2, their combination with vitamin B6, as well as Mg2+ deficiency led to a decrease in the dose of CaCl2 provoking heart rhythm disturbances in 50% animals and shortening of animal life span. Administration of the test magnesium salts increased the arrhythmogenic threshold; Mg2+ salts were comparable by their efficiency with Magne B6 and were far superior to MgSO4.