[The influence of activation of the ATP-sensitive potassium channels by flocalin on the function of the cardiovascular system].

In experiments on the anaesthetized dogs the influence of a new fluorine-containing opener of ATP-sensitive potassium (K(ATP)) channels flocalin on the cardiohemodynamic of great animals in vivo was studied. Flocalin introduced intravenously in doses 0.01 - 1.5 mgs/kg. It is shown that it reduces in dose-dependent manner a system arterial pressure, perfusion pressure in coronary artery and general peripheral resistance of vessels with maximal effects on 56.8 +/- 2.7, 22.4 +/- 4.7 and 47.2% +/- 6.5% accordingly at most dose 1.5 mgs/kg. Flocalin causes development of cardiodepressive reactions in heart, that is exhibited in dose-dependent the decrease of pressure in the left ventricle, speed of growth (dP/dt(max)) and reduction (dP/dt(min)) in it's of pressure with maximal effects on 37.1 +/- 5.1, 51.2 +/- 9.4 and 55.6% +/- 6.9% accordingly at introduction of most dose of flocalin. Diminish of the cardiac out put and heart rate with a maximal effects on 23.1% +/-12.7% and 19.2% +/- 1.7% accordingly at a dose 1.0 mgs/kg was shown. It should be noted that considerable reduction of heart rate and general peripheral resistance of vessels takes place only at the large doses of flocalin - 1 and 1.5 mgs/kg. Thus, it is shown that activation of K(ATP) channels by flocalin causes the dose-dependent decrease of pressure in the system of circulation of blood and contraction activity of myocardium.

[The changes of metabolism in myocardium at ischemia-reperfusion and activating of the ATP-sensitive potassium channels].

In experiments on the anaesthetized dogs with modeling of experimental ischemia (90 min) and reperfusion (180 min) it was investigated the changes of biochemical processes in the different areas of heart (intact, risk and necrotic zone) during intragastric introduction of medicinal form (tablets) of flocalin (the fluorine-containing opener of ATP-sensitive potassium channels) in a dose 2,2 mg/kg. The data analysis allowed to define a few possible cardioprotective mechanisms of flocalin action at ischemia-reperfusion conditions: the preservation of sufficient levels of de novo (by cNOS) NO synthesis, an inhibition of de novo (by iNOS) and salvage (by NADH-dependent nitratreductase) NO synthesis, an inhibition of L-arginine degradation by arginase, an inhibition of oxidizing metabolism due to limitation of ROS and RNS generation, inhibition of free arachidonic acid and eicosanoids synthesis, inhibition of ATP and GTP degradations and, possibly, stimulation of protective haem degradation. These changes may prevent formation of toxic peroxynitrite and suggest the possibility of participating in flocalin-mediated cardioprotective effects of warning a mitochondrial permeability transition pore (MPTP) opening and inhibition of apoptosis and/or necrosis of cardiomyocytes induced by it.

[Effect of medical form of flocalin on the course of myocardial reperfusion injury].

In experiments on anaesthetized dogs with modeling of experimental ischemia (90 min) and reperfusion (180 min), the cardioprotective influence of the pharmacological preconditioning caused by intragastric (with a help of catheter) introduction of medicinal form (tablets) of new fluorine-containing opener of ATP-sensitive potassium channels flocalin was shown. Flocalin was introduced in a dose 2.2 mg/kg, which in the conditions of physiological norm has a minimum influence on the parameters of cardiohemodynamic. The conducted research allowed to define the changes of these parameters during development of antiischemic protective effect of pharmacological preconditioning, caused by the medicinal form of flocalin, and describes basic cardioprotective mechanisms, related to the changes of cardiohemodynamic in the dynamics of ischemia-reperfusion of myocardium. In our opinion, to positive influences of flocalin, which are possibly related to cardioprotective action, it is possible to add the prevention of an increase of general peripheral resistance, resistance of coronal vessels of heart, and relative preservation of myocardium contractility in the period of reperfusion. Also these positive effects can be explained by moderate decrease of blood pressure that decreases the loading on the damaged heart and allows to preserve cardiac emission in the first period of ischemia. One of the major indexes of development of protective mechanism of pharmacological preconditioning caused by preischemic introduction of medicinal form of flocalin is the diminishing of infarct size of myocardium in experiments with ischemia-reperfusion of myocardium on 42.53% +/- 2.91% versus control experiments.

[Effect of a new activator of adenosine triphosphate-sensitive potassium channels flocalin on the glucose level in blood].

In experiments on the anaesthetized dogs we investigated the influence of a new fluorine-containing opener of ATP-sensitive potassium channels of sarcolemal and mitochondrial membranes flocalin on the level of glucose in arterial blood at physiological conditions and under ischemia (90 min) and reperfusion (180 min) of myocardium. It was shown that intravenous introduction of flocalin in doses 0,1 - 1,0 mg/kg did not change the level of glucose in blood. In experiments with ischemia-reperfusion of myocardium, flocalin also did not increase the level of glucose during all experiment (5,5 hours) after intragastric (with a help of catheter) introduction of drug form (tablets) at cardiorotective dose of 2,2 mg/kg. However, intravenous introduction of flocalin in the dose of 1,5 mg/kg, which 15 times exceeded a cardioprotective dose of 0,1 mg/kg increased the glucose level 1,33 fold. It should be noted that this increase was not sustained and the level of glucose restored to the initial level within 1 hour. Identical changes of indexes of cardiohemodynamic and the level of glucose in arterial blood under introduction of identical doses of flocalin at the beginning and at the end of experiment (total dose of flocalin reached 4 - 4,5 mg/kg) can testify the absence of cumulative effect of flocalin at these experimental conditions. Thus, strong cardioprotective properties, hypotoxicity and the absence of meaningful changes in a carbohydrate exchange allow to consider a new fluorine-containing opener of K(ATP) channels of flocalin as perspective drug for clinical use.

[Cardioprotective effects of flokalin in experiments in vivo: influence on hemodynamic and myocardial lesions in ischemia-reperfusion].

In experiments on anaesthetized dogs with modeling of experimental ischemia (90 min) and reperfusion (180 min) the cardioprotective influence of the preischemic activation of ATP-sensitive potassium (K(ATP)) channels by intravenous introduction of flokalin, a new fluorine-containing opener of these channels was shown. Flokalin was introduced in dose 0.1 mg/kg of animal body weight which practically did not change the parameters of hemodynamic in conditions of normoxia. Thus, the experiments performed about flokalin influence on changes of cardiohemodynamic during ischemia-reperfusion of myocardium showed certain features of ischemia-reperfusion syndrome development under conditions of K(ATP) channels activity stimulation. In our opinion, positive influence offlokalin can be explained by moderate decrease of blood pressure that decreases loading of the damaged heart and allows to preserve cardiac emission in the first period of ischemia. Also, these positive effects can be explained by prevention of the increase of coronal vessel resistance and relative preservation of myocardium contractility indexes by flokalin in the period of reperfusion. All protective properties of flokalin showed above result in diminishing of infarct size of myocardium after ischemia-reperfusion on 37% versus control experiments.

[Cardioprotective effects of activation of ATP-sensitive potassium channels in experiments in vivo: influence on blood biochemical parameters following ischemia-reperfusion of the myocardium].

In experiments on the anaesthetized dogs with modeling of experimental ischemia (90 min) and reperfusion (180 min), the participation of biochemical processes in the cardioprotective effect of the preischemic activation of ATP-sensitive potassium (KATP) channels caused by intravenous introduction of flokalin, a new fluorine-containing opener of these channels was shown. Flokalin was introduced in a dose 0.1 mg/kg of animal body weight which practically did not change the parameters of hemodynamic in normoxia. Thus, the experiments investigating the influence offlokalin on changes of biochemical parameters of arterial blood during ischemia-reperfusion of myocardium showed certain features of ischemia-reperfusion syndrome development during stimulation of K(ATP) channels. The analysis of biochemical parameters of blood showed that flokalin suppressed free radical reactions and had antioxidant properties: reduced quantity of H2O2 and NO3- (the last can interpreted as a reduction in peroxynitrites formation), prevented the decline of catalase and superoxide dismutase activity. Practically constant content of low-molecular nitrosothiols in blood during all duration of experiment and increase of NO2-level during reperfusion may indicate on intact functions of the NO system and protective influence of flokalin during ischemia-reperfusion of myocardium. Practically unchanged content of inorganic phosphorus and uric acid in blood during ischemia- reperfusion under conditions of preischemic introduction of flokalin indicates the prevention of ATP degradation and fomation of both superoxide anion by xanthinoxidase and peroxynitrite by it interaction with nitric oxide. All mentioned properties of flokalin related to the changes of biochemical parameters of arterial blood, together with the changes of parameters of hemodynamics, result in diminishment of infarct size of myocardium after ischemia-reperfusion by 37% versus control experiments. K(ATP) channels, flokalin, ischemia-reperfusion, free radikaly, NO system.

[Effects of RNA on blood circulation and its adrenergic and cholinergic regulation].

Experimental investigations of the impacts of microRNA agent nucleks on heart function, coronary and systemic circulation as well as on adrenergic and cholinergic mechanisms of cardiohaemodynamics regulation were performed on anaesthetized dogs. Bolus injection (0.1-100.0 mg) or prolonged infusion (2.5 mg/min) of nucleks into perfusion coronary artery blood stream induced coronary dilatation. Under the intracoronary infusion of nucleks we observed more pronounced coronary vasodilatation and left ventricle pressure elevation in response to adrenergic heart receptors stimulation by norepinephrine (0.05-5.0 mkg, intracoronary). Besides that the drug infusion into coronary blood stream promoted the acceleration of recovery processes of the studied cardiohaemnodynamic parameters after norepinephrine injection. After intracoronary infusion of nucleks the sensitivity of cholinergic receptors to the stimulation by acetylcholine (0.001-1.0 mkg, intracoronary) increased significantly. After NO-synthase blockade (L-NAME, infusion 2.0 mg/min, intracoronary) nucleks did not cause any effect on coronary vessels tone and heart activity both it did not change their adrenergic and cholinergic reactivity.

[Investigation of the heart function under condition of myocardial ischemia using a new method of electrocardiogram analysis].

UNLABELLED: The aim of the paper is to investigate ECG in phase space changes under condition of myocardial ischemia during experiments on entire organism. Regional ischemia was simulated in 13 dogs with the help of catheterization of coronary arteries and obturation of one of the left coronary artery branches by plastic embol. All experiments were done with closed chest and natural breathing. Duration of ischemia was 90 min. ECG in phase space was recorded every 10 min. Some parameters of ECG, first of all parameter reflecting symmetry of T wave were evaluated with the help of program-technical complex Fazograph. Rapid and statistically significant increase of parameter beta(Tau) under in fluence of myocardial ischemia was observed. Changes of beta(T) were the earliest and the most sensitive signs of ischemia among all parameters evaluated. CONCLUSION: Changes of T wave symmetry are sensitive signs of myocardial ischemia, which can be used in clinical practice.

[Insulin and endothelium-dependent mechanisms in regulation of coronary circulation]. / Insulin i endoteliizalezhni mekhanizmy rehuliatsiï koronarnoho krovoobihu.

Changes in cardiohemodynamics after intravenous administration of insulin (1.0 IU/kg) were investigated on anaesthetized dogs with closed chest. During the first 5-10 min (phase 1 of the response), coronary vasoconstriction, an enhancement of the cardiac activity and an increase in a coronary arteriovenous oxygen difference were observed. During the next 25-30 min (phase II) a long-term coronary dilation, an attenuation of the cardiac contractility and a decrease in the coronary arteriovenous oxygen difference occurred. An injection of insulin after preliminary inhibiting NO-synthase (L-MANE, intracoronary infusion, 1.0 mg/min), guanilatcyclase (100 micrograms ouabaine, intracoronary injection), Na+, K(+)-ATPase (methylene blue, intracoronary infusion, 5 mg/min) induced coronary vasoconstriction. Inhibiting muscarinic receptors with atropine (0.5 mg/kg i.v.) attenuated or absolutely abolished haemodynamic responses induced by insulin. Under beta-adrenergic blockade by propranolol (2.0 mg/kg i.v.) administrations of insulin resulted in coronary constriction, an augmentation of cardiac contractility and an elevation of the arterial blood pressure. The conception has being developed, according to which the degree and trends of induced by insulin changes in cardio-haemodynamics depend on the initial levels the sympathetic and parasympathetic activities, as well as on the synthesis of endothelial vaso- and cardiotropic substances, and their interactions with these systems.

[Circulatory changes in acute myocardial ischemia in dogs with experimental diabetes mellitus]. / Zminy krovobihu pry hostrii ishemii miokarda u sobak z eksperymental'nym tsukrovym diabetom.

On alloxane-diabetic dogs under chloralose anaesthesia without opening the chest catheterization, extracorporal perfusion and resistography of coronary arteries, catheterization and continuous drainage of coronary sinus, catheterization of major vessels and heart chambers were performed. Acute myocardial ischemia was induced by the 60 s cessation of left circumflex coronary artery extracorporal perfusion. The magnitude and peculiarity of the systemic circulation reactions during acute myocardial ischemia in dogs with moderate and mild hyperglycemia (less than 12 mmol/l), didn't differ from those in control group. But the degrees of coronary arteries dilation in the ischemic area and coronary sinus blood oxygen saturation reduction were less and the velocity of the coronary arteries resistance recovery to the base level in reperfusion period was more in these animals than in healthy dogs. In severe alloxane diabetes (hyperglycemia more than 12 mmol/l), the reflectory components of circulation reactions during myocardial ischemia, namely heart contractility function decrease, bradycardia, peripheral vessels resistance and arterial blood pressure reduction, were weakened or even absent, but the recovery velocity of cardiohaemodynamic parameters and the level of metabolic processes in myocardium was significantly slowed in the reperfusion period.

[The effect of insulin on cardiac activity and on the coronary and systemic circulations]. / Vplyv insulinu na diial'nist' sertsia, vintsevyi ta systemnyi krovoobih.

The studies were performed on healthy closed-chest chloralose-anaesthetized dogs using catheterization, extracorporal perfusion and resistography of coronary arteries and catheterization and continuous drainage of the coronary sinus. Insulin (0.1 and 1.0 IU/kg, i.v.) injected to healthy animals produced dose-dependent biphasic cardiohaemodynamic reactions. The first phase of the reaction includes transient (5-10 min) cardiac function strengthening, coronary arteries constriction, heart rate acceleration, myocardial oxygen consumption elevation, coronary sinus blood pH elevation and pO2 decrease. After that there arises more prolonged and constant dilation of coronary arteries reduction of the cardiac function, slowing of the heart rate, lowering of the myocardial oxygen consumption, decrease of cardiac venous blood pH and increase of pO2, reduction of T waves magnitude and ST segments shifts both in standard and breast leads. The second phase of the reaction is either attenuated or even absent after blockade of beta-adrenoceptors (propranolol, 0.5 mg/kg, i.v.). The results indicate that insulin effects on cardiohaemodynamics are realized through the interaction between insulin and heart and vessels of the adrenergic system.