This review summarizes the data on the implication of ubiquitous isoform of the carrier providing electroneutral symport of sodium, potassium and chloride (Na+, K+, 2Cl–-cotransport — NKCC1) in the regulation of smooth muscle contraction in the systemic and pulmonary circulation and its involvement in the pathogenesis of systemic (essential) and pulmonary hypertension with the special emphasis on the usage of NKCC1 as a novel antihypertensive target. In this connection we consider the data on the attenuation of the myogenic tone in the resistant vessels of the systemic circulation and afferent arteriole of the kidney as well as the action of inhaled loop diuretic on the contraction of the airway smooth muscle cells.

Objective. To study the effect of the synthetic analog of the platelet activation factor (based on the 1-alkyl-2-alkylcarbamoyl-glycerol) on the tone of vascular smooth muscle cells and hemodynamic parameters. Design and methods. We studied the vasodilator properties of 1-O-hexadecyl-2-O-methylcarbamoylglycerol, the substance from the group of 1-alkyl-2-alkylcarbamoylglycerols. Systemic arterial pressure, stroke volume and heart rate were recorded by the Biopac hardware complex in Wistar rats 3 hours after intragastric administration of the drug. We studied (the Myobath II Tissue bath system) mechanical tension of isolated aortic segments from Wistar and SHR rats precontracted with phenylephrine and nonisosomotic solutions. Using the Wire Myograph 620M system, we recorded changes in the contractility of the small mesenteric arteries, the artery of the gastrocnemius muscle and the renal interlobar arteries of the Wistar rats precontracted with methoxamine. Results. 1-O-hexadecyl-2-O-methylcarbamoylglycerol decreased arterial pressure in Wistar rats after intragastric administration due to the decrease in specific peripheral resistance, but does not exert an evident relaxation acting on isolated vessels pre-reduced by activation of α1-adrenoreceptors with phenylephrin and methoxamine. 1-O-hexadecyl-2-O-methylcarbamoylglycerol reduced the hyper-, hypo-, and isoosmotic contraction of the aortic segments from Wistar rats, but increased (isoosmotic contraction) or did not change (hyper- and hypoosmotic contraction) it in the vessels obtained from SHR rats. Conclusions. The pressure reducing effect of 1-O-hexadecyl-2-O-methylcarbamoylglycerol is not due to direct action on vascular cells. It might involve nervous/humoral mechanisms of blood pressure regulation. However, 1-O-hexadecyl-2-O-methylcarbamoylglycerol reduces the contraction amplitude induced by incubation in the non-isoosmotic environment in normotensive rats. However, the effect is not present in hypertensive rats indicating the possible involvement of NKCC in the mechanisms of the drug substance. 

Objective. Hydrogen sulfide (H2S) is one of gasotransmitters that participate in the regulation of a large number of cellular functions. H2S can also act as a pathological link in the development of vascular diseases, in particular hypertension. Na+, K+, 2Cl–-cotransporter (NKCC) might play an important role in vascular tone increasing due to involvement of chloride currents in the depolarization of smooth muscle cell membrane. Significant differences in the regulatory mechanisms of contractile properties of the vessels of systemic and pulmonary circulation might depend on the mechanisms of NKCC. So its role as a target for H2S requires investigation. Design and methods. The changes in mechanical tension of ring segments from pulmonary artery (PA) of WKY and SHR rats under the action of the donor of H2S (L-cysteine) was studied by organ bath technique. Results. L-cysteine caused multidirectional effects on mechanical tension of PA smooth muscle cells from WKY rats precontracted with 30 mM KCl. Bumetanide (100 μM) suppressed the relaxation but not constriction of the intact and endotheliumdenuded vascular segments caused by L-cysteine. In ring segments from PA of SHR rats, L-cysteine potentiated constriction in segments with intact endothelium but caused relaxation in endothelium-denuded segments.

Objective. To assess homoarginine (hArg) level in patients with ascending aortic aneurysm and aortic stenosis. Design and methods. The study included 26 patients with ascending aortic aneurysm and 19 patients with aortic stenosis. The comparison group consisted of 30 healthy donors. Plasma levels of hArg, asymmetric dimethylarginine (ADMA), and the parameters of mitochondrial dysfunction (pyruvic acid, PGC-1a protein, lactic acid, cytochrome C) were determined. Results. Patients with ascending aortic aneurysm and aortic stenosis demonstrated a decrease in the level of serum hArg (p = 0,002), most pronounced in the group with ascending aortic aneurysm, an increase in ADMA and markers of mitochondrial dysfunction-lactic acid, PGC-1a protein. There was no relation between hArg level and well-known metabolic markers of mitochondrial (lactic and pyruvic acids) and endothelial dysfunction (ADMA). The following factors contributed to the lowering of hArg levels: an increased body mass index (rs = –0,34, p = 0,02), impaired glucose tolerance (p = 0,006), and myocardial infarction (p = 0,09). In a subgroup of patients with a tricuspid aortic valve and ascending aortic aneurysm, an inverse relationship was found between hArg level and descending thoracic aortic diameter (rs = –0,5, p < 0,05). Conclusion. The decreased level of hArg is a marker of mitochondrial and endothelial dysfunction in patients with ascending aortic aneurysm and aortic stenosis, especially in patients with myocardial infarction, obesity and diabetes mellitus.

Background. Pulmonary arterial hypertension (PAH) is a relatively rare disease, but its therapy is expensive and effectiveness is moderate. One of important mechanisms of PAH pathogenesis is reduced formation of nitric oxide in pulmonary vascular endotheliocytes. Objective. To study the effect of oxacom (dinitrosyle iron complex with ligand glutathione), which already demonstrated long-term decline in blood pressure (BP) in systemic circulation, on pressure in pulmonary circulation. Design and method. To induce PAH, the standard monocrotalin rat model was used. Three weeks after monocrotalin introduction (60 mg/kg), a catheterization of the right ventricle was performed in anesthetized rats (100 mg/kg ketamine) through jugular vein and pressure was measured. Simultaneously, BP in femoral artery and ECG were recorded. Results. Systolic pressure in the right ventricle (SPRV) in rats after monocrotalin introduction doubled compared with the control group, from 35 to 70 mmHg, but myocardial contractility index fell by 28 %, also duration of QRS complex and the height of T-wave increased. Intravenous oxacom (40 mg/kg) quickly reduced SPRV by average of 12 ± 3 mmHg, and this level was maintained for an hour. This effect was absent in control rats. Similar BP changes in systemic circulation were observed in both groups. Inhalation of nitric oxide led to BP decrease only in animals with high level of SPRV. Inhalation of oxacom was ineffective. Conclusion. Oxacom is a promising substance for sustained pressure decline in the pulmonary circulation in PAH, but further investigations are needed for the development of a more suitable prolonged-action form of the drug.

Background. Hypertension (HTN) represents the most significant factor associated with the development of chronic heart failure (CHF) with preserved left ventricular ejection fraction (LVEF). Low-intensity systemic inflammation is considered an important element for the pathogenesis of both HTN and CHF. Objective. To set gender-dependent features of pro-inflammatory status in middle-aged patients with HTN complicated by non-severe CHF with preserved LVEF. Design and methods. The study involved 165 middle-aged subjects. The main study group comprised 104 patients (including 55 males) with HTN complicated by CHF with preserved LVEF. CHF diagnosis was confirmed by the elevated blood plasma N‑terminal brain natriuretic peptide precursor and 6‑minute walk test. Also, the main group was stratified depending on the presence of the 1st or the 2nd grade of left ventricular diastolic dysfunction (LVDD). The comparison group consisted of 30 patients with stage II HTN (including 15 males), and a control group — of 31 normotensive individuals (including 15 males). In all subjects we measured serum levels of C‑reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin‑6 (IL‑6). The data were processed by the program Statistica for Windows (version 10.0). Results. In each group the blood markers of proinflammatory status were normal. Males of the main group showed higher levels of CRP, TNF-alpha, IL‑6 than females. Hypertensive males and females with CHF with preserved LVEF demonstrated significantly higher indices of all parameters than in the comparison group. We also analyzed data depending significantly greater than in subjects with the 1st LVDD grade (both among males and females). Conclusions. In comparison with females, males with HTN complicated by CHF with preserved LVEF have significantly higher CRP, TNF-α, IL‑6 serum levels. Development of CHF with preserved LVEF in HTN patients is associated with increased intensity of the pro-inflammatory pattern among both males and females. Regardless of gender and clinical status of CHF, hypertensive patients with the 2nd grade of LVDD are characterized by higher serum levels of CRP, TNF-α, IL‑6 compared to those with the 1st grade of LVDD.

Background. Long-term prognosis of the patients after cardiac surgery is often explained by the relation to the main disease without consideration of possible negative prognostic impact of the post-surgery comorbidity, in particular, new-onset hypertension (HTN). Objective. To assess the risk of HTN development in patients after surgery for infective endocarditis (IE) in a prospective study. A special method of projective classification was used for decrease the contingency bias by application of several decisive rules instead of one. Design and methods. Altogether 92 IE patients (66 male and 26 female) with various valve diseases were retrospectively divided into two groups: fifty patients with HTN composed the first group and forty two formed the comparison group. The post-surgery follow-up period achieved up to 20 years. Initially, 133 pre- and post-surgery characteristics were included in analysis. Results. We found a gender-dependent difference in predictive factors. Out of all 133 factors, only eight presurgery variables and nine characteristics of early post-surgery period, were found to be common for men and women in HTN prediction: age at the time of surgery and symptoms of heart failure (HF) after surgery. For women, significant factors also included absence of thromboembolic events and HF after surgery, presence of permanent atrial fibrillation prior surgery and the education level. For men the variants included left ventricular end-diastolic dimension and pulmonary hypertension (both with the negative prediction value), and interventricular septal thickness and post-surgery size of the right ventricle (both with the positive prediction value), HF and arterial fibrillation paroxysms, presence of presurgery trioventricular block and mitral insufficiency. Conclusions. The projective classification assessment of HTN risk in patients after surgery for IE provided reliable definition of prognostic factors despite the heterogeneous group of patients.

Rho-kinase was shown to regulate the functions of almost all cells of our body. The key activator of Rhokinase is the small guanosine triphosphate (GTP)-binding protein RhoA, but RhoA-independent mechanisms of Rho-kinase regulation exist as well. In this review we describe the mechanisms affecting Rho-kinase activity in vascular smooth muscle and endothelial cells, Rho-kinase regulatory influences on fundamental physiological processes in these cells, as well as its role in the pathogenesis of vascular disorders in systemic and pulmonary arterial hypertension and diabetes mellitus.

Pulmonary hypertension (PH) encompasses a heterogeneous group of diseases that are characterized by elevated pulmonary artery pressures. Female gender is known to be one of the most powerful risk factors for the development of PH. However, only recent evidence has provided better understanding of the relationship between sex, gender, sex hormones, and PH. Estrogens have been found to be protective in cardiovascular system, but not in case of PH. This phenomenon was called “estrogen paradox”. This review focuses on pulmonary hypertension, sex hormone effects in PH, sex hormones synthesis, metabolism and receptor physiology, increased pulmonary vascular resistance, right ventricular failure.

Endothelium is a multilevel cellular structure that permeates all organs and systems of the body. A disorder of the regulation of the arterial tone underlies essential hypertension. However, its pathogenesis basis, despite intense efforts, remains unclear. The unfavorable role of emotional stress, hypodynamia, obesity and disorder of water-salt metabolism is obvious. However, the exact mechanisms and predictors of the development of arterial hypertension (HTN) are not currently defined. This opposes the prevention and detection of essential hypertension at an early stage. The investigation of endothelial function as a target and a predisposing factor for HTN development is promising and implies both scientific and applied clinical significance. Indeed, understanding of pathognomonic endothelial alterations for HTN development will clarify its pathogenesis and will help the development of the adequate treatment protocols. The paper reviews current data on the involvement of endothelial cells (EC) in the development of HTN. The role of lipid disorders in the physiological state of the endothelium is shown. The role of endothelial dysfunction in increasing production of active oxygen species and disorders in the nitric oxide metabolism is highlighted. The activity of the following enzyme is reviewed: NADPH (nicotinamide adenine dinucleotide phosphate) oxidase, cyclooxygenase, xantinoxydoreductase and endothelial NO synthase. The interaction of the endothelium and the extracellular matrix, as well as endothelium and smooth muscle cells, is also given according to the literature data. The role of ghrelin, produced by endothelium, in the regulation of vascular tone is highlighted. Methods of the EC assessment in vitro under hypoxia are presented. Based on the literature review, it is clear that the assessment of the endothelium under hypoxia is highly important, as well as the investigation of the influence of tissue and hemic hypoxia in vivo. These studies will help to establish the contribution of functional endothelial disturbances to the development of HTN.

Intense emotions cause arousal of the central nervous system, sympathetic activation, blood pressure (BP) increase and hyperventilation. Continuous negative emotions coming with hyperventilation lead to increase in CO2-chemosensitivity that keeps chronic hypocapnia constant and results in BP dysregulation and stable arterial hypertension (AH). The key mechanism of a hypertensive effect of chronic hyperventilation probably lies in sensitivity changes of CO2-chemoreceptors. Respiratory training with periodic hypercapnia has potential therapeutic effect in HTN by restoring CO2-chemoreceptor sensitivity and increasing antioxidant activity. Hypocapnia violates autoregulation mechanisms. Cerebral blood vessels lose their ability to neutralize BP surges, which negatively affects chemoreceptor-related processes of respiratory and BP regulation. With the HTN progression, cerebrovascular dysregulation occurs depending on the BP level. Moreover, hypocapnia is accompanied by the reduction of intracranial venous tone which can lead to increased intracranial pressure and problems with BP regulation in the brain. The threshold level of cardiovascular CO2-reactivity is normally higher than the threshold level of cerebrovascular CO2-reactivity. The changes in cardiovascular CO2-reactivity occur already in the initial period of HTN. Compared to healthy people, hypertensive patients develop slower BP reaction to hyper/hypocapnia, and hypercapnia induced low BP does not restore to the baseline level that can result from the BP dysregulation.
In general, cerebrovascular CO2-reactivity is decreased in HTN patients. However, the cerebrovascular vasodilator function is preserved better than the vasoconstrictor reserve demonstrating that cerebral vessel remodeling in HTN is characterized by luminal narrowing due to the vascular wall hypertrophy.

Objective. To investigate the effects of necroptosis inhibitors — necrosulfonamide and necrostatin‑1s — on morphofunctional characteristics of the myocardium in the model of prolonged cold preservation of the donor rat heart. Design and methods. The study was performed on 27 Wistar rats. The animals were divided into the following groups: 1) control (n = 7), 2) dimethylsulfoxide (DMSO, n = 6), 3) necrostatin‑1s (n = 8), 4) necrosulfonamide (n = 6). All test compounds were administered intraperitoneally 1 hour before the start of the experiment. Histidine-tryptophan-ketoglutarate (HTK) solution cooled to 4 °C was used as a preservative agent. DMSO was used as a solvent for necrostatin‑1s and necrosulfonamide. During the experiment, left ventricular pressure, heart rate and coronary flow were recorded. At the end of 8‑hour of ischemia and 2‑hour of reperfusion, myocardial infarct size was planimetrically evaluated. Results. Necrostatin-1s and necrosulfonamide show cardioprotective effects, as evidenced by the significantly lower levels of myocardial necrosis in these groups, as well as the best indices of intracardiac hemodynamics during reperfusion. In the groups of necrosulfonamide and necrostatin‑1s, myocardial infarct size was 32,2 ± 9,6 and 29,0 ± 9,2 %, respectively, which is significantly lower than in control groups and DMSO (54,4 ± 6,6 and 59,2 ± 5,6 %, respectively, p < 0,05). During reperfusion in necrosulfonamide and necrostatin‑1s groups, higher values of pulse intraventricular pressure and coronary flow rates were recorded, as well as lower diastolic intraventricular pressure, compared to control group and DMSO (p < 0,05). Conclusions. Necroptosis inhibitors necrostatin‑1s and necrosulfonamide improve morphofunctional characteristics of the myocardium state during prolonged cold preservation of the donor heart.