In the basis of the pathogenesis of cardiovascular disease, the leading role is given to endothelial vascular dysfunction, which can be the pathobiochemical target of the effect of corrective medicines.
It is known that many medicines with different mechanisms of indirect action on the function of vascular endothelium (ACE inhibitors, AT-II receptor blockers, L-lysine escinate, and medicines of metabolitotropic action).
The active substance (S)-2,6-diaminohexanoic acid 3-methyl-1,2,4-triazolo-5-thioacetate (the working name of Lizini, the new name is Angiolin) was synthesized in the Pharmatron Research Institute for the purpose of creating an effective metabolitotropic endothelioprotector which combines in its structure fragments of the molecules of thiotriazolin and L-lysine escinate and has high anti-ischemic, cardioprotective, neuroprotective, antioxidant and anti-inflammatory properties.
Due to the fact that endothelial dysfunction is a consequence of oxidative and nitrosating stress, screening of 11 compounds among 1,2,4-triazole derivatives was carried out on suspension of neurons in rats, among which angiolin was identified as a leader compound that exceeds anti-oxidant properties of other investigating substances.
In order to determine the safety of angiolin, experiments were conducted to study its acute and chronic toxicity on 3 species of animals by different ways of administration. These experiments showed that the medicine belongs to the class V of toxicity (practically non-toxic substances).
To determine and evaluate the average effective dose (ED50), studies were conducted on model of acute myocardial infarction. As a result of these studies, it was found that the effective dose of «Angiolin» is – 50 mg/kg.
Subsequently, the effect of the direct endothelioprotector angiolin and the metabolitotropic medicine of indirect action of mildronate on the ECG measures of rats, morphofunctional and biochemical characteristics of the myocardium, in acute myocardial infarction were compared. Angiolin (50 mg/kg) to a greater extent than mildronate (100 mg/kg) normalized ECG measures in rats, significantly lowering the heart, reducing the ST deviation, restoring to the control level the T wave amplitude. Angiolin normalized to a greater extent than mildronate morphofunctional characteristics of the myocardium, namely, reduced the necrosis region, increasing the concentration of RNA nuclei of cardiomyocytes, cytoplasm by. In this case, angiolin, in comparison with mildronate, to a greater extent reduced the tendency of nuclei of apoptotic destructively altered cardiomyocytes. Angiolin renewed the parameters of the synthesis system, metabolism, transport of nitric oxide (activity of NO-synthase, NO content, nitrotirosine, L-arginine) and thiol-disulphide system (content of methionine, cysteine, reduced sulfhydryl groups), energy metabolism indices (adenine nucleotide content, glycogen, glucose-6-phosphate, pyruvate, isocitrate, malate, creatine phosphokinase activity, malate dehydrogenase, cytochrome C-oxidase), prooxidant-antioxidant homeostasis (level of AFG, CFG, glutathione peroxidase SOD activity). In acute myocardial ischemia which was modeled by the occlusion of the branch of the descending coronary artery of rats, angiolin restored more than mildronate the content of ATP, activity of creatine phosphokinase in the myocardium and showed antioxidant action, reducing the content of AFG, CFG. In acute myocardial ischemia in rabbits, which was modeled by the introduction of caffeine and adrenaline, angiolin, by prophylactic intravenous administration (50 mg/kg) reconstructed the parameters of the contractile activity of the myocardium RILSH, RUILSH, Рmax and arterial pressure which exceeded the effect of mildronate.
On the model of doxorubicin chronic cardiac insufficiency in rats, angiolin to a greater extent than mildronate increased motor activity on 35th day, prevented the development of myocardial hypertrophy and prevented the loss of protein in the cytoplasm and mitochondria, reduced the density of nuclei of apoptotic and destructively altered cardiomyocytes, increasing the area, the density of nuclei, concentration RNA in the nuclei and the cytoplasm of cardiomyocytes, prevented the development of fibrosis and restored morphometric indices of endothelial cells. In chronic heart failure in rats, angiolin increased to a greater extent than mildronate the content of total NO synthase, L-arginine, eNOS density, decreased iNOS, the level of metabolites NO, nitrotirosin, reduced the levels of thiol-disulphide system (content of methionine, cysteine, total recovered thiols, glutathione reductase activity, glutathione peroxidase). Angiolin increased the level of energy metabolism of myocardium in rats with CHF (adenine nucleotide, lactate, pyruvate, malate, glutamate, aspartate, creatine phosphokinase activity). At an intravenous administration of angiolin (100 mg/kg), rabbits with doxorubicin CHF obser
