Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 10 de 10
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Adv Exp Med Biol ; 1131: 183-213, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646511

RESUMO

Ca2+ binding proteins (CBP) are of key importance for calcium to play its role as a pivotal second messenger. CBP bind Ca2+ in specific domains, contributing to the regulation of its concentration at the cytosol and intracellular stores. They also participate in numerous cellular functions by acting as Ca2+ transporters across cell membranes or as Ca2+-modulated sensors, i.e. decoding Ca2+ signals. Since CBP are integral to normal physiological processes, possible roles for them in a variety of diseases has attracted growing interest in recent years. In addition, research on CBP has been reinforced with advances in the structural characterization of new CBP family members. In this chapter we have updated a previous review on CBP, covering in more depth potential participation in physiopathological processes and candidacy for pharmacological targets in many diseases. We review intracellular CBP that contain the structural EF-hand domain: parvalbumin, calmodulin, S100 proteins, calcineurin and neuronal Ca2+ sensor proteins (NCS). We also address intracellular CBP lacking the EF-hand domain: annexins, CBP within intracellular Ca2+ stores (paying special attention to calreticulin and calsequestrin), proteins that contain a C2 domain (such as protein kinase C (PKC) or synaptotagmin) and other proteins of interest, such as regucalcin or proprotein convertase subtisilin kexins (PCSK). Finally, we summarise the latest findings on extracellular CBP, classified according to their Ca2+ binding structures: (i) EF-hand domains; (ii) EGF-like domains; (iii) ɣ-carboxyl glutamic acid (GLA)-rich domains; (iv) cadherin domains; (v) Ca2+-dependent (C)-type lectin-like domains; (vi) Ca2+-binding pockets of family C G-protein-coupled receptors.


Assuntos
Proteínas de Ligação ao Cálcio , Proteínas de Ligação ao Cálcio/metabolismo , Humanos , Espaço Intracelular/metabolismo
2.
Biochem Pharmacol ; : 113677, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31647926

RESUMO

The EMPA-REG OUTCOME (Empagliflozin, Cardiovascular Outcome Event Trial in patients with Type 2 Diabetes Mellitus (T2DM)) trial made evident the potentiality of pharmacological sodium-glucose cotransporter 2 (SGLT2) inhibition for treating patients with diabetes and cardiovascular disease. Since the effect of empagliflozin or other SGLT2 inhibitors on the whole cardiac metabolic profile was never analysed before, and with the purpose to contribute to elucidate the benefits at cardiac level of the use of empagliflozin, we explored the effect of the treatment with empagliflozin for six weeks on the cardiac metabolomic profile of Zucker diabetic fatty rats, a model of early stage T2DM, using untargeted metabolomics approach. Empagliflozin reduced significantly the cardiac content of sphingolipids (ceramides and sphingomyelins) and glycerophospholipids (major bioactive contributing factors linking insulin resistance to cardiac damage) and decreased the cardiac content of the fatty acid transporter cluster of differentiation 36 (CD36); induced significant decreases of the cardiac levels of essential glycolysis intermediaries 2,3-bisphosphoglycerate and phosphoenolpyruvate, and regulated the abundance of several amino acids of relevance as tricarboxylic acid suppliers and/or in the metabolic control of the cardiac function as glutamic acid, gamma-aminobutyric acid and sarcosine. Empagliflozin treatment activated the cardioprotective master regulator of cellular energyhomeostasis AMP-activatedproteinkinase (AMPK) and enhanced autophagy at cardiac level, while it decreased significantly the cardiac mRNA levels of the pro-inflammatory cytokines interleukin-6 (IL-6), chemerin, TNF-α and MCP-1, reinforcing the hypothesis of a direct role for empagliflozin in attenuating cardiac inflammation. Our results provide an advancement on the knowledge of the mechanisms linking the therapy with empagliflozin with protective effects on the development of cardiometabolic diseases whose course is associated with remarkable cardiac bioenergetics dysregulation and disarrangement in cardiac metabolome and lipidome.

3.
Future Med Chem ; 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30801201

RESUMO

AIM: Hydralazine has led to the synthesis of phthalazinone derivatives which induce vasorelaxation. METHODS: A new series of 2-(aminoalkyl)-4-benzyl-2H-phthalazin-1-one derivatives has been synthesized to study their vasorelaxant activity. RESULTS: At the highest-studied concentration, most of the new compounds relaxed the denuded aortic rings precontracted with phenylephrine by 72.9-85.7%. Compound 25 (C25) suppressed almost totally the contractile effects of phenylephrine, high KCl concentration, ionomycin and caffeine related to the activation of Ca2+ channels, whereas its inhibitory effect was reversed with high CaCl2 concentrations. CONCLUSION: Vasodilator effects of C25 appear to be due exclusively to the reversible blockage of different calcium channels. As broad range calcium channel blocker, C25 seems to be suitable as a pharmacological tool for calcium channel research.

4.
Cell Physiol Biochem ; 44(5): 1796-1809, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29216624

RESUMO

BACKGROUND/AIMS: The atherosclerotic apolipoprotein E-deficient (apoE-/-) mouse exhibits impaired vasodilation and enhanced vasoconstriction responsiveness. The objectives of this study were: a) to determine the relative contribution of cyclooxygenases (Cox-1 and Cox-2), thromboxane A2 (TXA2) and endothelin-1 (ET-1) to enhancing vascular hyperresponsiveness in this model of atherosclerosis and b) to investigate the beneficial effects of the phosphodiesterase 5 inhibitor sildenafil on this endothelial dysfunction. METHODS: Adult male apoE-/- mice were treated with sildenafil (40 mg/kg/day, for 3 weeks) and compared with non-treated ApoE-/- and wild-type mice. The beneficial effects of sildenafil on vascular contractile response to phenylephrine (PE) in aortic rings were evaluated before and after incubation with Cox-1 (SC-560) or Cox-2 (NS-398) inhibitors or the TP antagonist SQ-29548, and on contractile responsiveness to ET-1. RESULTS: ApoE-/- mice exhibited enhanced vasoconstriction to PE (Rmax ∼35%, p<0.01), which was prevented by treatment with sildenafil. The enhanced PE-induced contractions were abolished by both Cox-1 inhibition and TP antagonist, but were not modified by Cox-2 inhibition. Aortic rings from ApoE-/- mice also exhibited enhanced contractions to ET-1 (Rmax ∼30%, p<0.01), which were attenuated in sildenafil-treated ApoE-/- mice. In addition, we observed augmented levels of vascular proinflammatory cytokines in ApoE-/- mice, which were partially corrected by treatment with sildenafil (IL-6, IL-10/IL-6 ratio and MCP-1). CONCLUSION: The present data show that the Cox-1/TXA2 pathway prevails over the Cox-2 isoform in the mediation of vascular hypercontractility observed in apoE-/-mice. The results also show a beneficial effect of sildenafil on this endothelial dysfunction and on the proinflammatory cytokines in atherosclerotic animals, opening new perspectives for the treatment of other endothelium-related cardiovascular abnormalities.


Assuntos
Apolipoproteínas E/genética , Ciclo-Oxigenase 1/metabolismo , Citrato de Sildenafila/farmacologia , Tromboxano A2/metabolismo , Vasoconstrição/efeitos dos fármacos , Animais , Apolipoproteínas E/deficiência , Compostos Bicíclicos Heterocíclicos com Pontes , Ciclo-Oxigenase 1/química , Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Ácidos Graxos Insaturados , Hidrazinas/farmacologia , Interleucina-10/análise , Interleucina-6/análise , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nitrobenzenos/farmacologia , Fenilefrina/farmacologia , Pirazóis/farmacologia , Receptores de Tromboxanos/antagonistas & inibidores , Receptores de Tromboxanos/metabolismo , Sulfonamidas/farmacologia
5.
Life Sci ; 155: 102-9, 2016 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-27142830

RESUMO

AIMS: We investigated the implication of PKA and Epac proteins in the endothelium-independent vasorelaxant effects of cyclic AMP (cAMP). MAIN METHODS: Cytosolic Ca(2+) concentration ([Ca(2+)]c) was measured by fura-2 imaging in rat aortic smooth muscle cells (RASMC). Contraction-relaxation experiments were performed in rat aortic rings deprived of endothelium. KEY FINDINGS: In extracellular Ca(2+)-free solution, cAMP-elevating agents induced an increase in [Ca(2+)]c in RASMC that was reproduced by PKA and Epac activation and reduced after depletion of intracellular Ca(2+) reservoirs. Arginine-vasopressin (AVP)-evoked increase of [Ca(2+)]c and store-operated Ca(2+) entry (SOCE) were inhibited by cAMP-elevating agents, PKA or Epac activation in these cells. In aortic rings, the contractions induced by phenylephrine in absence of extracellular Ca(2+) were inhibited by cAMP-elevating agents, PKA or Epac activation. In these conditions, reintroduction of Ca(2+) induced a contraction that was inhibited by cAMP-elevating agents, an effect reduced by PKA inhibition and reproduced by PKA or Epac activators. SIGNIFICANCE: Our results suggest that increased cAMP depletes intracellular, thapsigargin-sensitive Ca(2+) stores through activation of PKA and Epac in RASMC, thus reducing the amount of Ca(2+) released by IP3-generating agonists during the contraction of rat aorta. cAMP rise also inhibits the contraction induced by depletion of intracellular Ca(2+), an effect mediated by reduction of SOCE after PKA or Epac activation. Both effects participate in the cAMP-induced endothelium-independent vasorelaxation.


Assuntos
Cálcio/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Vasoconstrição , Animais , Aorta/citologia , Aorta/metabolismo , Células Cultivadas , AMP Cíclico/metabolismo , Ativação Enzimática , Masculino , Músculo Liso Vascular/citologia , Músculo Liso Vascular/metabolismo , Ratos , Ratos Endogâmicos WKY
6.
Adv Exp Med Biol ; 740: 461-82, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22453954

RESUMO

The role of Ca(2+) as a key and pivotal second messenger in cells depends largely on a wide number of heterogeneous so-called calcium binding proteins (CBP), which have the ability to bind this ion in specific domains. CBP contribute to the control of Ca(2+) concentration in the cytosol and participate in numerous cellular functions by acting as Ca(2+) transporters across cell membranes or as Ca(2+)-modulated sensors, i.e., decoding Ca(2+) signals. In this chapter we review the main Ca(2+)-modulated CBP, starting with those intracellular CBP that contain the structural EF-hand domain: parvalbumin, calmodulin, S100 proteins and calcineurin. Then, we address intracellular CBP lacking the EF-hand domain: CBP within intracellular Ca(2+) stores (paying special attention to calreticulin and calsequestrin), annexins and proteins that contain a C2 domain, such as protein kinase C (PKC) or sinaptotagmin. Finally, extracellular CBP have been classified in six groups, according to their Ca(2+) binding structures: (i) EF-hand domains; (ii) EGF-like domains; (iii) γ-carboxyl glutamic acid (GLA)-rich domains; (iv) cadherin domains; (v) Ca(2+)-dependent (C)-type lectin-like domains; (vi) Ca(2+)-binding pockets of family C G-protein-coupled receptors. For all proteins, we briefly review their structure, location and function and additionally their potential as pharmacological targets in several human diseases.


Assuntos
Proteínas de Ligação ao Cálcio/fisiologia , Animais , Anexinas/fisiologia , Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/química , Humanos , Estrutura Terciária de Proteína , Receptores de Detecção de Cálcio/fisiologia
7.
J Nutr Biochem ; 21(4): 304-9, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19369049

RESUMO

UNLABELLED: Gallic acid autoxidation was monitored by absorption spectroscopy and H(2)O(2) production; vascular effects related to the autoxidation process were studied on intact and rubbed aortic rings from WKY rats. Gallic acid autoxidation in an oxygenated physiological salt solution (37 degrees C, pH=7.4) mostly occurred in a 2-h time period. Superoxide anions, H(2)O(2) and gallic acid quinones were produced during gallic acid autoxidation. In rings partially precontracted with phenylephrine, 0.1-3 microM gallic acid induced marked and largely endothelium-dependent contractions, 10-30 microM gallic acid induced endothelium-independent contractions and 0.1-0.3 mM gallic acid induced complete, fast-developing, endothelium-independent relaxations. Superoxide dismutase (SOD) shifted the endothelium-dependent gallic acid contractions to the right, and N(G)-nitro-l-arginine abolished them. Indomethacin suppressed the endothelium-independent gallic acid contractions, and catalase abolished the endothelium-independent contractions and relaxations. Gallic acid (30 microM) inhibited the relaxant effects of acetylcholine and sodium nitroprusside. In rings maximally precontracted with KCl, 0.1-100 microM gallic acid did not modify the tone, whereas 0.3 mM induced complete, slow-developing, endothelium-independent relaxations. Moreover, 0.3 mM gallic acid induced an irreversible impairment of ring reactivity and the release of lactate dehydrogenase. Catalase and N-acetyl cysteine suppressed the deleterious effects induced by gallic acid in the rings. IN CONCLUSION: (a) gallic acid is rapidly and nonenzymatically oxidized in physiological solutions, generating superoxide anions, H(2)O(2) and quinones; (b) superoxide anions (by destroying NO) and low H(2)O(2) levels (by activating cyclooxygenase) both increase vascular tone; (c) moderate H(2)O(2) levels decrease vascular tone; (d) high H(2)O(2) and quinone levels cause irreversible relaxations due to cellular damage.


Assuntos
Aorta Torácica/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Ácido Gálico/química , Ácido Gálico/farmacologia , Estresse Oxidativo , Acetilcisteína/farmacologia , Animais , Aorta Torácica/fisiologia , Catalase/metabolismo , Morte Celular/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase/farmacologia , Relação Dose-Resposta a Droga , Endotélio Vascular/fisiopatologia , Feminino , Depuradores de Radicais Livres/farmacologia , Ácido Gálico/análogos & derivados , Ácido Gálico/antagonistas & inibidores , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/farmacologia , Técnicas In Vitro , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/fisiologia , Fármacos Neuromusculares/antagonistas & inibidores , Fármacos Neuromusculares/farmacologia , Oxirredução , Quinonas/antagonistas & inibidores , Quinonas/química , Quinonas/farmacologia , Ratos , Ratos Endogâmicos WKY , Superóxidos/antagonistas & inibidores , Superóxidos/química , Superóxidos/farmacologia
8.
Free Radic Res ; 43(3): 295-303, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19191109

RESUMO

UNLABELLED: Dopamine autoxidation in an oxygenated physiological salt solution (37 degrees C, pH=7.4) mostly occurred in a 2.5 h time period. H(2)O(2) and dopamine quinones were produced during dopamine autoxidation. In partially pre-contracted rat aortic rings, 10-100 microm dopamine induced endothelium-independent contractions and 0.3-1 mm dopamine induced complete, slow-developing endothelium-independent relaxations. Indomethacin and catalase suppressed the endothelium-independent dopamine contractions. Catalase strongly reduced the endothelium-independent dopamine relaxations. Furthermore, 1 mm dopamine for 60 min followed by a 90 min washout period induced the release of lactate dehydrogenase and the complete impairment of ring reactivity to phenylephrine and KCl. Pre-treatment with catalase or glutathione prevented dopamine-induced deleterious effects so that further concentration-response curves to phenylephrine and KCl could be obtained. The phenylephrine potency was maintained in rings pre-treated with glutathione but not in rings pre-treated with catalase. IN CONCLUSION: (1) dopamine is rapidly and non-enzymatically oxidized in physiological solutions, generating H(2)O(2) and quinones; (2) low H(2)O(2) levels increase vascular tone by activating cyclooxygenase; (3) high H(2)O(2) levels cause irreversible relaxations due to unspecific cellular damage; and (4) dopamine quinones cause a specific alteration in the phenylephrine response.


Assuntos
Dopamina/metabolismo , Peróxido de Hidrogênio/metabolismo , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/enzimologia , Aorta Torácica/metabolismo , Catalase/farmacologia , Dopamina/química , Dopamina/farmacologia , Feminino , Humanos , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/farmacologia , Técnicas In Vitro , Indometacina/farmacologia , L-Lactato Desidrogenase/metabolismo , Contração Muscular/efeitos dos fármacos , Oxidantes/química , Oxidantes/metabolismo , Oxidantes/farmacologia , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Cloreto de Potássio/farmacologia , Ratos , Ratos Endogâmicos WKY , Espectrofotometria Ultravioleta
9.
Vascul Pharmacol ; 43(2): 128-38, 2005 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-15994130

RESUMO

Four main vascular effects of hydrogen peroxide (H2O2) were studied in intact and rubbed aortic rings from WKY rats. In rings partially precontracted with phenylephrine: 1-30 microM H2O2 induced an increase of tone, 100 microM H2O2 produced a transient contraction followed by a fast-developing endothelium-independent relaxation, and 0.3 mM H2O2 induced a fast-developing relaxation followed by a slow-developing endothelium-independent relaxation. Superoxide dismutase (SOD) or dimethyl sulfoxide (DMSO)/manitol did not significantly modify the H2O2 effects, while catalase suppressed them. Indomethacin abolished the increase of tone elicited by H2O2 and revealed a small endothelium-dependent relaxation, which was suppressed by N(G)-nitro-L-arginine (L-NA), high K+ or tetraethylammonium (TEA). TEA strongly inhibited the fast-developing relaxation while indomethacin, glybenclamide, 1H-[1,2,4]Oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), cafeic acid or eicosatriynoic acid (ETI) did not affect the relaxation. In rings precontracted with 70 mM KCl, 1-100 microM H2O2 induced a small increase of tone and 0.3 mM a slow-developing relaxation. Catalase or Fe2+-EDTA/vitamin C suppressed the slow-developing relaxation while deferoxamine did not modify it. In rings partially precontracted with arachidonic acid, 1-30 microM H2O2 induced higher contractile effects than in rings partially precontracted with phenylephrine. H2O2 at 0.3 mM for one hour induced a persistent impairment on the reactivity of the rings and the release of lactate dehydrogenase. In summary, H2O2 produces: (1) contractions mediated by direct activation of cyclooxygenase; 2) endothelium-dependent relaxations related to activation of endothelial K+ channels and NO synthesis; 3) reversible endothelium-independent relaxations mediated by activation of smooth muscle K+ channels; and 4) irreversible endothelium-independent relaxations related to cellular damage, caused by H2O2 but not by hydroxyl radicals.


Assuntos
Aorta Torácica/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Vasoconstrição/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Aorta Torácica/metabolismo , Aorta Torácica/fisiologia , Ácido Araquidônico/farmacologia , Ácido Ascórbico/farmacologia , Catalase/farmacologia , Relação Dose-Resposta a Droga , Feminino , Técnicas In Vitro , Indometacina/farmacologia , L-Lactato Desidrogenase/metabolismo , Nitroprussiato/farmacologia , Fenilefrina/farmacologia , Cloreto de Potássio/farmacologia , Ratos , Ratos Wistar , Tetraetilamônio/farmacologia , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
10.
Bioorg Med Chem ; 11(10): 2301-6, 2003 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-12713841

RESUMO

Ten zoanthamine-type alkaloids from two marine zoanthids belonging to the Zoanthus genus (Zoanthus nymphaeus and Zoanthus sp.) along with one semisynthetic derivative were evaluated for their antiplatelet activities on human platelet aggregation induced by several stimulating agents. 11-Hydroxyzoanthamine (11) and a synthetic derivative of norzoanthamine (16) showed strong inhibition against thrombin-, collagen- and arachidonic acid-induced aggregation, zoanthenol (15) displayed a selective inhibitory activity induced by collagen, while zoanthaminone (10) behaved as a potent aggregant agent. These evaluations allowed us to deduce several structure-activity relationships and suggest some mechanisms of action for this type of compounds.


Assuntos
Alcaloides/farmacologia , Antozoários/química , Anticoagulantes/farmacologia , Plaquetas/efeitos dos fármacos , Compostos Heterocíclicos/farmacologia , Inibidores da Agregação de Plaquetas/farmacologia , Alcaloides/classificação , Alcaloides/isolamento & purificação , Animais , Ácido Araquidônico , Colágeno , Desenho de Drogas , Avaliação Pré-Clínica de Medicamentos , Compostos Heterocíclicos/química , Humanos , Estrutura Molecular , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/química , Relação Estrutura-Atividade , Trombina
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA