Recruitment of functionally active heart beta2-adrenoceptors in the initial phase of endotoxic shock in pithed rats

A supersensitivity of the beta-adrenoceptor-mediated chronotropic response has been demonstrated in atria isolated from rats subjected to septic shock. Our study was undertaken to investigate whether bacterial endotoxin/LPS affects the increase in heart rate induced by beta-adrenoceptor agonists in the rat also in vivo. In pithed and vagotomized rats, the nonselective beta-adrenoceptor agonist isoprenaline (0.05-0.15 nmol/kg) and agonists at the high- and low-affinity state of beta1-adrenoceptors, that is, prenalterol (0.3-3 nmol/kg) and (+/-)-4-[3-[(1,1-dimethylethyl)amino]-2-hydroxypropoxy]-1,3-dihydro-2H-benzimidazole-2-one (CGP 12177; 3-6 nmol/kg), respectively, and at beta2-adrenoceptors, that is, fenoterol (1-5 nmol/kg), increased heart rate by 50 to 60 beats/min. Administration of LPS (0.4, 1, and 1.5 mg/kg), under continuous infusion of vasopressin, dose-dependently amplified the chronotropic response to isoprenaline, prenalterol, and fenoterol (by 80%, 50%, and 100%, respectively) but not to CGP 12177. The beta2-adrenoceptor antagonist erythro-(+/-)-1-(7-methylindan-4-yloxy)-3-isopropylaminobutan-2-ol (ICI 118551 0.1 mumol/kg) did not affect the chronotropic responses of isoprenaline, fenoterol, and prenalterol under non-endotoxic conditions, but abolished the potentiation of tachycardia produced by LPS (1.5 mg/kg). The beta1-adrenoceptor antagonist (+/-)-2-hydroxy-5-[2-[[2-hydroxy-3-[4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl]-phenoxy]propyl]-amino]ethoxy]-benzamide CGP 20712A; 0.1 mumol/kg almost completely reduced the chronotropic effects of isoprenaline, fenoterol, and prenalterol both in control rats and in animals exposed to LPS (1.5 mg/kg). We conclude that LPS sensitizes cardiac beta-adrenoceptors by recruiting functionally active beta2-adrenoceptors, but the amplification of tachycardia occurs only when both beta1- and beta2-adrenoceptors are concomitantly activated. The pithed rat may serve as a model to examine the beta-adrenoceptor supersensitivity in vivo.     

Neoplastic pericarditis--the role of different diagnostic procedures

The aim of the study was to assess the role of different diagnostic procedures in the recognition of malignant pericarditis. Consecutive medical records of the patients with pericardial effusion treated with pericardiocentesis or pericardioscopy in the period of 1982-2002 were analyzed retrospectively. Criteria of neoplastic pericarditis were: positive result of pericardial fluid cytology and/or neoplastic infiltration found in pericardial biopsy specimen. Criteria of non-neoplastic pericarditis were: negative result of pericardial fluid cytology and pericardial biopsy specimen, no neoplastic disease diagnosed at presentation and during 3-years of follow up. Malignant pericarditis was diagnosed in 47 patients (pts), nonmalignant in 51. Echocardiographic signs of cardiac tamponade were found in 80% of pts with neoplastic pericarditis and 40% of pts with non-malignant disease (p = 0.0001). Chest CT scan revealed the presence of enlarged mediastinal lymph nodes in 94% of pts with malignant pericarditis and only 11% of pts with non-malignant disease (p = 0.00001). Pericardial thickness on CT scan exceeded 8 mm in 75% of the pts with malignant pericarditis and 8% of pts with nonmalignant disease (p = 0.0003). Pericardial fluid (pf) CEA concentration was significantly higher in the patients with neoplastic pericarditis than in the pts with non-malignant process. CEA > 5 ng/ml and Cyfra 21-1>50 ng/ml were found in 43% of the pts with malignant pericarditis and none of the pts with benign pericarditis. Thus we recommend chest CT scan and pericardial fluid tumor markers (CEA and Cyfra 21-1) assessment as the procedures helpful in the recognition of malignant pericarditis.     

Exaggerated increase of exercise-induced pulmonary artery pressure in systemic sclerosis patients predominantly results from left ventricular diastolic dysfunction

Objective

High prevalence of exaggerated pulmonary artery pressure response to exercise (EPAPR) was reported in patients with systemic sclerosis (SSc). However, pathophysiology of this phenomenon has not been well defined. Therefore, we evaluated the frequency and potential aetiology of EPAPR in SSc patients.

Methods

We included 85 patients (79 female, 6 male, mean age 54.3 ± 13.9 years) with SSc. Transthoracic echocardiography followed by exercise Doppler echocardiography (EDE) were performed. A positive EDE was defined when at least 20 mmHg increase of tricuspid regurgitation peak gradient (TRPG) was recorded. Right heart catheterization (RHC) with exercise was performed in positive EDE patients and in subjects with resting TRPG >31 mmHg.

Results

Resting TRPG >31 mmHg and/or positive EDE was found in 30 patients and they were referred to RHC. Finally, RHC was performed in 20 patients (16 pts resting TRPG >31 mmHg and 4 others normal resting TRPG and positive EDE). In 12 (60 %) of them an EPAPR with elevated pulmonary capillary wedge pressure (PCWP) was observed. Interestingly, mean left atrium (LA) diameter was greater in an EPAPR with elevated PCWP patients than in subjects with normal exercise response (39.36 ± 5.6 vs. 35.53 ± 3.48, p = 0.03). In EPAPR with elevated PCWP group greater mean value of E/E′ of mitral lateral annulus was observed (7.98 ± 3.35 vs. 6.27 ± 1.94, p = 0.03). In the univariate logistic regression analysis increased LA diameter was significant predictor of EPAPR with elevated PCWP (OR 1.199, 95 % CI 1.029–1.396, p = 0.019).

Conclusions

Despite very well-known risk of PAH in systemic sclerosis patients, the excessive increase of PAP during exercise is more commonly caused by left ventricular diastolic dysfunction than pulmonary arterial vasculopathy.     

Do effects of propranolol on the skeletal system depend on the estrogen status?

BackgroundPropranolol, a nonselective β-adrenergic receptor antagonist, was reported to favorably affect the skeletal system in different animal models. The aim of the study was to investigate whether the effects of propranolol on the skeletal system depend on the estrogen status.MethodsThe in vivo experiments were carried out on the following groups of mature female Wistar rats: sham-operated control rats, sham-operated rats receiving propranolol, ovariectomized (OVX) control rats, OVX rats receiving propranolol, OVX rats receiving estradiol, OVX rats receiving estradiol and propranolol. Propranolol hydrochloride (10 mg/kg po) and/or estradiol (0.1 mg/kg po) were administered daily for 4 weeks. Bone mass, mineral and calcium content, macrometric and histomorphometric parameters, and mechanical properties were examined. In vitro, effects of estradiol and propranolol on the formation of mouse osteoclasts and on the mRNAexpression of genes related to osteoclastogenesis, bone formation and mineralization, as well as adrenergic and estrogen signalling in mouse osteoblasts were investigated.Results and conclusionPropranolol exerted some favorable effects on the rat skeletal system in vivo, independently of the estrogen status. However, in vitro studies indicated a possibility of some antagonistic relations between the estradiol and propranolol effects.     

Nutrition Strategy and Life Style in Polycystic Ovary Syndrome—Narrative Review

Here we present an extensive narrative review of the broadly understood modifications to the lifestyles of women with polycystic ovary syndrome (PCOS). The PubMed database was analyzed, combining PCOS entries with causes, diseases, diet supplementation, lifestyle, physical activity, and use of herbs. The metabolic pathways leading to disturbances in lipid, carbohydrate, and hormonal metabolism in targeted patients are described. The article refers to sleep disorders, changes in mental health parameters, and causes of oxidative stress and inflammation. These conditions consistently lead to the occurrence of severe diseases in patients suffering from diabetes, the fatty degeneration of internal organs, infertility, atherosclerosis, cardiovascular diseases, dysbiosis, and cancer. The modification of lifestyles, diet patterns and proper selection of nutrients, pharmacological and natural supplementation in the form of herbs, and physical activity have been proposed. The progress and consequences of PCOS are largely modifiable and depend on the patient’s approach, although we have to take into account also the genetic determinants.     

Circulating brain-derived neurotrophic factor concentration is downregulated by intralipid/heparin infusion or high-fat meal in young healthy male subjects

OBJECTIVE

Insulin resistance and type 2 diabetes are associated with an increased risk of neurodegenerative diseases. Brain-derived neurotrophic factor (BDNF) regulates neuronal differentiation and synaptic plasticity, and its decreased levels are supposed to play a role in the pathogenesis of Alzheimer’s disease and other disorders. The aim of the current study was to estimate the effects of hyperinsulinemia and serum free fatty acids (FFA) elevation on circulating BDNF concentration in humans.

RESEARCH DESIGN AND METHODS

We studied 18 healthy male subjects (mean age 25.6 ± 3.0 years; mean BMI 26.6 ± 4.8 kg/m²). Serum and plasma BDNF concentration was measured in the baseline state and in the 120 and 360 min of euglycemic hyperinsulinemic clamp with or without intralipid/heparin infusion. Furthermore, plasma BDNF was measured in 20 male subjects (mean age 22.7 ± 2.3 years; mean BMI 24.9 ± 1.5 kg/m²) 360 min after a high-fat meal.

RESULTS

Insulin sensitivity was reduced by ∼40% after 6 h of intralipid/heparin infusion (P < 0.001). During both clamps, serum and plasma BDNF followed the same pattern. Hyperinsulinemia had no effect on circulating BDNF. Raising FFA had no effect on circulating BDNF in 120 min; however, it resulted in a significant decrease by 43% in serum and by 35% in plasma BDNF after 360 min (P = 0.005 and 0.006, respectively). High-fat meal also resulted in a decrease by 27.8% in plasma BDNF (P = 0.04).

CONCLUSIONS

Our data show that raising FFA decreases circulating BDNF. This might indicate a potential link between FFA-induced insulin resistance and neurodegenerative disorders.Several studies have proven that phenotypes associated with insulin resistance are at increased risk for developing cognitive decline and neurodegeneration (1). The incidences of Alzheimer’s disease, vascular dementia, and major depression were higher in individuals with type 2 diabetes than in those without (1). Furthermore, cognitive impairment is also increased in patients with prediabetes and metabolic syndrome (1).Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family, which interacts with high affinity with tyrosine receptor kinase B (2). BDNF is abundantly expressed in central and peripheral nervous system and can cross the blood-brain barrier in both directions (3). Recent studies have shown that BDNF is also produced in nonneurogenic tissues, including skeletal muscle and vascular endothelium, and is stored in platelets (4,5). Because serum contains the factors released from the platelets, it could be an important issue whether BDNF concentration is measured in serum or in plasma. In the study of Rasmussen et al. (6), it was reported that the brain contributed to more than 70% of plasma BDNF in healthy humans. The changes in plasma BDNF were considered to reflect its changes in the brain (7). However, serum BDNF concentration has also been reported to closely correlate with the cortical BDNF level (8), suggesting that it can reflect the BDNF level in the brain as well. Dietary restriction increases the number of newly generated neuronal cells, induces BDNF expression in the dentate gyrus of rats (9), and increases serum BDNF in humans (10). Physical activity increases BDNF measured both in serum and in plasma (7,11).BDNF is a key protein in regulating neuronal survival, differentiation, and synaptic plasticity and seems important for learning and memory function (12). Numerous data indicate that BDNF has specific effects on central pathways involved in appetite regulation and energy expenditure (2). BDNF might also regulate glucose metabolism (13). It reduces food intake and lowers blood glucose in genetically modified (db/db) obese mice (13). The hypoglycemic effect of BDNF cannot be ascribed solely to the hypophagic effect of BDNF, because BDNF administration improves insulin resistance in db/db mice, even when food intake is controlled.Low plasma BDNF levels were observed not only in neurodegenerative diseases but also in type 2 diabetes and obesity (14). We observed decreased serum BDNF concentration in young nonobese subjects with low insulin sensitivity (15). Insulin resistance might play a role in common pathogenesis of neurodegenerative and metabolic disorders, and decreased BDNF may explain the clustering of these diseases. However, the mechanism connecting insulin resistance with neurodegeneration is still unclear. It is widely accepted that free fatty acids (FFA) induce insulin resistance (16). It is noteworthy that experimental studies indicate that a high-fat diet (HFD) disrupts cognition and contributes to neurodegenerative diseases (17). Therefore, the aim of the current study was to estimate the effects of hyperinsulinemia and serum FFA elevation on circulating BDNF concentration in humans.     

Helicobacter pylori promotes apoptosis, activates cyclooxygenase (COX)-2 and inhibits heat shock protein HSP70 in gastric cancer epithelial cells

Objective

Apoptosis plays an important role in the regulation of gastric epithelial cell number and gastrointestinal disorders induced by Helicobacter pylori (Hp). Heat shock proteins (HSPs) are involved in cell integrity, cell growth and in gastric mucosa colonized by Hp. COX-2 was implicated in Hp-induced carcinogenesis but the effects of this germ and CagA cytotoxin on HSP70, COX-2, Bax and Bcl-2 in gastric cancer epithelial cells have been little studied.

Material and methods

We determined the expression for HSP70, Bax and Bcl-2 in human gastric epithelial MKN7 cells incubated with live strain Hp (cagA?+?vacA+) with or without co-incubation with exogenous CagA and NS-398, the selective COX-2 inhibitor. After 3–48?h of incubation, the expression of HSP70, COX-2, Bax and Bcl-2 mRNA and proteins were determined by RT-PCR and immunoprecipitation.

Results

Hp inhibited expression for HSP70 and this was significantly potentiated by exogenous CagA. Co-incubation of epithelial cells with Hp, without or with CagA increased Bax expression and simultaneously decreased expression for Bcl-2. The increase in COX-2 mRNA and Bax expression were significantly inhibited by NS-398. We conclude that Hp promotes apoptosis in adenocarcinoma gastric epithelial cells in vitro and this is associated with activation of COX-2 and inhibition of HSP70.