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1.
J Med Chem ; 56(20): 7804-20, 2013 Oct 24.
Article in English | MEDLINE | ID: mdl-24102516

ABSTRACT

Structural modifications of nonsteroidal anti-inflammatory drugs (NSAIDs) have successfully reduced the side effect of gastrointestinal ulceration without affecting anti-inflammatory activity, but they may increase the risk of myocardial infarction with chronic use. The fact that nitroxyl (HNO) reduces platelet aggregation, preconditions against myocardial infarction, and enhances contractility led us to synthesize a diazeniumdiolate-based HNO-releasing aspirin and to compare it to an NO-releasing analogue. Here, the decomposition mechanisms are described for these compounds. In addition to protection against stomach ulceration, these prodrugs exhibited significantly enhanced cytotoxcity compared to either aspirin or the parent diazeniumdiolate toward nonsmall cell lung carcinoma cells (A549), but they were not appreciably toxic toward endothelial cells (HUVECs). The HNO-NSAID prodrug inhibited cylcooxgenase-2 and glyceraldehyde 3-phosphate dehydrogenase activity and triggered significant sarcomere shortening on murine ventricular myocytes compared to control. Together, these anti-inflammatory, antineoplasic, and contractile properties suggest the potential of HNO-NSAIDs in the treatment of inflammation, cancer, or heart failure.


Subject(s)
Aspirin/chemical synthesis , Aspirin/pharmacology , Azo Compounds/chemistry , Nitric Oxide/chemistry , Nitrogen Oxides/chemistry , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Aspirin/chemistry , Carcinoma, Non-Small-Cell Lung/pathology , Cell Line, Tumor , Cell Survival/drug effects , Cells, Cultured , Cyclooxygenase 2/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+)/metabolism , Humans , Lung Neoplasms/pathology , Male , Mice , Mice, Inbred C57BL , Models, Chemical , Molecular Structure , Myocytes, Cardiac/cytology , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Prodrugs/chemical synthesis , Prodrugs/chemistry , Prodrugs/pharmacology , Sarcomeres/drug effects , Sarcomeres/metabolism
2.
Diabetes ; 61(12): 3094-105, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22807033

ABSTRACT

In type 2 diabetes, hyperglycemia and increased sympathetic drive may alter mitochondria energetic/redox properties, decreasing the organelle's functionality. These perturbations may prompt or sustain basal low-cardiac performance and limited exercise capacity. Yet the precise steps involved in this mitochondrial failure remain elusive. Here, we have identified dysfunctional mitochondrial respiration with substrates of complex I, II, and IV and lowered thioredoxin-2/glutathione (GSH) pools as the main processes accounting for impaired state 4→3 energetic transition shown by mitochondria from hearts of type 2 diabetic db/db mice upon challenge with high glucose (HG) and the ß-agonist isoproterenol (ISO). By mimicking clinically relevant conditions in type 2 diabetic patients, this regimen triggers a major overflow of reactive oxygen species (ROS) from mitochondria that directly perturbs cardiac electro-contraction coupling, ultimately leading to heart dysfunction. Exogenous GSH or, even more so, the fatty acid palmitate rescues basal and ß-stimulated function in db/db myocyte/heart preparations exposed to HG/ISO. This occurs because both interventions provide the reducing equivalents necessary to counter mitochondrial ROS outburst and energetic failure. Thus, in the presence of poor glycemic control, the diabetic patient's inability to cope with increased cardiac work demand largely stems from mitochondrial redox/energetic disarrangements that mutually influence each other, leading to myocyte or whole-heart mechanical dysfunction.


Subject(s)
Diabetes Mellitus, Type 2/metabolism , Glutathione/pharmacology , Mitochondria/drug effects , Mitochondria/metabolism , Muscle Cells/drug effects , Muscle Cells/metabolism , Palmitates/pharmacology , Animals , Glucose/pharmacology , Isoproterenol/pharmacology , Mice , Models, Biological , Oxidation-Reduction/drug effects , Reactive Oxygen Species/metabolism
3.
Lipids Health Dis ; 10: 71, 2011 May 11.
Article in English | MEDLINE | ID: mdl-21569357

ABSTRACT

BACKGROUND: Environmental stress plays an important role in the development of glucose intolerance influencing lipid and glucose metabolism through sympathetic nervous system, cytokines and hormones such as glucocorticoids, catecholamines and glucagon. Otherwise, fish oil prevents glucose intolerance and insulin resistance. Although the mechanisms involved are not fully understood, it is known that sympathetic and HPA responses are blunted and catecholamines and glucocorticoids concentrations can be modulated by fish consumption. The aim of the present study was to evaluate whether fish oil, on a normal lipidic diet: 1) could prevent the effect of footshock-stress on the development of glucose intolerance; 2) modified adiponectin receptor and serum concentration; and 3) also modified TNF-α, IL-6 and interleukin-10 (IL-10) levels in adipose tissue and liver. The study was performed in thirty day-old male Wistar randomly assigned into four groups: no stressed (C) and stressed (CS) rats fed with control diet, and no stressed (F) and stressed (FS) rats fed with a fish oil rich diet. The stress was performed as a three daily footshock stress sessions. RESULTS: Body weight, carcass fat and protein content were not different among groups. FS presented a reduction on the relative weight of RET. Basal serum glucose levels were higher in CS and FS but 15 min after glucose load just CS remained with higher levels than other groups. Serum corticosterone concentration was increased in CS, this effect was inhibited in FS. However, 15 min after footshock-stress, corticosterone levels were similar among groups. IL-6 was increased in EPI of CS but fish oil consumption prevented IL-6 increase in FS. Similar levels of TNF-α and IL-10 in RET, EPI, and liver were observed among groups. Adipo R1 protein concentration was not different among groups. Footshock-stress did not modify AdipoR2 concentration, but fish oil diet increases AdipoR2 protein concentration. CONCLUSIONS: Footshock-stress promotes glucose intolerance associated to corticosterone serum level and epididymal white adipose tissue IL-6 concentration increase. The fish oil consumption by stressed rats normalized the stress responses. These results suggested that fish oil intake could be useful to minimize or prevent the development of diseases associated to the stress.


Subject(s)
Corticosterone/blood , Electroshock , Feeding Behavior/drug effects , Fish Oils/administration & dosage , Fish Oils/pharmacology , Glucose Intolerance/prevention & control , Stress, Physiological/drug effects , Adiponectin/blood , Animals , Area Under Curve , Blood Glucose/metabolism , Body Composition/drug effects , Cytokines/metabolism , Glucose Intolerance/blood , Insulin/blood , Male , Organ Specificity/drug effects , Rats , Rats, Wistar , Receptors, Adiponectin/metabolism
4.
Hepatol Int ; 5(2): 740-6, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21484143

ABSTRACT

PURPOSE: The aim of this study was to use the single cell gel (comet) assay to investigate whether blood, liver, heart, kidney, and brain are particularly sensitive organs for DNA damage in cirrhotic rats to predict genetic instability induced by cirrhosis. METHODS: A total of 16 male Wistar rats (negative control, n = 8; experimental, n = 8) were submitted to bile duct ligation during 28 days. RESULTS: Cirrhosis was able to induce genetic damage in liver and brain cells, as depicted by the mean tail moment. No genetic damage was induced in blood, heart, or kidney cells (i.e., no significant statistically differences were noticed when compared with negative control). CONCLUSIONS: In conclusion, our results suggest that cirrhosis could contribute to DNA damage in liver and brain cells.

5.
J Cardiovasc Pharmacol ; 51(1): 78-85, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18209572

ABSTRACT

We investigated the ability of S-nitroso-N-acetylcyseine (SNAC) to prevent structural and functional myocardial alterations in hypercholesterolemic mice. C57BL6 wild-type (WT) and LDL-R-/- male mice (S) were fed a standard diet for 15 days. LDL-R-/- mice (S) showed an 11% increase in blood pressure, 62% decrease in left atrial contractility, and lower CD40L and eNOS expression relative to WT. LDL-R-/- mice fed an atherogenic diet for 15 days (Chol) showed significant increased left ventricular mass compared to S, which was characterized by: (1) 1.25-fold increase in the LV weight/body weight ratio and cardiomyocyte diameter; (2) enhanced expression of the NOS isoforms, CD40L, and collagen amount; and (3) no alteration in the atrial contractile performance. Administration of SNAC to Chol mice (Chol + SNAC) (0.51 micromol/kg/day for 15 day, IP) prevented increased left ventricular mass, collagen deposit, NOS isoforms, and CD40L overexpression, but it had no effect on the increased blood pressure or atrial basal hypocontractility. Deletion of the LDL receptor gene in mice resulted in hypertension and a marked left atrial contractile deficit, which may be related to eNOS underexpression. Our data show that SNAC treatment has an antiinflammatory action that might contribute to prevention of structural and functional myocardial alterations in atherosclerotic mice independently of changes in blood pressure.


Subject(s)
Acetylcysteine/analogs & derivatives , Anti-Inflammatory Agents/pharmacology , Hypercholesterolemia/drug therapy , Hypertrophy, Left Ventricular/prevention & control , Receptors, LDL/genetics , Acetylcysteine/pharmacology , Animals , Blood Pressure/drug effects , CD40 Ligand/drug effects , CD40 Ligand/metabolism , Gene Expression Regulation, Enzymologic/drug effects , Hypercholesterolemia/complications , Hypertension/etiology , Hypertension/physiopathology , Hypertrophy, Left Ventricular/etiology , Inflammation/drug therapy , Inflammation/etiology , Inflammation/physiopathology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Myocardial Contraction/drug effects , Nitric Oxide Synthase Type III/drug effects , Nitric Oxide Synthase Type III/metabolism
6.
Ann N Y Acad Sci ; 1148: 377-83, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19120131

ABSTRACT

Several cardiovascular disorders have been related to alterations in beta-adrenoceptor (beta-AR) signaling at or beyond the receptor level. During the stress reaction, the sympathetic-adrenal medullary system and the hypothalamus-pituitary-adrenal cortex axis are activated, causing beta-AR overstimulation and remodeling of the beta(1)/beta(2)/beta(3)-AR ratio in cardiomyocytes. In a model of foot-shock stress, we described decreased beta(1)-AR signaling occurring simultaneously with increased beta(2)-AR signaling, whereas the response to the nonconventional agonist, CGP12177, was not altered. These alterations may play an adaptive role to the increased sympathetic drive to the heart, protecting the cardiac tissue from the cardiotoxic effects mediated by beta(1)-ARs overstimulation without altering cardiac output, since this would be sustained by the beta(2)-AR, which would also protect myocytes from apoptosis. Moreover, the selective enhancement of the beta(2)-AR population might help to diminish the risk of overstimulation since this adrenoceptor subtype couples to both, stimulatory G (Gs) and inhibitory G (Gi) proteins. On the other hand, in the model of neurogenic hypertension, the decrease in beta(1)-AR-mediated response is not followed by increase in the beta(2)-AR-mediated response. However, the response to CGP12177, which was desensitized 48 h after the surgery, was normalized 7 days after that, when beta(1)-AR were downregulated. Therefore, both experimental models provided evidence that the classical isoform of beta(1)-AR and the recently described low-affinity isoform of beta(1)-AR show independent behavior and provide the heart with adaptive mechanisms to increased sympathetic stimulation during stress.


Subject(s)
Adaptation, Physiological , Heart/physiology , Myocytes, Cardiac/metabolism , Protein Isoforms/metabolism , Receptors, Adrenergic, beta-1/metabolism , Receptors, Adrenergic, beta-2/metabolism , Stress, Psychological , Adrenergic beta-Agonists/pharmacology , Adult , Animals , Epinephrine/pharmacology , Female , Homeostasis , Humans , Isoproterenol/pharmacology , Male , Myocytes, Cardiac/cytology , Myocytes, Cardiac/drug effects , Norepinephrine/pharmacology , Propanolamines/pharmacology , Rats , Signal Transduction/drug effects , Signal Transduction/physiology
7.
Ann N Y Acad Sci ; 1148: 504-8, 2008 Dec.
Article in English | MEDLINE | ID: mdl-19120148

ABSTRACT

We have analyzed the perceived stress index, the basal salivary cortisol levels, and the awakening cortisol response (ACR) in 86 volunteers of low (LSES) and high socioeconomic status (HSES). The LSES presented higher perceived stress index and basal salivary cortisol levels, nonaltered ACR, or cortisol diurnal rhythm. We have concluded that the LSES is associated with high perceived stress index and salivary cortisol levels, which could impact negatively in health, and that it is related to the daily life stress experienced by individuals in the LSES group. Because the LSES corresponds to about 30% of the total Brazilian population, this conclusion might have a great impact on public health policies and costs.


Subject(s)
Hydrocortisone/analysis , Saliva/chemistry , Stress, Psychological , Adult , Brazil , Culture , Female , Humans , Male , Middle Aged , Population Groups , Socioeconomic Factors , Stress, Psychological/economics , Stress, Psychological/physiopathology , Stress, Psychological/psychology , Surveys and Questionnaires , Young Adult
8.
Stress ; 9(2): 69-84, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16895831

ABSTRACT

Most modern theories about stress recognize that although stress is not a disease, it may be the trigger for the majority of diseases when allostatic overload has been generated. During stress, the glucocorticoids and catecholamines play a key role in the regulation of physiological parameters and homeostasis during stress. In the heart, positive chronotropic, inotropic, and lusitropic responses to catecholamines are mediated by various subtypes of adrenergic receptors (beta-ARs), mainly beta1- and beta2-adrenergic receptors. beta-ARs also control cardiomyocyte growth and death, thus contributing to cardiac remodelling. The structural basis of each beta-AR subtype, as well as their signalling pathways, and adaptive responses to stress are discussed. The participation of beta3- and putative beta4-ARs in the control of cardiac function is also discussed, with emphasis on low affinity beta-AR isoforms and the role they play in the response to the catecholamines under stress. The changes in beta-AR signalling under pathogenic conditions as well as under stress are reviewed.


Subject(s)
Receptors, Adrenergic, beta/physiology , Stress, Physiological , Adaptation, Physiological , Animals , Heart/physiology , Models, Biological , Receptors, Adrenergic, beta/genetics
9.
Eur J Pharmacol ; 513(1-2): 109-18, 2005 Apr 18.
Article in English | MEDLINE | ID: mdl-15878715

ABSTRACT

In this study, we investigated whether the responses of right atria from sinoaortic denervated rats to CGP12177 (4(3-t-butylamino-2-hydroxypropoxy benzidimidazole-2 one, hydrochloride)), isoprenaline and norepinephrine desensitized in parallel and whether CGP12177 interacted with distinct conformations of beta-adrenoceptors. Right atria from rats 48 h after sinoaortic denervation were subsensitive to isoprenaline, norepinephrine and CGP12177. One week after sinoaortic denervation, the sensitivity to CGP12177 had recovered whereas the responses to isoprenaline and norepinephrine were still subsensitive, suggesting that the binding sites for these molecules showed independent behavior. In atria from 48 h sinoaortic-denervated rats, propranolol or 3 microM CGP20712A (2-hydroxy-5(2-((2-hydroxy-3-(4-((methyl-4-trifluormethyl)1H imidazole-2-yl)-phenoxypropyl) amino) ethoxy)-benzamide monomethane sulphonate)) blocked the responses to 10 nM-1 microM CGP12177 and steepened the curves. The concentration-response curves to CGP12177 in the presence of ICI118,551 (erythro-DL-1(-methylindan-4-yloxy)-3-isopropylamino-butan-2-ol) were biphasic, suggesting that CGP12177 interacted with at least two conformations of beta-adrenoceptors that showed negative cooperativism, one acting through beta(2)-adrenoceptor-Gi and the other via beta(1)-adrenoceptor-Gs. This hypothesis was confirmed in right atria from sinoaortic-denervated rats treated with pertussis toxin.


Subject(s)
GTP-Binding Protein alpha Subunits, Gi-Go/metabolism , Receptors, Adrenergic, beta/metabolism , Adrenergic alpha-Agonists/pharmacology , Adrenergic beta-Agonists/pharmacology , Adrenergic beta-Antagonists/pharmacology , Animals , Dose-Response Relationship, Drug , Heart/drug effects , Heart/physiology , Heart Atria/drug effects , Heart Atria/innervation , Imidazoles/pharmacology , In Vitro Techniques , Isoproterenol/pharmacology , Male , Myocardial Contraction/drug effects , Norepinephrine/pharmacology , Pertussis Toxin/pharmacology , Propanolamines/pharmacology , Protein Binding , Protein Conformation , Rats , Rats, Wistar , Receptors, Adrenergic, beta/chemistry , Receptors, Adrenergic, beta-1/chemistry , Receptors, Adrenergic, beta-1/metabolism
10.
J Inorg Biochem ; 98(11): 1921-32, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15522418

ABSTRACT

The [Ru(II)(Hedta)NO(+)] complex is a diamagnetic species crystallizing in a distorted octahedral geometry, with the Ru-N(O) length 1.756(4) A and the RuNO angle 172.3(4) degrees . The complex contains one protonated carboxylate (pK(a)=2.7+/-0.1). The [Ru(II)(Hedta)NO(+)] complex undergoes a nitrosyl-centered one-electron reduction (chemical or electrochemical), with E(NO+/NO)=-0.31 V vs SCE (I=0.2 M, pH 1), yielding [Ru(II)(Hedta)NO](-), which aquates slowly: k(-NO)=2.1+/-0.4x10(-3) s(-1) (pH 1.0, I=0.2 M, CF(3)COOH/NaCF(3)COO, 25 degrees C). At pHs>12, the predominant species, [Ru(II)(edta)NO](-), reacts according to [Ru(II)(edta)NO](-)+2OH(-)-->[Ru(II)(edta)NO(2)](3-), with K(eq)=1.0+/-0.4 x 10(3) M(-2) (I=1.0 M, NaCl; T=25.0+/-0.1 degrees C). The rate-law is first order in each of the reactants for most reaction conditions, with k(OH(-))=4.35+/-0.02 M(-1)s(-1) (25.0 degrees C), assignable mechanistically to the elementary step comprising the attack of one OH(-) on [Ru(II)(edta)NO](-), with subsequent fast deprotonation of the [Ru(II)(edta)NO(2)H](2-) intermediate. The activation parameters were DeltaH(#)=60+/-1 kJ/mol, DeltaS(#)=-31+/-3 J/Kmol, consistent with a nucleophilic addition process between likely charged ions. In the toxicity up-and-down tests performed with Swiss mice, no death was observed in all the doses administered (3-9.08 x 10(-5) mol/kg). The biodistribution tests performed with Wistar male rats showed metal in the liver, kidney, urine and plasma. Eight hours after the injection no metal was detected in the samples. The vasodilator effect of [Ru(II)(edta)NO](-) was studied in aortic rings without endothelium, and was compared with sodium nitroprusside (SNP). The times of maximal effects of [Ru(II)(edta)NO](-) and SNP were 2 h and 12 min, respectively, suggesting that [Ru(II)(edta)NO](-) releases NO slowly to the medium in comparison with SNP.


Subject(s)
Edetic Acid/analogs & derivatives , Ruthenium/chemistry , Animals , Crystallography, X-Ray , Edetic Acid/chemistry , Edetic Acid/pharmacokinetics , Electrochemistry , Male , Mice , Models, Molecular , Molecular Conformation , Nitric Oxide/chemistry , Nitric Oxide/pharmacokinetics , Ruthenium/pharmacokinetics , Tissue Distribution
11.
Can J Physiol Pharmacol ; 80(8): 783-9, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12269788

ABSTRACT

We examined the effect of three daily foot-shock stress sessions on glucose homeostasis, insulin secretion by isolated pancreatic islets, insulin sensitivity of white adipocytes, and glycogen stores in the liver and soleus muscle of rats. Stressed rats had plasma glucose (128.3 +/- 22.9 mg/dL) and insulin (1.09 +/- 0.33 ng/mL) levels higher than the controls (glucose, 73.8 +/- 3.5 mg/dL; insulin, 0.53 +/- 0.11 ng/mL, ANOVA plus Fisher's test; p < 0.05). After a glucose overload, the plasma glucose, but not insulin, levels remained higher (area under the curve 8.19 +/- 1.03 vs. 4.84 +/- 1.33 g/dL 30 min and 102.7 +/- 12.2 vs. 93.2 +/- 16.1 ng/mL 30 min, respectively). Although, the area under the insulin curve was higher in stressed (72.8 +/- 9.8 ng/mL) rats than in control rats (34.9 +/- 6.9 ng/mL) in the initial 10 min after glucose overload. The insulin release stimulated by glucose in pancreatic islets was not modified after stress. Adipocytes basal lipolysis was higher (stressed, 1.03 +/- 0.14; control, 0.69 +/- 0.11 micromol of glycerol in 60 min/100 mg of total lipids) but maximal lipolysis stimulated by norepinephrine was not different (stressed, 1.82 +/- 0.35; control, 1.46 +/- 0.09 micromol of glycerol in 60 min/100 mg of total lipids) after stress. Insulin dose-dependently inhibited the lipolytic response to norepinephrine by up to 35% in adipocytes from control rats but had no effect on adipocytes from stressed rats. The liver glycogen content was unaltered by stress, but was lower in soleus muscle from stressed rats than in control rats (0.45 +/- 0.04 vs. 0.35 +/- 0.04 mg/100 mg of wet tissue). These results suggest that rats submitted to foot-shock stress develop hyperglycemia along with hyperinsulinemia as a consequence of insulin subsensitivity in adipose tissue, with no alteration in the pancreatic sensitivity to glucose. Foot-shock stress may therefore provide a useful short-term model of insulin subsensitivity.


Subject(s)
Adipocytes/drug effects , Insulin Resistance/physiology , Insulin/metabolism , Insulin/pharmacology , Stress, Physiological/metabolism , Adipocytes/metabolism , Animals , Electric Stimulation , Insulin Secretion , Islets of Langerhans/drug effects , Islets of Langerhans/metabolism , Male , Rats , Rats, Wistar
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