Pulmonary arterial hypertension (PAH) is accompanied by changes in the pulmonary and systemic circulation. We studied the effect of PAH on the function of the left ventricle (LV). Left ventricular pressure and volume were simultaneously recorded in vivo in rats with monocrotaline-induced PAH (60 mg/kg). LV contractility and mechanical indexes were calculated. In addition, the relationships between LV maximum rate of contraction (dP/dtmax) or relaxation (dP/dtmin) and left ventricular end-diastolic volume (EDV) were assessed. PAH leads to a significant decrease in cardiac output at a constant HR as well as to a decrease in stroke volume at unchanged LV ejection fraction. In rats with PAH, the slopes of the dP/dtmax-EDV and dP/dtmin-EDV curves were greater than in control animals by 1.93 and 2.5 times, respectively. Thus, PAH leads to a compensatory increase in the dependence of LV contractility and "intensity" of LV relaxation on EDV.

Complete preservation of the antihypertensive activity of the freeze-dried drug Oxacom has been demonstrated after storing it for 15 years at room temperature in vessels with the air pumped out; this is due to the presence of a binuclear form of a dinitrosyl iron complex with glutathione in this drug. It was proposed that the oxidation of glutathione ligands in the composition of dinitrosyl iron complexes by air gradually penetrating into the vessels, which could lead to the decomposition of these complexes, was prevented by a significant amount of free (not included in dinitrosyl iron complexes) glutathione in this drug.

The reason for the lack of the hypotensive effect of gaseous NO, as introduced by inhalation into the bodies of animals and humans, has been identified. Since this defect was completely eliminated by inhalation of NO simultaneous with intravenous administration of low molecular mass thiol solutions to animals (rats), it is concluded that gaseous NO entering through the lungs into the blood circulating in a large circle of blood circulation converts into nitrosonium cation (NO + ) as a result of single-electron oxidation, which is unable to exert vasodilating and thereby hypotensive effects on animals and humans. The binding of NO + to low molecular mass thiols leads to its transformation into S-nitrosothiols, followed by the release of this nitrosyl agent in the form of neutral NO molecules characterized by hypotensive activity. The formation of dinitrosyl iron complexes with thiol-containing ligands in the blood and tissues of organs of experimental animals in these experiments, which could cause a hypotensive effect, was not detected. The hypotensive effect of inhaled NO, which was found in the lungs, could be due to the penetration of NO through the outer wall of blood vessels with subsequent activation of the enzyme guanylate cyclase, an inducer of vasodilation and hypotension, directly in the walls of blood vessels.

Pulmonary arterial hypertension (PAH) is characterized by an increase of a pressure in the pulmonary circulation; PAH is accompanied by activation of the sympathetic (SNS) and the renin-angiotensin-aldosterone system (RAAS). However, PAH-associated changes in baroreceptor regulation of systemic circulation, which is tightly interwoven with SNS and RAAS, have not been studied. The baroreceptor response (BRR) was studied in a chronic monocrotaline (MCT) model of PAH in rats (Wistar, 290 ± 30 g, 2–4 months). Phenylephrine as an agonist of α1-adrenergic receptor and sodium nitroprusside as NO donor were gradually administered to chronically catheterized, non-anesthetized control animals and animals with PAH (4 weeks after MCT administration) to induce vasomotor responses. Mean arterial pressure and heart rate (HR) were recorded under the action of vasoactive compounds alone or under the action of vasoactive compounds in presence of angiotensin-II (ATII), atropine. The parameters characterizing baroreceptor change in HR including maximal and minimal heart rate (HRmax, HRmin), reflex tachycardia (TBRR) and bradycardia (BBRR), range (ABRR) and the baroreceptor response sensitivity index (SIBRR) were calculated. A significant decrease in HRmax, TBRR, ABBR (but not BBRR), as well as the sensitivity index of BRR was observed in rats with PAH. ATII induces significant and different changes in the BRR parameters in control rats and in rats with PAH if administered 4 weeks after the start of the experiment. In rats with PAH, ATII causes less pronounced changes in HRmax, TBRR, and BBRR than in control animals. ATII insignificantly affects parasympathetic component of the baroreceptor reflex in rats with PAH. Thus, at least in the MCT-mediated model in rats, PAH significantly deteriorates the baroreceptor regulation of HR. This effect manifests in a decrease in the range and sensitivity of the baroreceptor response. Also, PAH unequally affects the sympathetic and parasympathetic control of the baroreceptor regulation of HR. On the other hand, ATII exhibits weak ability to alter BRR in rats with HAP. In conclusion, PAH leads to a disfunction of immediate, reflex mechanisms HR and systemic circulation control.

It has been demonstrated that “Oxacom”, a freeze-dried preparation, retains, throughout its period of storage in the ampoule in the absence of oxygen for 15 years at ambient temperature, the same hypotensive activity due to the presence of a binuclear form of dinitrosyl iron complex with glutathione. It is suggested that an oxidation reaction where glutathione ligands as constituents of dinitrosyl iron complexes react with the oxygen, the content of which gradually increase in the preparation, could lead to the degradation of these complexes, but it was prevented due to the presence of a considerable amount of free, not included in dinitrosyl iron complexes glutathione molecules in this preparation.

The major property of the myocardium that determines left ventricular (LV) filling is its distensibility. The simplest measure for its assessment is the LV end-diastolic pressure–volume ratio, although it can vary within a wide range and is highly dependent on inflow and resistance boundary conditions, making distensibility difficult to assess. Here, we consider six calculated indices of LV diastolic stiffness, most of which are based on Hooke’s law, comparing their stability, variation, and correlation coefficients with different hemodynamic parameters. The diastolic stiffness index No. 4 proved to be the only measure that takes into account an increase in LV stiffness over diastole. It shows a weak dependence on LV ejection fraction, heart rate, and other parameters of LV hemodynamics, and hence can be used to assess LV diastolic distensibility in various cardiac pathologies.

Pulmonary arterial hypertension (PAH) is characterized by an increase of a pressure in the pulmonary circulation; PAH is accompanied by activation of the sympathetic (SNS) and the renin-angiotensin-aldosterone system (RAAS). However, PAH-associated changes in baroreceptor regulation of systemic circulation, which is tightly interwoven with SNS and RAAS, have not been studied. The baroreceptor response (BRR) was studied in a chronic monocrotaline (MCT) model of PAH in rats (Wistar, 290 ± 30 g, 2–4 months). Phenylephrine as an agonist of α1-adrenergic receptor and sodium nitroprusside as NO donor were gradually administered to chronically catheterized, non-anesthetized control animals and animals with PAH (4 weeks after MCT administration) to induce vasomotor responses. Mean arterial pressure and heart rate (HR) were recorded under the action of vasoactive compounds alone or under the action of vasoactive compounds in presence of angiotensin-II (ATII), atropine. The parameters characterizing baroreceptor change in HR including maximal and minimal heart rate (HRmax, HRmin), reflex tachycardia (TBRR) and bradycardia (BBRR), range (ABBR) and the baroreceptor response sensitivity index (SIBRR) were calculated. A significant decrease in HRmax, TBRR, ABBR (but not BBRR), as well as the sensitivity index of BRR was observed in rats with PAH. ATII induces significant and different changes in the BRR parameters in control rats and in rats with PAH if administered 4 weeks after the start of the experiment. In rats with PAH, ATII causes less pronounced changes in HRmax, TBRR, and BBRR than in control animals. ATII insignificantly affects parasympathetic component of the baroreceptor reflex in rats with PAH. Thus, at least in the MCT-mediated model in rats, PAH significantly deteriorates the baroreceptor regulation of HR. This effect manifests in a decrease in the range and sensitivity of the baroreceptor response. Also, PAH unequally affects the sympathetic and parasympathetic control of the baroreceptor regulation of HR. On the other hand, ATII exhibits weak ability to alter BRR in rats with HAP. In conclusion, PAH leads to a disfunction of immediate, reflex mechanisms HR and systemic circulation control.

Aim. To study the relaxation structure of the left ventricle (LV) in patients who underwent ventriculography.Material and methods. LV ventriculography was performed in 37 patients. Before catheterization, echocardiography was performed in each patient. In 6 patients, the LV ejection fraction (EF) was below 40%; these patients with systolic dysfunction were not included in the study. In 31 patients, the LV EF was higher than 50%. In this group, 13 patients had NYHA functional class (FC) 2-3 chronic heart failure (CHF); the rest of the patients had FC 1 CHF. Eighteen of 31 patients had stable ischemic heart disease; 50% of these patients had a history of myocardial infarction; the rest of the patients had hypertension and atrial and ventricular arrhythmias. The dynamics of the LV pressure decrease was analyzed from the moment of the maximum rate of pressure drop, which usually coincides with the closure of the aortic valves. The pressure drop curve was logarithmized with natural logarithms and divided into 4-5 sections with different degrees of curve slope. The relaxation time constant was calculated for each section. Its inverse value characterizes the relaxation time constant (tau).Results. In 31 patients with LV EF 52-60%, three types of the dynamics of the relaxation rate constant were identified during the pressure decrease in the isovolumic phase: in 9 patients, the isovolumic relaxation constant (IRC) steadily increased as the pressure decreased; in 13 patients, it continuously decreased; and in 9 patients, the dynamics of IRC change was intermediate, with an initial increase followed by a decrease.Conclusion. In diastolic dysfunction, one group of patients had an adaptation type associated with an increase in the LV wall elasticity, while the other group had a different type of adaptation associated with its decrease. Each type has advantages and disadvantages. This is probably due to changes in the structure of the sarcomeric protein connectin (titin).

The cardiohemodynamics was studied 2 and 4 weeks after myocardial infarction modeling in Wistar rats. We compared the data obtained by echocardiography (echoCG) and catheterization of the left ventricle. The myocardial infarction was modeled by ligation of the left anterior descending coronary artery. EchoCG and the left ventricle catheterization were performed before and after myocardial infarction modeling. Similar results were obtained by both methods, namely the left ventricle dilatation, bradycardia, a reduced ejection fraction and delayed relaxation. According to echoCG, the end-diastolic left ventricle volume increased by 2 times, and initial diastolic left ventricle volume - by more than 5 times. The left ventricle catheterization showed lower rise, by 32 and 69%, respectively. The overestimated volume of the left ventricle in myocardial infarction according to echoCG data in comparison with catheterization can be explained by changes in the geometry of the ventricle (bulging of a part of the ventricular wall).

Aim To study the left ventricular (LV) contractile and pumping function during the recovery phase following ligation of the anterior descending coronary artery (CA). Material and methods Cardiodynamic parameters were studied in Wistar rats 2-4 weeks after experimental myocardial infarction (MI). MI was induced by ligation of the anterior descending CA under zoletil anesthesia. LV catheterization was performed with a standard FTH-1912B-8018 PV catheter inserted into the LV through the right carotid artery. Results After the induction of MI, the mortality rate of animals was 50 %. Survived animals developed significant LV dilatation and a decrease in ejection fraction (EF) by an average of 31%. However, major indexes of the pumping function, including minute volume, heart work, and maximum ejection velocity, were within a normal range whereas the maximum filling velocity was almost doubled. Approximately 50 % of hearts with dilated LV had normal EF, delayed relaxation, and increased LV diastolic pressure, which qualified this group as a diastolic dysfunction group. The systolic dysfunction group with EF less than 50 % of normal had similar values of myocardial contractility and relaxation but differed from the diastolic dysfunction group in more than 50% reduced maximum LV ejection velocity and 1.7 times increased elasticity of the arterial wall. A close inverse correlation was found between these values (r= -0.91). Conclusion The study results showed that, with a similar myocardial contractile function, the cardiac pumping function is determined by the elasticity of the aortic wall. Therefore, restriction of reactive fibrosis during MI is an important task of modern cardiology.

The aim of the present study was to investigate the protective effects of a mitochondrial-targeted antioxidant such as plastomitin through ROS hypergeneration in animals. The average rate of the generation of highly reactive oxygen radicals during oxidative stress, induced by doxorubicin injection in rats and a protective impact of plastomitin use were investigated. The experiments were carried out with rat heart tissue homogenates using EPR spectroscopy. It was found that in case of doxorubicin injection in rats, there is a significant 26% increase in the rate of short-lived reactive oxygen species generation in the homogenate but when doxorubicin and plastomitin were used in combination, this effect was greatly suppressed.

The rate and depth of myocardial relaxation determine left ventricular (LV) filling in early diastole. To analyze the relaxation phase, the method of logarithm of LV pressure fall in rats was used. A gradual acceleration of relaxation was found during the transition from the isovolumic phase to the auxovolumic phase, immediately before the opening of the atrioventricular valves. The relaxation rate constant in this phase has been inversely correlated with the values of the minimum LV diastolic pressure and LV endsystolic volume. The results suggest that the gradual acceleration of relaxation is due to the straightening of the spring-like structure of connectin (titin), which is compressed during contraction.

The reason has been elucidated why gaseous nitric oxide inhalation does not produce hypotensive effect in human and animal organisms. The defect was completely removed when low molecular thiol solutions were added by intravenous pathway simultaneously with gaseous NO inhalation into the animals (rats). The proposition was made that gaseous NO molecules including through the lungs into the circulation of the blood are transformed as a result of one-electron mechanism oxidation into nitosonium cation (NO+) which are not capable of vasodilating and thereby hypotensive action on men and animals. NO+ cation binding with low molecular thiols results in the S-nitrosothiol (RS-NO) formation with following release of the nitrosyl component from the RS-NO in the form of neutral NO molecule characterized with hypotensive activity. The formation of another NO donor - dinitrosyl iron complexes with thiol-containing ligands did not occur in the animals. Hypotensive action observed in lungs could be determined by gaseous NO penetration trough external vascular wall followed by the activation of vasodilation and hypotensia inductor - guanylate cyclase enzyme immediately inside of vascular walls.

Pulmonary arterial hypertension (PAH) accompanied by an arterial pressure increase in the pulmonary circulation, remodeling of pulmonary arteries and a change in its sensitivity to regulatory factors; PAH is accompanied by activation of the sympathetic nervous system and renin-angiotensin-aldosterone system and increased production of atrial natriuretic peptide. The change in the sensitivity of the vessels of the systemic circulation (SC) to regulatory influences in PAH has not been investigated. Vasoconstrictor reactions in SC with monocrotaline (MCT) were studied in the work models of PAH in rats (Wistar, 350 ± 50 g, 4 months). Mean arterial pressure (MAP) was recorded against the background of a double autonomous blockade with the administration of the α1-adrenergic receptor agonist (α1-AR) phenylephrine (Phe) to conscious rats at the start of experiment, then 2 and 4 weeks after the induction of PAH with MCT or saline injection for control animals. Registration of MAP under the action of Phe was also performed during angiotensin-II (ATII) infusion. The maximal amplitude (A max) of the change in MAP and the longest half-return time of MAP (T ΔMAP1/2) to the baseline level in rats in response to the Phe injection were estimated. It was found that in response to Phe, A max did not change in rats with PAH, whereas in control animals it significantly increased. In rats with PAH 2 (n = 6) and 4 weeks after the induction of PAH with MCT, T ΔMAP1/2 is significantly less than in control rats. ATII leads to delayed changes in T ΔMAP1/2 in both control rats and rats with PAH. In rats with PAH, the potentiation with angiotensin T ΔMAP1/2 is significantly less than in control rats. Thus, in animals with PAH, the ability of the resistive arteries of the systemic circulation to maintain tone in response to the activation of α1-AR decreases. In addition, PAH suppresses the ability of ATII to stimulate sympathetic responses in the SC. Firstly, in vivo, it has been demonstrated remodeling and changing the functional state of the pulmonary circulation leads to changes in the regulation of vascular tone of the systemic circulation.

Современные подходы к лечению пациентов с легочной артериальной гипертензией (ЛАГ) — редким заболеванием с неблагоприятным прогнозом, — включают применение специфических вазодилататоров, механизм действия которых направлен на один из путей патогенеза этого заболевания. Эндогенный оксид азота (NO) — одна из важнейших молекул с широкой палитрой воздействия на тонус сосудов, тромбоцитарную и лейкоцитарную активность, пролиферацию гладкомышечных клеток и фибробластов, а также воспалительный и иммунный ответ. Недостаток NO, находящийся в основе хронического спазма сосудов, пролиферации, тромбоза in situ при ЛАГ, является мишенью для создания новых препаратов. Перспективным направлением при ЛАГ считается применение прямых аналогов эндогенных доноров NO живых организмов. Таким препаратом становится синтетический динитрозильный комплекс железа с глутатионом — Оксаком Применение внутривенных инфузий Оксакома в течение 5 последовательных дней может рассматриваться в качестве лекарственной стратегии для пациентов с клиническим ухудшением ЛАГ с целью снижения давления в легочной артерии, стабилизации гемодинамики, что приведет к сокращению сроков пребывания в стационаре.

The effect of dinitrosyl iron complexes with a ligand based on N-acetyl-L-cysteine, a stabilized NO form, via sublingual administration of this compound into the rat body was analyzed. It was found by EPR that as a result of its introduction, the formation and accumulation of dinitrosyl iron complexes with protein ligands is registered in the liver tissue. Moreover, as a result of the action of dinitrosyl iron complexes with N-acetyl-L-cysteine, a significant increase in the total NO level in heart and liver tissues is registered with the most significant effect in the liver of the animal.

Aim To study left ventricular (LV) hemodynamics in presence of decreased blood inflow to the heart as well as changes in myocardial content of energy metabolites in diabetic rats. Material and methods Diabetic cardiomyopathy is characterized by impaired heart contractility and by transition of cardiomyocyte energy metabolism fatty acids exclusively as a source of energy. This reduces the efficiency of energy utilization and increases the heart vulnerability to hypoxia. This study was performed on rats with type 1 diabetes mellitus induced by administration of streptozotocin (60 mg/kg). The LV pump function was studied with a catheter that allows simultaneous measurement of LV pressure and volume in each cardiac cycle. Results Blood glucose was approximately sixfold increased at 2 weeks. Heart failure was detected with decreases in ejection fraction by 27%, minute volume by 39%, and stroke work by 41%. Systolic dysfunction was based on a decrease in LV peak ejection velocity by more than 50%. Furthermore, the LV developed pressure and contractility index were within the normal range, while 1.5 times increased arterial stiffness was the factor that hampered ejection. The sum of adenine nucleotides was decreased by 21%, the ATP content was decreased by 29%, and also creatine phosphate formation was reduced in the myocardium of diabetic rats. Lactate content in the diabetic myocardium was increased almost threefold, which indicated mobilization of aerobic glycolysis. With the reduced preload, equal diastolic volume (0.3 ml), and equal blood pressure (60 mm Hg), the diabetic heart pump function did not differ from the control. Conclusion In type 1 diabetes mellitus, decreases in functional load and oxygen consumption normalize the myocardial pump function with disturbed energy metabolism.

The cardiohemodynamics was studied 1 week after the administration of streptozotocin (60 mg / kg) or 2 weeks after a dose of 30 mg / kg. All rats had a significantly elevated level of glucose in the blood (up to 27—31 mM). In an echocardiographic study, about 1/3 of diabetic animals exhibited systolic dysfunction, and the remaining 2/3 — diastolic dysfunction with an increase in isovolumic relaxation time by 1.5 times. The catheterization of the left ventricle (LV) with a sensor that allows simultaneous measuring LV pressure and volume in both groups revealed decreased cardiac output by 25—31% and maximal ejection rate by 34—50%. However, LV developed pressure, the maximal rate of its development and the level of blood pressure remained within the control values, thus reduced LV ejection rate was probably due to increased arterial stiffness — a negative correlation was found between these indicators (r = - 0.70). The diastolic dysfunction group differed from systolic dysfunction by a significantly smaller end diastolic volume by 22%. Thus, in type 1 diabetes, LV remodeling with reduced end diastolic volume allows to maintain a normal ejection fraction in the presence of distinct heart failure.