Effect of an acute β-adrenergic blockade on exercise intensity corresponding to the lactate minimum

β-Adrenoreceptor blockade is reported to impair endurance, power output and work capacity in healthy subjects and patients with hypertension. The purpose of this study was to investigate the effect in eighth athletic males of an acute β-adrenergic blockade with propranolol on their individual power output corresponding to a defined lactate minimum (LM). Eight fit males (cyclist or triathlete) performed a protocol to determine the power output corresponding to their individual LM (defined from an incremental exercise test after a rapidly induced exercise lactic acidosis). This protocol was performed twice in a double-blind randomized order by each athlete first ingesting propranolol (80mg) and in a second trial a placebo, 120 minutes respectively prior to the test sequence. The blood lactate concentration obtained 7 minutes after anaerobic exercise (a Wingate test) was significantly lower after acute β-adrenergic blockade (8.6 ± 1.6mM) than under the placebo condition (11.7 ± 1.6mM). The work rate at the LM was lowered from 215.0 ± 18.6 to 184.0 ± 18.6 watts and heart rate at the LM was reduced from 165 ± 1.5 to 132 ± 2.2 beats/minute as a result of the blockade. There was a non-significant correlation (r = 0.29) between the power output at the LM with and without acute β-adrenergic blockade. In conclusion, since the intensity corresponding to the LM is related to aerobic performance, the results of the present study, are able to explain in part, the reduction in aerobic power output produced during β-adrenergic blockade.

Influence of angiotensin II receptor subtypes of the paraventricular nucleus on the physiological responses induced by angiotensin II injection into the medial septal area

Objective - We determined the effects of losartan and PD 123319 (antagonists of the AT1 and AT2 angiotensin receptors, respectively), and [Sar1, Ala8] ANG II (a relatively peptide antagonist of angiotensin receptors) injected into the paraventricular nucleus (PVN) on water and 3% NaCl intake, and the diuretic, natriuretic, and pressor effects induced by administration of angiotensin II (ANG II) into the medial septal area (MSA) of conscious rats. Methods - Holtzman rats were used. Animals were anesthetized with tribromoethanol (20 mg) per 100 grams of body weight, ip. A stainless steel guide cannula was implanted into the MSA and PVN. All drugs were injected in 0.5-μl volumes for 10-15 seconds. Seven days after brain surgery, water and 3% NaCl intake, urine and sodium excretion, and arterial blood pressure were measured. Results - Losartan (40 nmol) and [Sar1, Ala8] ANG II (40 nmol) completely eliminated whereas PD 123319 (40 nmol) partially blocked the increase in water and sodium intake and the increase in arterial blood pressure induced by ANG II (10 nmol) injected into the MSA. The PVN administration of PD 123319 and [Sar1, Ala8] ANG II blocked whereas losartan attenuated the diuresis and natriuresis induced by MSA administration of ANG II. Conclusion - MSA involvement with PVN on water and sodium homeostasis and arterial pressure modulation utilizing ANGII receptors is suggested.

Cytokine gene variants and venous thrombotic risk in the BRATROS (BRAZILIAN THROMBOSIS STUDY)

Introduction: Venous thrombosis (VT) and inflammation are two closely related entities. In the present investigation we assessed whether there is a relation between genetic modifiers of the inflammatory response and the risk of VT. Materials and methods: 420 consecutive and unrelated patients with an objective diagnosis of deep VT and 420 matched controls were investigated. The frequencies of the following gene polymorphisms were determined in all subjects: TNF-α- 308 G/A, LT-α+ 252 A/G, IL-6-174 G/C, IL1-ra 86 bp VNTR, IL-10-1082 A/G and CD-31 125 C/G. Results: Overall odds ratio (OR) for VT related to TNF-α- 308 G/A, LT-α+ 252 A/G, IL-6-174 G/C, A1 allele (4 bp repeat) of the IL1-ra 86 bp VNTR, IL-10-1082 A/G and CD-31 125 C/G were respectively: 1.0 (CI95: 0.8-1.5), 1.3 (CI95: 1.0-1.7), 1.1 (CI95: 0.9-1.5), 1.6 (CI95: 1-2.5), 1.2 (CI95: 0.8-1.7) and 0.8 (CI95: 0.6-1.1). A possible interaction between polymorphisms was observed only for the co-inheritance of the mutant alleles of the LT-α+ 252 A/G and IL-10-1082 G/A polymorphisms (OR = 2; CI95: 1.1-3.8). The risk of VT conferred by factor V Leiden and FII G20210A was not substantially altered by co-inheritance with any of the cytokine gene polymorphisms. Conclusions: Cytokine gene polymorphisms here investigated did not significantly influence venous thrombotic risk. © 2006 Elsevier Ltd. All rights reserved.

Analysis of agonist and antagonist effects on thyroid hormone receptor conformation by hydrogen/deuterium exchange

Thyroid hormone receptors (TRs) are ligand-gated transcription factors with critical roles in development and metabolism. Although x-ray structures of TR ligand-binding domains (LBDs) with agonists are available, comparable structures without ligand (apo-TR) or with antagonists are not. It remains important to understand apo-LBD conformation and the way that it rearranges with ligands to develop better TR pharmaceuticals. In this study, we conducted hydrogen/deuterium exchange on TR LBDs with or without agonist (T 3) or antagonist (NH3). Both ligands reduce deuterium incorporation into LBD amide hydrogens, implying tighter overall folding of the domain. As predicted, mass spectroscopic analysis of individual proteolytic peptides after hydrogen/ deuterium exchange reveals that ligand increases the degree of solvent protection of regions close to the buried ligand-binding pocket. However, there is also extensive ligand protection of other regions, including the dimer surface at H10-H11, providing evidence for allosteric communication between the ligand-binding pocket and distant interaction surfaces. Surprisingly, Cterminal activation helix H12, which is known to alter position with ligand, remains relatively protected from solvent in all conditions suggesting that it is packed against the LBD irrespective of the presence or type of ligand. T 3, but not NH3, increases accessibility of the upper part of H3-H5 to solvent, and we propose that TR H12 interacts with this region in apo-TR and that this interaction is blocked by T 3 but not NH3.Wepresent data from site-directed mutagenesis experiments and molecular dynamics simulations that lend support to this structural model of apo-TR and its ligand-dependent conformational changes. (Molecular Endocrinology 25: 15-31, 2011). Copyright © 2011 by The Endocrine Society.

Gastrointestinal changes associated to heart failure

Over the last decade, several studies were conducted on the gastrointestinal changes associated to chronic heart failure. This article presents a literature review on the physiopathology and clinical consequences of pathological digestive changes of heart failure patients. Structural and functional abnormalities of the gastrointestinal tract, such as edema of absorptive mucosa and intestinal bacterial overgrowth, have been leading to serious clinical consequences. Some of these consequences are cardiac cachexia, systemic inflammatory activation and anemia. These conditions, alone or in combination, may lead to worsening of the pre-existing ventricular dysfunction. Although currently there is no therapy specifically earmarked for gastrointestinal changes associated to heart failure, the understanding of digestive abnormalities is germane for the prevention and management of systemic consequences.

VEGF-C expression in oral cancer by neurotransmitter-induced activation of beta-adrenergic receptors

The aim of this study was to investigate the expression of vascular endothelial growth factor type C (VEGF-C) in oral squamous cell carcinoma (OSCC) cell lines through norepinephrine-induced activation of beta-adrenergic receptors. Human OSCC cell lines (SCC-9 and SCC-25) expressing beta-adrenergic receptors were stimulated with different concentrations of norepinephrine (0.1, 1, and 10 μM) and 1 μM of propranolol, and analyzed after 1, 6, and 24 h. VEGF-C gene expression and VEGF-C production in the cell supernatant were evaluated by real-time PCR and by ELISA, respectively. The results showed that beta-adrenergic receptor stimulation by different concentrations of norepinephrine or blocking by propranolol did not markedly alter VEGF-C expression by SCC-9 and SCC-25 cells. VEGF-C protein levels produced by oral malignant cell lines after stimulation with different norepinephrine concentrations or blocking with propranolol was statistically similar (p > 0.05) to those of the control group (nonstimulated OSCC cell lines). Our findings suggest that stimulation of beta-adrenergic receptors by means of norepinephrine does not seem to modulate the VEGF-C expression in OSCC cell lines. These findings reinforce the need for further studies in order to understand the responsiveness of oral cancer to beta-adrenergic receptor stimulation or blockage, especially with regard to VEGF-C production. © 2012 International Society of Oncology and BioMarkers (ISOBM).

Profiles of gene polymorphisms in cytokines and toll-like receptors with higher risk for gastric cancer

Background: Chronic inflammation and gastric carcinogenesis show a close association, so gene polymorphisms that modify the intensity of the inflammatory response may contribute to variations in gastric cancer risk. Aims: The purpose of this study was to investigate the combined effect of the pro- and anti-inflammatory cytokines and toll-like receptors polymorphisms on the chronic gastritis and gastric cancer risk in a Brazilian population sample. Methods: We evaluated 669 DNA samples (200 of gastric cancer [GC], 229 of chronic gastritis [CG], and 240 of healthy individuals [C]). Ten polymorphisms were genotyped: IL-1RN and TLR2 -196 to -174 del using the allele-specific PCR method and TNF-A (rs1800629; rs1799724), TNF-B (rs909253), IL-8 (rs4073; rs2227532), IL-10 (rs1800872) and TLR4 (rs4986790; rs4986791) using PCR-RFLP. Results: Polymorphisms TNF-A-308G/A, IL-8-251A/T, TNF-B + 252A/G and TLR4 + 1196C/T were not associated with risk of any gastric lesion. However, an association with increased risk for GC was observed for polymorphisms IL-1RNL/2 (p < 0.001), TNF-A-857C/T (p = 0.022), IL-8-845T/C (p < 0.001), IL-10-592C/A (p < 0.001), TLR2ins/del (p < 0.001), and TLR4 + 896A/G (p = 0.033). In CG, an association was observed only with polymorphisms IL-1RNL/2 and IL-10-592A/C (p < 0.001 for both). A combined analysis of these six polymorphisms associated with GC revealed a profile with two to four combined genotypes which confer a higher risk of gastric carcinogenesis, with an OR increased 2.95-fold to 50.4-fold, highlighting the combinations IL-1RN2/TNF-A-857T/IL-8-845C, IL-1RN2/IL-8-845C/TLR2del, IL-1RN2/IL-10-592A/TLR4 + 896G, IL-10-592A/TLR2del/ TLR4 + 896G, and IL-1RN2/TNFA-857T/IL8-845C/TLR2del. Conclusions: Our findings evidenced that the combined effect of polymorphisms in genes involved in the inflammatory process may potentiate the risk of gastric cancer, thus emphasizing the importance of evaluating multiple polymorphisms together. © 2012 Springer Science+Business Media New York.

Caracterização de osteoblastos diferenciados de células-tronco mesenquimais da medula óssea de ratos espontâneamente hipertensos (SHR)

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Gabaergic and opioid receptors mediate the facilitation of NaCl intake induced by α₂-adrenergic activation in the lateral parabrachial nucleus

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Aerobic training attenuates nicotinic acetylcholine receptor changes in the diaphragm muscle during heart failure

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Role of the alfa1- and alfa2-adrenoceptors of the lateral hypothalamus in the dipsogenic response to central angiotensin II in rats

The present experiments were conducted to investigate the role of the α1- and α2-adrenergic receptors of the lateral hypothalamus (LH) on the drinking response elicited by intracerebroventricular (i.c.v) injections of carbachol and angiotensin II (AII) in rats. Clonidine (an α2-adrenergic agonist) injected into the LH produced a dose-dependent reduction of the drinking responses elicited by i.c.v. administration of carbachol and AII. The α1-adrenergic agonist phenylephrine injected into the LH reduced the dipsogenic response to i.c.v. AII, but not to carbachol. Injection of yohimbine (an α2-adrenergic antagonist) and prazosin (an α1-adrenergic antagonist) into the LH also reduced the water intake produced by i.c.v. injection of AII. Previous injection of α1- or α2-adrenergic antagonists into the LH increased the antidipsogenic effect of clonidine or phenylephrine injected into the same area on the water intake induced by i.c.v. AII. These results show that the α1- and α2-adrenergic receptors of the LH are involved in the control of drinking responses elicited by i.c.v. injection of AII in rats. They also show that clonidine, but not phenylephrine, suppresses the drinking induced by i.c.v. carbachol. The data suggest that the discharge of central α-adrenergic receptors has a dual (inhibitory and excitatory) effect on water intake induced by central AII. © 1991.

Interação entre as vias de sinalização de receptores serotoninérgicos e Β-adrenérgicos em artéria femoral de ratos

Fundamento: A doença coronária tem sido amplamente estudada em pesquisas cardiovasculares. No entanto, pacientes com doença arterial periférica (DAP) têm piores resultados em comparação àqueles com doença arterial coronariana. Portanto, os estudos farmacológicos com artéria femoral são altamente relevantes para a melhor compreensão das respostas clínicas e fisiopatológicas da DAP. Objetivo: Avaliar as propriedades farmacológicas dos agentes contráteis e relaxantes na artéria femoral de ratos. Métodos: As curvas de resposta de concentração à fenilefrina contrátil (FC) e à serotonina (5-HT) e os agentes relaxantes isoproterenol (ISO) e forskolina foram obtidos na artéria femoral de ratos isolada. Para as respostas ao relaxamento, os tecidos foram contraídos com FC ou 5-HT. Resultados: A potência de classificação na artéria femoral foi de 5-HT > FC para as respostas contráteis. Em tecidos contraídos com 5-HT, as respostas de relaxamento ao isoproterenol foram praticamente abolidas em comparação aos tecidos contraídos com FC. A forskolina, um estimulante da adenilil ciclase, restaurou parcialmente a resposta de relaxamento ao ISO em tecidos contraídos com 5-HT. Conclusão: Ocorre uma interação entre as vias de sinalização dos receptores β-adrenérgicos e serotoninérgicos na artéria femoral. Além disso, esta pesquisa fornece um novo modelo para estudar as vias de sinalização serotoninérgicas em condições normais e patológicas que podem ajudar a compreender os resultados clínicos na DAP.

Renal- and calcium-dependent vascular effects of Polybia paulista wasp venom

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Changes in sodium, potassium-ATPase induced by repeated fencamfamine: the roles of cyclic AMP-dependent protein kinase and the nitric oxide-cyclic GMP pathway

Fencamfamine (FCF) is an indirect dopamine agent with effects similar to amphetamine and cocaine. In the present study, we investigate changes in Na,K-ATPase, cyclic AMP-dependent protein kinase (PKA) and nitric oxide synthase (NOS) activity and cyclic GMP levels in the nucleus accumbens (NAc) and striatum (ST) of animals acutely or repeatedly treated with FCF (3.5 mg/kg). Na,K-ATPase had a similar activity in control and repeatedly treated animals, but was reduced in the NAc of the acute group. This enzyme was reduced in the ST in acute and repeatedly treated animals, compared to the control group. Expression of the alpha(1,2,3)-Na,K-ATPase isoforms in the NAc and the ST was not altered in all groups studied. Acute FCF induced a significant increase in PKA activity in both the ST and the NAc. Repeatedly treated animals showed a higher increase in PKA activity in the NAc, but not in the ST, when compared to the acute group. There was also an increase in both NOS activity and cyclic GMP levels only in the NAc of FCF repeatedly treated animals compared to the acute and control groups. We suggest that chronic FCF treatment is linked to a modification in Na,K-ATPase activity through the PKA and NO-cyclic GMP pathway. (C) 2003 Elsevier Ltd. All rights reserved.

Cardiovascular effects of noradrenaline microinjected into the insular cortex of unanesthetized rats

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)