Background As a low grade systemic inflammation plays an important role in the pathogenesis of atherosclerosis-associated diseases and diabetes mellitus (DM) there is an interest in the relevance of circulating markers of immune inflammation to clinical manifestation of cardiovascular disease (CVD), especially in the setting of DM. Purpose Purpose of our investigation was to assess the predictive value of numerous immune markers (pro-inflammatory cytokines, anti-connective tissue antibodies) in relation with circulating markers of endothelial dysfunction (ED) in persons with documented ischemic heart disease (IHD), DM, and asymptomatic atherosclerosis (AA). Methods 393 persons (147 pts with IHD, 126 pts with T2DM, 120 pts with AA) were observed during 3-year period. The baseline levels of pro-inflammatory cytokines (IL1β, IL6, TNF-α), antibodies against connective tissue components (collagen – antiC-ab, hyaluronic acid – antiHA-ab, chondroitin sulfate antiCS-ab), soluble markers of ED: von Willebrand factor (vWf), endothelin 1 (ET-1), endogenous NO synthase (eNOs) were evaluated by ELISA. The incidence and severity of cardiovascular events (CVE) in the relation with baseline levels of measured markers were evaluated by cluster analysis in 4 cohorts formed according to presence of AA, current IHD and T2DM (AA, IHD, T2DM, IHD+T2DM). From 2 to 4 clusters were separated depending on the incidence and severity of CVE. Results We have defined that in AA the numerous of circulating markers: ET-1, IL-1β, TNFα, antiC-ab, antiCS-ab was associated with clinically significant CVE. In IHD the most severe clinical manifestations were documented in cluster, characterized by increased ET1, vWf, IL6, antiC-ab levels and decreased eNOs, In T2DM without evidenced IHD CVE were associated with next profile: ET1, eNOs, IL-6, antiC-ab, and antiHA-ab. In combination of IHD with T2DM the worst cluster was presented with raised levels of vWf, TNF-α, IL-6, antiC-ab, anti-HA and CRP as well as decreased eNOs. Conclusions Circulating markers of ED and immune-mediated inflammation reflect the clinical manifestation of IHD in high-risk persons with AA and T2DM. Cluster analysis has demonstrated the relationship between specific baseline profile of investigated biomarkers and clinical significant CVE. Obtained data broads our understanding regarding the inflammatory mechanism of atherosclerosis and also suggest a set of circulating markers as predictors of adverse cardiovascular events.
An hour and half after injection of norepinephrine its concentration in the mucosa of the lesser curvature of the stomach increases and in the greater curvature decreases. Stimulation of muscarinic receptors with pilocarpine leads to a marked rise of norepinephrine concentration in the esophageal mucosa and in the mucosa of the lesser curvature. It is supposed that stimulation of muscarinic receptors of the gastrointestinal tract after injection of exogenous norepinephrine induces accumulation of this transmitter in structures with abundant cholinergie innervation. Selective norepinephrine accumulation in the mucosa of the esophagus and lesser gastric curvature is apparently due to its high permeability for norepinephrine contained in saliva.Key Words: catecholamines; esophageal mucosa; stomach Stimulation of exocrine gastrointestinal glands is accompanied by enhanced release of various growth factors (epithelial, nerve, etc.) [3,4,6,7]. This process depends on activity of sympathetic nervous system [7,8,10]. However, the possibility of accumulation of norepinephrine (NE) in esophageal and gastric mucosa induced by high plasma concentration of this transmitter against the background or without pilocarpineinduced stimulation of muscarinie receptors remains unclear. MATERIALS AND METHODSExperiments were carried out on 58 random-bred male rats weighing 250+50 g divided into 3 groups: intact rats, rats injected with 40 lxg/kg NE followed by stimulation of gastrointestinal muscarinie receptors with pilocarpine (1 mg/kg), and rats injected with NE (40-100 p.g/kg). Department of Pathological Physiology, Therapeutic Faculty, Moscow Medical Stornatological InstituteThe animals were deprived of food 24 h before the experiment to synchronize the function of exotrine gastrointestinal glands and had free access to water. The rats were narcotized with Nembutal (40 mg/kg) 20 min after NE injection. Forty-five minutes later the animals received pilocarpine (1 mg/kg), and secretory cycle was stimulated for 40 min. The contents of NE and epinephrine (E) in blood (0.5 ml) and mucosa specimens (10 nag) from the esophagus and the lesser and greater curvatures of the stomach were measured by high-performance liquid chromatography with electrochemical detection [1]. The data were processed statistically using the Student's t test. RESULTSIn control animals the concentration of NE in mucosa specimens far surpassed its plasma content. Plasma and tissue concentrations of E were much lower than those of NE (Table 1). Intraperitoneal injection of NE changed NE and E concentrations in the mucosa but not in the plasma: the content of NE increased
Norepinephrine and epinephrine contents in oral, esophageal, and gastric mucosa are studied in rats by high-performance liquid chromatography 24 h, 3 days, and 7 days after removal of the main salivary glands. A 24-h deficiency of saliva leads to a sharp decrease in the norepinephrine contents in oral and esophageal mucosa. Three days after the surgery, norepinephrine content is normalized in the mucosa of the upper gastrointestinal tract. The most pronounced changes in the contents of both catecholamines in the mucosa of the upper gastrointestinal tract were observed on day 7o Severe insufficiency of salivation caused pronounced phasic changes in the catecholamine contents, indicating that the mucosa of the esophagus and lesser and greater curvatures of the stomach receive catecholamines from saliva. Insufficient supply of saliva leads to the development of inflammatory and dystrophic processes in esophageal and gastric mucosa. Key Words: catecholamines; sialadenectomy; esophageal and gastric mucosaSaliva secreted by the main salivary glands is the major source of catecholamines for oral mucosa [2][3][4]. It is unclear whether catecholamines from saliva supply esophageal and gastric mucosa. This study is an attempt to clarify this issue. MATERIALS AND METHODSExperiments were performed On 42 outbred male albino rats weighing 200+30 g. Submandibular and parotid salivary gland were extirpated under Nembutal anesthesia (40 mg/kg body weight). Shamoperated animals served as a control. Mucosa samples (10 g) from oral cavity, esophagus, and lesser and greater curvature of the stomach were collected under Nembutal anesthesia (40 mg/kg) 24 h, 3 days, and 7 days after the surgery. Function of salivary glands was synchronized by depriving the rats of food for 24 h with free access to water. The contents of RESULTSIn healthy rats, the contents of NEP and EP were maximal in esophageal mucosa and the content of EP in the lesser curvature of the stomach (Tables 1 and 3). This finding suggests that for normal functioning the esophagus requires higher concentration of NEP than oral mucosa and stomach. Twenty-four hours of after removal of the main salivary glands NEP contents sharply decreased in oral and esophageal mucosa and remained unchanged in lesser and greater curvatures of the stomach. Epinephrine content changed only in the greater curvature. Three days after the surgery, NEP concentration in the mucosa of the upper gastrointestinal tract was restored to the original level. The concentration of EP was increased in oral mueosa and decreased in esophagus and greater curvature of the stomach. These
Objective: to determine the level of circulating markers of endothelial dysfunction (endothelin‑1, von Willebrand factor (vfV), endothelial NO-synthase (e‑NOS)) in the blood serum of patients with type 2 diabetes mellitus (DM), as well as to assess the pathogenetic significance endothelial dysfunction in the development of diabetic nephropathy.Materials and methods: the study included 93 patients with type 2 DM, including 28 men (30.1%) and 65 women (69.9%), aged 30 to 79 years, the average age of patients was 59.7±8.4 of the year. The main group included patients with both newly diagnosed type 2 DM and a long-term diabetic history. The duration of the disease averaged 9.5±7.5 years. The majority of patients with DM type 2 (92.5%) at the time of inclusion in the study had various variants of microvascular complications of diabetes, only a small number of patientsin this group (7.5%) had no signs of diabetic angiopathy. Signs of various stages of diabetic nephropathy were observed in 60 patients (69.2%). The comparison group consisted of 30 patients with essential arterial hypertension, including 12 men (40%) and 18 women (60%), aged 34 to 70 years, on average 56.1 ± 8.1 years. The control group consisted of 32 apparently healthy individuals. In all patients, along with routine methods of clinical, laboratory and instrumental examination, the level of circulating markers of endothelial dysfunction (endothelin‑1, von Willebrand factor (vWF), endothelial NO-synthase (e‑NOS)) in blood serum was measured using enzyme-linked immunosorbent assay (ELISA).Results: in patients with DM type 2 and diabetic nephropathy, a statistically significant increase in the concentration of circulating markers of endothelial dysfunction was revealed in comparison with hypertensive patients and healthy individuals. An increase in the level of endothelin‑1 relative to the borderline reference value was found in 73 (78.5±4.1%), vfV in 63 (67.7±4.8%) and e‑NOS in 65 (69.9±4.7%) of patients with DM type 2. In the groups of participants with hypertension and healthy individuals, endothelial imbalance was noted by us significantly less often than in patients with DM type 2, the levels of endothelin‑1 and vfV in people with hypertension were increased in more cases than in healthy individuals. It was noted that the levels of circulating markers of endothelial dysfunction increase with an increase in the duration of DM type 2, and also significantly increase under conditions of carbohydrate decompensation.Conclusion: the results obtained confirm the pathogenetic role of endothelial dysfunction in the development of diabetic nephropathy in patients with type 2 diabetes, increasing endothelial imbalance in persons with a long diabetic history and lack of compensation for carbohydrate metabolism.
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