Remote postconditioning (RPost) has a great therapeutic potential for protecting the myocardium during ischemiareperfusion in clinical practice. At the same time, an important problem limiting the use of conditioning effects in the clinic is the presence of metabolic disorders in the patient. The aim of this work was to assess the effect of induced metabolic syndrome (iMetS) on the efficacy of the infarct-limiting effect of remote ischemic postconditioning (RPost) in rats and to study the mechanisms of this effect.The study was carried out on Wistar rats. MetS was induced by high-carbohydrate high-fat diet. Criteria of metabolic syndrome were an increase in the weight of animals, abdominal fat volume, the development of arterial hypertension, hypercholesterolemia, an increase in triglycerides in serum, hyperleptinemia, hyperglycemia, the development of a state of insulin resistance by a significant increase in the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) index and glucose tolerance. All animals were subjected to 45 min coronary occlusion and 120 min reperfusion.RPost led to a twofold reduction of infarct size in rats with intact metabolism (р < 0.0001), while in rats with iMetS a decrease in infarct size during RPost was 25 % (p = 0.00003), which was significantly lower than in animals without iMetC (р < 0.0001). A direct correlation was found between of infarct size during RPost and the serum leptin level of rats with iMetC.The presented data suggested that a decrease in the efficiency of remote postconditioning in rats with diet-induced metabolic syndrome depends on leptin content in blood.
The role of reactive oxygen species (ROS) in ischemic and reperfusion (I/R) injury of the heart has been discussed for more than 40 years. It has been demonstrated that reperfusion triggers a multiple increase in free radical generation in the isolated heart. Antioxidants were found to have the ability to mitigate I/R injury of the heart. However, it is unclear whether their cardioprotective effect truly depends on the decrease of ROS levels in myocardial tissues. Since high doses and high concentrations of antioxidants were experimentally used, it is highly likely that the cardioprotective effect of antioxidants depends on their interaction not only with free radicals but also with other molecules. It has been demonstrated that the antioxidant N-2-mercaptopropionyl glycine or NDPH oxidase knockout abolished the cardioprotective effect of ischemic preconditioning. Consequently, there is evidence that ROS protect the heart against the I/R injury.
Background. The discovery of new pharmacological agents for myocardial protection during reperfusion injury is an urgent goal of modern physiology and pharmacology.The aim of the study. To identify the potential for protecting the myocardium from reperfusion injury by administering the delta-2 opioid receptor agonist deltorphin-II prior to reperfusion in old rats with diet-induced metabolic syndrome.Materials and methods. The study was performed on Wistar rats aged 60 days (young rats) and 450 days (old rats) before the onset of a study. Metabolic syndrome (MetS) was modeled for 84 days with a high-carbohydrate high-fat diet (16 % protein, 21 % fat, 46 % carbohydrate) with the replacement of drinking water with 20 % fructose solution. Myocardial infarction was performed by 45-min coronary occlusion followed by 120-min reperfusion; the size of the area of the necrotic myocardium was determined relative to the size of the hypoperfusion zone. The delta-2 opioid receptor agonist deltorphin-II was administered once intravenously 5 minutes before the end of ischemia.Results. It was found that coronary occlusion and subsequent reperfusion both in groups of young and old rats led to the formation of myocardial infarction (necrosis), the size of which was 45 % of the size of the risk zone. Administration of deltorphin-II in old rats led to a limitation of infarct size to 30 % of the size of the risk zone, i. e. 1.7-fold. The use of deltorphin-II in old rats with MetS contributed to a decrease in infarct size to 27 % of the size of the risk zone (1.5 times). The obtained results demonstrate the cardioprotective efficacy of the delta-2 opioid receptor agonist deltorphin-II in aging and metabolic syndrome in rats.Conclusions. These data may serve as a basis for conducting preclinical studies of deltorphin-II as a drug for treatment of acute myocardial infarction.
The increase in cardiovascular diseases and metabolic disorders associated with longevity actualizes the study of the effect of high-calorie diets on heart aging.Aim: the experimental study of the effect of a high-carbohydrate hig -fat diet on the myocardium in young and old age.Material and Methods. A morphological study of the myocardium was carried out in four groups of male Wistar rats: group 1 - 150-day-old animals were kept on a standard diet; 2nd - 150 days, kept at a high-carbohydrate high-fat diet (HCHFD) for 90 days (from 60 days of age); 3rd - 540 days old, kept on a standard diet; 4th - 540 days old, kept at HCHFD for 90 days (from450 days of age). ELISA method in blood serum was used to determine the concentration of fibronectin, transforming growth factor beta-1, connective tissue growth factor.Results. In groups 2-4, leukostasis, focal lympho-monocytic infiltration of the myocardial stroma, an increase in the number of myocardial cells with karyopyknosis and edema of the perinuclear zone of the sarcoplasm, contracture disorders, and an increase in the specific volume of the connective tissue of the stroma were detected. The defeat of myocardial cells and fibrosis were most pronounced in group 4. HCHFD increased the concentration of fibronectin in animals in both age groups with predominance in group 4, caused a tendency to increase the content of transforming growth factor beta-1, connective tissue growth factor in blood serum. Thus, HCHFD accelerates and enhances age-related changes in the white rat myocardium.
Microvascular obstruction (MVO) of coronary arteries increases the mortality rate and major adverse cardiac events in patients with acute myocardial infarction (AMI) and percutaneous coronary intervention (PCI). According to preliminary data platelets, inflammation, Ca2+ overload, neuropeptide Y, and endothelin-1 could be involved in the pathogenesis of MVO. Many questions related to the pathogenesis of MVO remain unanswered. The role of endothelial cell damage in the formation of MVO in patients with AMI and PCI is unknown. It is unclear whether nitric oxide (NO) production reduces or decreases sensitivity of smooth muscle cells of coronary arteries to NO in patients with MVO. It was obtained only indirect evidence on the involvement of inflammation in the development of MVO. The role of ROS in the pathogenesis of MVO is not studied. The role of necroptosis and pyroptosis in the pathogenesis of MVO in patients with AMI and PCI is also not studied.The significance of thromboxane A, vasopressin, angiotensin II, and prostacyclin in the formation of MVO is unknown before. It was not obtained conclusive evidence on the involvement of coronary artery spasm in the development of MVO. Correlation analysis of the neuropeptide Y, endothelin-1 levels and the MVO size in patients with AMI and PCI was not performed. It is not clear whether endogenous adrenaline exacerbates MVO or, conversely, prevents MVO.
An analysis of published data and the results of our own studies showed that activation of peripheral δ2-opioid receptor (δ2-OR) increases cardiac tolerance to reperfusion. It has been established that this δ2-OR is localized in cardiomyocytes. Endogenous opioids are not involved in the regulation of cardiac resistance to reperfusion in non-adapted rats. The infarct-limiting effect of δ2-OR agonist deltorphin II depends on the activation of following protein kinases: PKCδ, ERK1/2, PI3K, PCG. SarcKATP channel and MPT pore are hypothetical end effectors of the cardioprotective effect of deltorphin II.
Background. Mortality from acute myocardial infarction with ST-segment elevation in cardiac hospitals ranges from 4.5 to 7 %, and these data has not decreased in recent years. The most common cause of death in patients is cardiogenic shock, the likelihood of which directly depends on infarct size. It is quite clear that there is an urgent need to create drugs to limit the size of infarction and prevent the occurrence of cardiogenic shock.The aim. To evaluate the role of reactive oxygen species and redox-sensitive protein kinases in the infarction-limiting effect of opioid peptide deltorphin II in cardiac reperfusion in rats.Materials and methods. Coronary occlusion (45 min) and reperfusion (120 min) were performed in rats anesthetized with α-chloralose. The selective δ2-opioid receptor agonist deltorphin II, a hydroxyl radical scavenger 2-mercaptoprpionyl glycine (2-MPG), a superoxide radical scavenger tempol, the protein kinase Cδ (PKCδ) inhibitor rottlerin, the PI3-kinase inhibitor wortmannin, the inhibitor of ERK1/2 kinase PD98059 were injected before of reperfusion of the heart.Results. Deltorphin II contributed to a two-fold decrease in infarction size. Injection of 2-MPG, tempol, rottlerin, wortmannin, PD98059 alone had no effect on infarction size in rats. 2-MPG and tempol did not affect the infarction-reducing effect of deltorphin II. Rottlerin, wortmannin, and PD98059 eliminated the cardioprotective effect of deltorphin II.Conclusion. The infarction-reducing effect of deltorphin II does not depend on the production of superoxide radical and hydroxyl radical. Superoxide radical and hydroxyl radical do not play a significant role in reperfusion injury of the heart after coronary occlusion (45 min). PKCδ, PI3-kinase, and ERK1/2 kinase are involved in the infarction-limiting effect of deltorphin II in myocardial reperfusion.
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