RESUMO
The N-salicyloyltryptamine (NST) is an indole derivative compound analogue to the alkaloid N-benzoyltryptamine. In the present study, the antiedematogenic activity of NST was investigated in animal models. Firstly, the acute toxicity for NST was assessed according to the OECD Guideline no. 423. The potential NST-induced antiedematogenic activity was evaluated by carrageenan-induced paw edema in rats, as well as by dextran-, compound 48/80-, histamine-, serotonin-, capsaicine-, and prostaglandin E2-induced paw edema in mice. The effect of NST on compound 48/80-induced ex vivo mast cell degranulation on mice mesenteric bed was investigated. No death or alteration of behavioral parameters was observed after administration of NST (2000 mg/kg, i.p.) during the observation time of 14 days. The NST (100 and 200 mg/kg, i.p.) inhibited the carrageenan-induced edema from the 1st to the 5th hour (**p<0.01; ***p<0.001). The edematogenic activity induced by dextran, compound 48/80, histamine, serotonin, capsaicin, and prostaglandin E2 was inhibited by NST (100 mg/kg, i.p.) throughout the observation period (**p<0.01; ***p<0.001). The pretreatment with NST (50, 100 or 200 mg/kg, i.p) attenuates the compound 48/80-induced mast cell degranulation (**p<0.01; ***p<0.001). Thus, the inhibition of both mast cell degranulation and release of endogenous mediators are probably involved in the NST-induced antiedematogenic effect.
Assuntos
Anti-Inflamatórios/farmacologia , Edema/tratamento farmacológico , Salicilatos/farmacologia , Triptaminas/farmacologia , Animais , Anti-Inflamatórios/toxicidade , Carragenina , Modelos Animais de Doenças , Edema/induzido quimicamente , Feminino , Membro Posterior , Mediadores da Inflamação , Masculino , Camundongos , Peptídeos/efeitos dos fármacos , Ratos Wistar , Salicilatos/toxicidade , Fatores de Tempo , Triptaminas/toxicidadeRESUMO
ABSTRACT The N-salicyloyltryptamine (NST) is an indole derivative compound analogue to the alkaloid N-benzoyltryptamine. In the present study, the antiedematogenic activity of NST was investigated in animal models. Firstly, the acute toxicity for NST was assessed according to the OECD Guideline no. 423. The potential NST-induced antiedematogenic activity was evaluated by carrageenan-induced paw edema in rats, as well as by dextran-, compound 48/80-, histamine-, serotonin-, capsaicine-, and prostaglandin E2-induced paw edema in mice. The effect of NST on compound 48/80-induced ex vivo mast cell degranulation on mice mesenteric bed was investigated. No death or alteration of behavioral parameters was observed after administration of NST (2000 mg/kg, i.p.) during the observation time of 14 days. The NST (100 and 200 mg/kg, i.p.) inhibited the carrageenan-induced edema from the 1st to the 5th hour (**p<0.01; ***p<0.001). The edematogenic activity induced by dextran, compound 48/80, histamine, serotonin, capsaicin, and prostaglandin E2 was inhibited by NST (100 mg/kg, i.p.) throughout the observation period (**p<0.01; ***p<0.001). The pretreatment with NST (50, 100 or 200 mg/kg, i.p) attenuates the compound 48/80-induced mast cell degranulation (**p<0.01; ***p<0.001). Thus, the inhibition of both mast cell degranulation and release of endogenous mediators are probably involved in the NST-induced antiedematogenic effect.
Assuntos
Animais , Masculino , Feminino , Ratos , Triptaminas/farmacologia , Salicilatos/farmacologia , Edema/tratamento farmacológico , Anti-Inflamatórios/farmacologia , Peptídeos/efeitos dos fármacos , Fatores de Tempo , Carragenina , Triptaminas/toxicidade , Salicilatos/toxicidade , Ratos Wistar , Mediadores da Inflamação , Modelos Animais de Doenças , Edema/induzido quimicamente , Membro Posterior , Anti-Inflamatórios/toxicidadeRESUMO
Glucagon-like peptide-1 (GLP-1) is a gut incretin hormone considered a promising therapeutic agent for type 2 diabetes because it stimulates beta cell proliferation and insulin secretion in a glucose-dependent manner. Cumulative evidence supports a role for GLP-1 in modulating renal function; however, the mechanisms by which GLP-1 induces diuresis and natriuresis have not been completely established. This study aimed to define the cellular and molecular mechanisms mediating the renal effects of GLP-1. GLP-1 (1 µg·kg(-1)·min(-1)) was intravenously administered in rats for the period of 60 min. GLP-1-infused rats displayed increased urine flow, fractional excretion of sodium, potassium, and bicarbonate compared with those rats that received vehicle (1% BSA/saline). GLP-1-induced diuresis and natriuresis were also accompanied by increases in renal plasma flow and glomerular filtration rate. Real-time RT-PCR in microdissected rat nephron segments revealed that GLP-1 receptor-mRNA expression was restricted to glomerulus and proximal convoluted tubule. In rat renal proximal tubule, GLP-1 significantly reduced Na(+)/H(+) exchanger isoform 3 (NHE3)-mediated bicarbonate reabsorption via a protein kinase A (PKA)-dependent mechanism. Reduced proximal tubular bicarbonate flux rate was associated with a significant increase of NHE3 phosphorylation at the PKA consensus sites in microvillus membrane vesicles. Taken together, these data suggest that GLP-1 has diuretic and natriuretic effects that are mediated by changes in renal hemodynamics and by downregulation of NHE3 activity in the renal proximal tubule. Moreover, our findings support the view that GLP-1-based agents may have a potential therapeutic use not only as antidiabetic drugs but also in hypertension and other disorders of sodium retention.
Assuntos
Peptídeo 1 Semelhante ao Glucagon/metabolismo , Rim/metabolismo , Natriuréticos/administração & dosagem , Animais , AMP Cíclico/urina , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Exenatida , Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Receptor do Peptídeo Semelhante ao Glucagon 1 , Hipoglicemiantes/farmacologia , Rim/efeitos dos fármacos , Natriuréticos/metabolismo , Ácidos Pentanoicos/farmacologia , Peptídeos/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de Glucagon/metabolismo , Trocador 3 de Sódio-Hidrogênio , Trocadores de Sódio-Hidrogênio/metabolismo , Tiazolidinas/farmacologia , PeçonhasRESUMO
The objective of this study was to find out if lipopolysaccharide (LPS) administered intraperitoneally affects sodium and water intake and renal excretion in dehydrated rats. LPS (0.3-5 mg/kg b.w.) inhibited 0.3M NaCl intake induced by subcutaneous injection of the diuretic furosemide (FURO, 10 mg/kg b.w.) combined with the angiotensin converting enzyme inhibitor, captopril (CAP, 5 mg/kg b.w.). Only the highest doses of LPS (2.5 and 5 mg/kg) inhibited water intake induced by FURO/CAP. LPS (0.6 mg/kg) reduced urinary volume and sodium excretion, but had no effect on mean arterial pressure or heart rate of rats treated with FURO/CAP. LPS (0.3-5.0 mg/kg) abolished intracellular thirst and reduced by 50% the urine sodium concentration of rats that received 2 ml of 2M NaCl by gavage. LPS (0.3-5.0 mg/kg) also reduced thirst in rats treated with FURO alone (10 mg/rat sc). The results suggest that LPS has a preferential, but not exclusive, inhibitory effect on sodium intake and on intracellular thirst. The inhibition of hydro-mineral intake and the antinatriuresis caused by LPS in dehydrated rats may contribute to the multiple effects of the endotoxin on fluid and electrolyte balance and be part of the strategy to cope with infections.
Assuntos
Antidiuréticos/farmacologia , Apetite/efeitos dos fármacos , Desidratação/metabolismo , Lipopolissacarídeos/farmacologia , Cloreto de Sódio/metabolismo , Análise de Variância , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Captopril/farmacologia , Modelos Animais de Doenças , Diuréticos/farmacologia , Ingestão de Líquidos/efeitos dos fármacos , Furosemida/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Masculino , Peptídeos/efeitos dos fármacos , Ratos , Solução Salina Hipertônica/administração & dosagem , Cloreto de Sódio/sangue , Cloreto de Sódio/urina , Sede/efeitos dos fármacosRESUMO
BACKGROUND: Previously, we measured bone alkaline phosphatase (b-ALP) and terminal C-telopeptide of collagen type I (CTX) in saliva. The present longitudinal experimental study sought to determine whether salivary concentrations of b-ALP and CTX have the same response as in serum samples under different conditions: normal, increased, and reduced bone remodeling. METHODS: Thirty rats were ovariectomized (OVX) to induce osteopenia 60 days after surgery, and 10 rats were sham operated. Then, the rats were divided into four groups and treated as follows for 45 days: group 1 (G1) = SHAM + vehicle; group 2 (G2) = OVX + 8 microg olpadronate (OPD)/100 g of body weight; group 3 (G3) = OVX + 4 microg OPD/100 g of body weight; and group 4 (G4) = OVX + vehicle. Saliva and serum CTX and b-ALP were determined at 60 days (baseline) and at 75 days (T(75)). Lumbar spine and proximal tibia bone mineral density (BMD) was determined using dual-energy x-ray absorptiometry at baseline and at 105 days. RESULTS: SHAM baseline and T(75) salivary b-ALP and CTX levels correlated with serum concentrations (P <0.01 and P <0.004, respectively). A correlation was observed between saliva and serum concentrations of b-ALP and CTX in OVX at baseline (P <0.0001 and P <0.004, respectively). Baseline salivary b-ALP and CTX levels were lower in SHAM animals compared to OVX groups (P <0.01). After treatment, T(75) saliva and serum CTX remained higher in G4 compared to G1 (P <0.05), was lower in G2 than in G1 (P <0.01) and G3 (P <0.01), and was similar in G1 and G3. Changes in BMD were the result of variations in salivary CTX levels due to OPD treatment (P <0.05). CONCLUSIONS: Saliva determinations may prove to be practical and reliable for the detection of systemic signs of increased bone remodeling, particularly in cases involving pediatric, obese, and elderly patients, and in screening large populations. Moreover, saliva CTX may be one of the best candidate markers to detect the activity and severity of periodontal disease.
Assuntos
Fosfatase Alcalina/análise , Doenças Ósseas Metabólicas/metabolismo , Remodelação Óssea/fisiologia , Colágeno Tipo I/análise , Peptídeos/análise , Saliva/química , Absorciometria de Fóton , Fosfatase Alcalina/sangue , Fosfatase Alcalina/efeitos dos fármacos , Animais , Biomarcadores/análise , Biomarcadores/sangue , Densidade Óssea/efeitos dos fármacos , Densidade Óssea/fisiologia , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/uso terapêutico , Doenças Ósseas Metabólicas/sangue , Doenças Ósseas Metabólicas/tratamento farmacológico , Remodelação Óssea/efeitos dos fármacos , Colágeno Tipo I/sangue , Colágeno Tipo I/efeitos dos fármacos , Difosfonatos/administração & dosagem , Difosfonatos/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Vértebras Lombares/patologia , Ovariectomia , Peptídeos/sangue , Peptídeos/efeitos dos fármacos , Veículos Farmacêuticos , Ratos , Ratos Wistar , Saliva/efeitos dos fármacos , Tíbia/patologia , Fatores de TempoRESUMO
The interplay of different proteases and glycosaminoglycans is able to modulate the activity of the enzymes and to affect their structures. Human plasma kallikrein (huPK) is a proteolytic enzyme involved in intrinsic blood clotting, the kallikrein-kinin system and fibrinolysis. We investigated the effect of heparin on the action, inhibition and secondary structure of huPK. The catalytic efficiency for the hydrolysis of substrates by huPK was determined by Michaelis-Menten kinetic plots: 5.12x10(4) M-1 s-1 for acetyl-Phe-Arg-p-nitroanilide, 1.40x10(5) M-1 s-1 for H-D-Pro-Phe-Arg-p-nitroanilide, 2.25x10(4) M-1 s-1 for Abz-Gly-Phe-Ser-Pro-Phe-Arg-Ser-Ser-Arg-Gln-EDDnp, 4.24x10(2)M-1 s-1 for factor XII and 5.58x10(2) M-1 s-1 for plasminogen. Heparin reduced the hydrolysis of synthetic substrates (by 2.0-fold), but enhanced factor XII and plasminogen hydrolysis (7.7- and 1.4-fold, respectively). The second-order rate constants for inhibition of huPK by antithrombin and C1-inhibitor were 2.40x10(2) M-1 s-1 and 1.70x10(4) M-1 s-1, respectively. Heparin improved the inhibition of huPK by these inhibitors (3.4- and 1.4-fold). Despite the fact that huPK was able to bind to a heparin-Sepharose matrix, its secondary structure was not modified by heparin, as monitored by circular dichroism. These actions may have a function in the control or maintenance of some pathophysiological processes in which huPK participates.
Assuntos
Inibidores Enzimáticos/farmacologia , Heparina/farmacologia , Peptídeos/metabolismo , Calicreína Plasmática/antagonistas & inibidores , Calicreína Plasmática/metabolismo , Antitrombinas/farmacologia , Catálise , Proteína Inibidora do Complemento C1/farmacologia , Fator XII/efeitos dos fármacos , Fator XII/metabolismo , Humanos , Hidrólise , Peptídeos/efeitos dos fármacos , Calicreína Plasmática/química , Plasminogênio/efeitos dos fármacos , Plasminogênio/metabolismo , Estrutura Secundária de Proteína , Fatores de Tempo , alfa 1-Antitripsina/farmacologiaRESUMO
In this paper, we review our current understanding of the medicinal chemistry of the major peptide systems, which influence body fluid homeostasis. Electrolytes play pivotal roles in intra- and intercellular communication, acid-base equilibrium and, when bound to several macromolecules, they regulate a myriad of enzymatic proteins, receptors and transcription factors. Cell turgor influences the plasma membrane, which activates mechanically-gated ion channels or mechanoreceptors, and the expression of a number of genes which underlie long-term metabolic responses to hormones, substrates and reactive oxygen intermediates. The altered kinetics and enzymatic cleavage of peptides during water-electrolyte imbalance can contribute to cardiac and renal damage associated with elevated blood pressure. Identification of the enzymes which are responsible for cleavage, together with emerging information about the mechanisms of action and structures of regulatory and effector peptides, has laid a foundation for the discovery of novel drugs, some of which are in use or are now undergoing evaluation in experimental trials. The development of models of hydrosaline challenge with relative efficiency to induce selective water-electrolyte imbalance has permitted the identification of kallikrein-kinin, renin-angiotensin-aldosterone, vasopressin-oxytocin, thyrotropin-releasing hormone and luteinizing hormone-releasing hormone as susceptible substrates. At present, the angiotensin-I converting enzyme inhibitors are well-known efficacious, orally active, blood pressure-lowering agents which have been used in hypertensive patients. In addition to several new analogues of this class of drug, some selective dual inhibitors of angiotensin-I converting enzyme and neutral endopeptidase and inhibitors of aminopeptidases are now also being rationally assayed and their beneficial effects on hypertension and hydromineral balance indicate that this type of drug may have powerful therapeutic effects for disorders of body fluid homeostasis.
Assuntos
Líquidos Corporais/fisiologia , Homeostase/fisiologia , Peptídeos/metabolismo , Animais , Líquidos Corporais/efeitos dos fármacos , Modelos Animais de Doenças , Homeostase/efeitos dos fármacos , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/fisiopatologia , Proteínas de Membrana/metabolismo , Peptídeo Hidrolases/efeitos dos fármacos , Peptídeos/efeitos dos fármacos , Inibidores de Proteases/farmacologia , Sódio/metabolismo , Equilíbrio Hidroeletrolítico/efeitos dos fármacos , Equilíbrio Hidroeletrolítico/fisiologiaRESUMO
Two novel toxic peptides (Tc30 and Tc32) were isolated and characterized from the venom of the Brazilian scorpion Tityus cambridgei. The first have 37 and the second 35 amino acid residues, with molecular masses of 3,871.8 and 3,521.5, respectively. Both contain three disulfide bridges but share only 27% identity. They are relatively potent inhibitors of K(+)-currents in human T lymphocytes with K(d) values of 10 nM for Tc32 and 16 nM for Tc30, but they are less potent or quite poor blockers of Shaker B K(+)-channels, with respective K(d) values of 74 nM and 4.7 microM. Tc30 has a lysine in position 27 and a tyrosine at position 36 identical to those of charybdotoxin. These two positions conform the dyad considered essential for activity. On the contrary, Tc32 has a serine in the position equivalent to lysine 27 of charybdotoxin and does not contain any aromatic amino acid. Due to its unique primary sequence and to its distinctive preference for K(+)-channels of T lymphocytes, it was classified as the first example of a new subfamily of K(+)-channel-specific peptides (alpha-KT x 18.1). Tc30 is a member of the Tityus toxin II-9 subfamily and was given the number alpha-KT x 4.4.
Assuntos
Peptídeos/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/toxicidade , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/efeitos dos fármacos , Venenos de Escorpião/toxicidade , Sequência de Aminoácidos , Animais , Brasil , Humanos , Canal de Potássio Kv1.3 , Dados de Sequência Molecular , Peptídeos/genética , Bloqueadores dos Canais de Potássio/química , Bloqueadores dos Canais de Potássio/isolamento & purificação , Canais de Potássio/genética , Venenos de Escorpião/química , Venenos de Escorpião/isolamento & purificação , Escorpiões , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Superfamília Shaker de Canais de Potássio , Spodoptera , TransfecçãoRESUMO
The effect of the administration of seven doses of the hepatocarcinogen thioacetamide on the chemical composition of rat liver nuclear envelope subfractions: associated chromatin, nuclear membranes and pore complex-lamina fraction, is analyzed. No alteration in DNA, RNA or phospholipid content is observed after the hepatocarcinogen treatment. Electrophoretic studies of each subfraction from thioacetamide treated rats show differences in the relative proportions of some polypeptides when compared with the controls. Examination of the wheat germ agglutinin binding polypeptides of each subfraction reveals a decrease in the stain of two pore complex-lamina nucleoporins of 85 and 164 kDa and an increase in one of 93 kDa; this observation can be due to changes in the quantity and/or in the agglutinin binding capacity of the nucleoporin as a result of thioacetamide administration. In view of the participation of nucleoporins in the nucleocytoplasmic transport, the changes observed suggest a relationship between changes of some O-linked N-acetyl glucosamine polypeptides components of the nuclear pore complex and the altered transport of some RNA species observed after thioacetamide administration.
Assuntos
Carcinógenos/farmacologia , Fígado/ultraestrutura , Membrana Nuclear/química , Proteínas Nucleares/efeitos dos fármacos , Peptídeos/efeitos dos fármacos , Porinas/análise , Tioacetamida/farmacologia , Animais , Masculino , Membrana Nuclear/ultraestrutura , Proteínas Nucleares/química , Peptídeos/química , Ratos , Ratos Sprague-DawleyRESUMO
The effect of the administration of seven doses of the hepatocarcinogen thioacetamide on the chemical composition of rat liver nuclear envelope subfractions: associated chromatin, nuclear membranes and pore complex-lamina fraction, is analyzed. No alteration in DNA, RNA or phospholipid content is observed after the hepatocarcinogen treatment. Electrophoretic studies of each subfraction from thioacetamide treated rats show differences in the relative proportions of some polypeptides when compared with the controls. Examination of the wheat germ agglutinin binding polypeptides of each subfraction reveals a decrease in the stain of two pore complex-lamina nucleoporins of 85 and 164 kDa and an increase in one of 93 kDa; this observation can be due to changes in the quantity and/or in the agglutinin binding capacity of the nucleoporin as a result of thioacetamide administration. In view of the participation of nucleoporins in the nucleocytoplasmic transport, the changes observed suggest a relationship between changes of some O-linked N-acetyl glucosamine polypeptides components of the nuclear pore complex and the altered transport of some RNA species observed after thioacetamide administration.