RESUMO
BACKGROUND: Nesidioblastosis is a rare cause of endocrine disease which represents between 0.5% - 5% of cases. This has been associated with other conditions, such as in patients previously treated with insulin or sulfonylurea, in anti-tumour activity in pancreatic tissue of patients with insulinoma, and in patients with other tumours of the Langerhans islet cells. In adults it is presented as a diffuse dysfunction of ß cells of unknown cause. CLINICAL CASE: The case concerns 46 year-old female, with a history of Sheehan syndrome of fifteen years of onset, and with repeated events characterized with hypoglycaemia in the last three years. Body scan was performed with octreotide, revealing an insulinoma in the pancreatic region. A distal pancreatectomy was performed on the patient. The study reported a pancreatic fragment 8.5 × 3 × 1.5 cm with abnormal proliferation of pancreatic islets in groups of varying size, some of them in relation to the ductal epithelium. Histopathology study was showed positive for chromogranin, confirmed by positive synaptophysin, insulin and glucagon, revealing islet hyperplasia with diffuse nesidioblastosis with negative malignancy. The patient is currently under metabolic control and with no remission of hypoglycaemic events. CONCLUSIONS: Nesidioblastosis is a disease of difficult diagnosis should be considered in all cases of failure to locate an insulinoma, as this may be presented in up to 4% of persistent hyperinsulinaemic hypoglycaemia.
Assuntos
Nesidioblastose/diagnóstico , Feminino , Humanos , Pessoa de Meia-IdadeRESUMO
We have shown that angiotensin II (Ang II) does not diffuse across the vessel wall, remaining intravascularly confined and acting solely on the coronary endothelial luminal membrane (CELM) receptors. A sustained intracoronary infusion of Ang II causes transient coronary vasoconstriction (desensitization) due to membrane internalization of CELM Ang II type 1 receptors (CELM-AT1R). In contrast, sustained intracoronary infusion of a non-diffusible polymer of Ang II (Ang II-Pol, 15,000 kDa) causes a sustained vasoconstriction by preventing CELM-AT1R internalization. In addition, a sustained intracoronary infusion of Ang II leads to a depressed response following a secondary Ang II administration (tachyphylaxis) that is reversed by Ang II-Pol. These findings led us to hypothesize that the rate of desensitization, tachyphylaxis, and AT1R internalization were dependent on Ang II-Pol molecular weight. To test this hypothesis, we synthesized Ang II-Pols of the following molecular weights (in kDa): 1.3, 2.7, 11, 47, 527, 3270 and 15,000. Vasoconstriction was measured following intracoronary infusion of Ang II-Pols in Langendorff-perfused guinea pig hearts at constant flow. The CELM protein fraction was extracted using the silica pellicle technique at different time points in order to determine the rate of AT1R internalization following each Ang II-Pol infusion. CELM-AT1R density was quantified by Western blot. We found that the rate of desensitization and the tachyphylaxis effect varied inversely with the molecular weight of the Ang II-Pols. Inversely proportional to the molecular weight of Ang II-Pol the CELM-AT1R density decreases over time. These results indicate that the mechanism responsible for the decreased rate of desensitization and tachyphylaxis by higher molecular weight Ang II polymers is due to reduction in the rate of CELM-AT1R internalization. These Ang II polymers would be valuable tools for studying the relationship between AT1R internalization and physiological effects.
Assuntos
Angiotensina II/metabolismo , Endotélio Vascular/metabolismo , Polímeros/química , Receptor Tipo 1 de Angiotensina/metabolismo , Vasoconstrição/efeitos dos fármacos , Angiotensina II/administração & dosagem , Angiotensina II/química , Animais , Western Blotting , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/metabolismo , Endotélio Vascular/efeitos dos fármacos , Cobaias , Peso Molecular , Fatores de TempoRESUMO
Diverse intracoronary hormones cause their cardiac effects solely via activation of their coronary endothelial luminal membrane (CELM) receptors. To test this hypothesis for Ang II, we synthesized: a) two large polymers of Ang II (Ang II-POL) and Losartan (Los-POL) which act only in the CELM's AT1R because they cannot cross the endothelial barrier and b) biotin-labeled Ang II (Ang II-Biotin) and Ang II-POL-Biotin to be identified by microscopy in tissues. Sustained coronary perfusion of Ang II (potentially diffusible) or Ang II-POL caused a positive inotropic effect (PIE) and an increase in coronary perfusion pressure (CPP) of equal magnitude that were blocked by Losartan and Los-POL. However, Ang II effects, in contrast to Ang II-POL effects, were transient due to desensitization and resulted in tachyphylaxis to a second administration of Ang II or Ang II-POL. Furthermore, if Ang II and Ang II-POL acted differently on the same receptor; a competition of effects would be expected. This was demonstrated by infusing simultaneously a molar ratio of Ang II:Ang II-POL. As this molar ratio decreased, Ang II-induced desensitization and tachyphylaxis decreased. Intravascularly-administered Ang II-Biotin and Ang II-POL-Biotin remained bound and confined to the endothelium. Our results support the hypothesis and indicate intravascular Ang II, not by mass exchange with the interstitium, but by an action restricted to the CELM's AT1R, causes release of endothelial chemical messengers that exert physiological effects and modulate the effects and metabolism of paracrine Ang II. Endocrine Ang II controls and communicates with its paracrine counterparts solely through endothelial receptors.
Assuntos
Angiotensina II/metabolismo , Endotélio Vascular/metabolismo , Losartan/farmacologia , Receptor Tipo 1 de Angiotensina/metabolismo , Angiotensina II/administração & dosagem , Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Biotina/química , Vasos Coronários/metabolismo , Dextranos/química , Difusão , Losartan/administração & dosagem , Losartan/química , Comunicação Parácrina , Polímeros/química , Ratos , Ratos WistarRESUMO
BACKGROUND: Ischemia and ischemia-reperfusion (I/R) are common clinical insults that disrupt the molecular structure of coronary vascular endothelial luminal membrane (VELM) that result in diverse microvasculature dysfunctions. However, the knowledge of the associated biochemical changes is meager. We hypothesized that ischemia and I/R-induced structural and functional VELM alterations result from biochemical changes. First, these changes need to be described and later the mechanisms behind be identified. METHODS: During control conditions, in isolated perfused rat hearts VELM proteins were labeled with biotin. The groups of hearts were: control (C), no flow ischemia (I; 25 min), and I/R (I; 25 min, reperfusion 30 min). The biotinylated luminal endothelial membrane proteins in these three different groups were examined by 2-D electrophoresis and identified. But, it must be kept in mind the proteins were biotin-labeled during control. RESULTS: A comparative analysis of the protein profiles under the 3 conditions following 2D gel electrophoresis showed differences in the molecular weight distribution such that MW(C) > MW(I) > MW(I/R). Similar analysis for isoelectric points (pH(i)) showed a shift toward more acidic pHi under ischemic conditions. Of 100 % proteins identified during control 66% and 88% changed their MW-pH(i) during ischemia and I/R respectively. Among these lost proteins there were 9 proteins identified as adhesins and G-protein coupled receptors. GENERAL SIGNIFICANCE: I and I/R insults alter MW-pH(i) of most luminal glycocalyx proteins due to the activation of nonspecific hydrolizing mechanisms; suspect metalloproteases and glycanases. This makes necessary the identification of hydrolyzing enzymes reponsible of multiple microvascular dysfunctions in order to maintain the integrity of vascular endothelial membrane. VELM must become a target of future therapeutics.
RESUMO
Coronary blood flow applied to the endothelial lumen modulates parenchymal functions via paracrine effectors, but the mechanism of flow sensation is unknown. We and others have demonstrated that coronary endothelial luminal membrane (CELM) oligosaccharides and lectins are involved in flow detection, and we proposed that cardiac effects of coronary flow result from a reversible flow-modulated lectin-oligosaccharide interaction. Recently, glycosylated and amiloride-sensitive Na(+)/Ca(++) channels (ENaCs) have been proposed to be involved in the flow-induced endothelial responses. Because N-acetylglucosamine (GlcNac) is one of the main components of glycocalyx oligosaccharides (i.e., hyaluronan [-4GlcUAbeta1-3GlcNAcbeta1-](n)), the aim of this article is to isolate and define CELM GlcNac-binding lectins and determine their role in cardiac and vascular flow-induced effects. For this purpose, we synthesized a 460-kDa GlcNac polymer (GlcNac-Pol) with high affinity toward GlcNac-recognizing lectins. In the heart, intracoronary administration of GlcNac-Pol upon binding to CELM diminishes the flow-dependent positive inotropic and dromotropic effects. Furthermore, GlcNac-Pol was used as an affinity probe to isolate CELM GlcNac-Pol-recognizing lectins and at least 35 individual lectinic peptides were identified, one of them the beta-ENaC channel. Some of these lectins could participate in flow sensing and in GlcNac-Pol-induced effects. We also adopted a flow-responsive and well-accepted model of endothelial-parenchymal paracrine interaction: isolated blood vessels perfused at controlled flow rates. We established that flow-induced vasodilatation (FIV) is blocked by endothelial luminal membrane (ELM) bound GlcNac-Pol, nitro-l-arginine methyl ester and indomethacin, amiloride, and hyaluronidase. The effect of hyaluronidase was reversed by infusion of soluble hyaluronan. These results indicate that GlcNac-Pol inhibits FIV by competing and displacing intrinsic hyaluronan bound to a lectinic structure such as the amiloride-sensitive ENaC. Nitric oxide and prostaglandins are the putative paracrine mediators of FIV.
Assuntos
Acetilglucosamina/metabolismo , Circulação Coronária/fisiologia , Endotélio Vascular/fisiologia , Lectinas/metabolismo , Miocárdio/metabolismo , Animais , Cromatografia de Afinidade , Cobaias , Masculino , Contração Miocárdica/fisiologia , Vasodilatação/fisiologiaRESUMO
Diverse intracoronary agonists cause cardiac effects while acting on coronary endothelial luminal membrane (CELM) receptor. Our data show: a) the presence of AT(1)R in isolated CELM and in all cardiac cell types and b) sustained intracoronary infusions of Ang II-POL, a large sized molecule (approximately 15,000 kDa) confined to the vessel lumen that can only act on CELM's AT(1)R or Ang II (approximately 1 kDa); both exert the same maximum positive inotropic (PIE) and coronary constriction (CPP). The effects of these two agonists are blocked by Losartan and by Sar-POL; a large size antagonist (approximately 15,000 kDa) that acts only on CELM. Ang II effects are transient due to desensitization and cause tachyphylaxis to Ang II and toward Ang II-POL suggesting that both Ang II and Ang II-POL act on the same receptor group. In contrast, Ang II-POL effects are sustained and do not cause tachyphylaxis. The results show that intravascular Ang II and Ang II-POL act differentially by an unknown mechanism on CELM's AT(1)R and suggest that intravascular Ang II and Ang II-POL cause PIE and CCP by activation limited to CELM's AT(1)R through an unknown mechanism that is space-confined to the CELM's AT(1)R.
Assuntos
Vasos Coronários/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Receptor Tipo 1 de Angiotensina/agonistas , Angiotensina II/farmacologia , Animais , Vasos Coronários/fisiologia , Endotélio Vascular/fisiologia , Losartan/farmacologia , Ratos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/análise , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Saralasina/farmacologia , Vasoconstrição/efeitos dos fármacosRESUMO
The coronary endothelial luminal membrane (CELM) glycocalyx has diverse molecules involved in blood flow signal transduction. Evidence suggests that some of these structures may be lectinic. To test this, we synthesized two monosaccharide polymers (Mon-Pols) made of Mannose (Man-Pol) or Galactose (Gal-Pol) covalently coupled to Dextran (70 kDa) and used them as lectin affinity probes. In situ intracoronary infusion of both polymers resulted in CELM-binding but only Man-Pol caused a reduction in flow-induced positive inotropism and dromotropism. To demonstrate that our lectinic probes could bind to CELM lectins, a representative CELM protein fraction was isolated via intracoronary infusion of a cationic silica colloid and either Mannose- or Galactose-binding lectins were purified from the CELM protein fraction using the corresponding Mon-Pol affinity chromatography resin. Resin-bound CELM proteins were eluted with the corresponding monosaccharide. 2D-SDS-PAGE (pH 4-7) revealed 9 Mannose- and approximately 100 Galactose-selective CELM lectins. In summary, the CELM glycocalyx contains Mannose- and Galactose-binding lectins that may be involved in translating coronary flow into a cardiac parenchymal response.
Assuntos
Velocidade do Fluxo Sanguíneo/fisiologia , Vasos Coronários/fisiologia , Endotélio Vascular/fisiologia , Galectinas/fisiologia , Lectina de Ligação a Manose/fisiologia , Músculo Liso Vascular/fisiologia , Animais , Técnicas Biossensoriais , Glicocálix/fisiologia , Coração/efeitos dos fármacos , Coração/fisiologia , Humanos , Mamíferos , Contração Muscular/fisiologia , Relaxamento Muscular/fisiologia , Vasoconstrição/fisiologia , Vasodilatação/fisiologiaRESUMO
We hypothesized that Angiotensin II (Ang II), like other circulating hormones, acts exclusively intravascularly. To activate or block solely intravascular Ang II receptors, Ang II and its peptide receptor blocker saralasin (Sar) were covalently coupled to a inert polymer (POL, MW >4000 kD) forming Ang II-POL and Sar-POL. These two nonpermeable polymers, Ang II and Sar, were intracoronarily administered into the isolated, saline-perfused rat hearts. Ang II-POL and Ang II caused a dose-dependent ventricular positive inotropic (+I) and vasoconstrictor effects (+V) which were blocked by Sar. Sar-POL blocked their +I but not their +V. Thus, Ang II and Ang II-POL act on endothelial luminal receptors through paracrine mechanisms. +I were blocked solely by purinoceptor antagonists and paralleled by augmented venous release of ATP degradation products (adenosine, inosine and hypoxanthine). In contrast, +V were blocked solely by aspirin, indomethacin or a thromboxane A2 receptor antagonist. Intracoronary administration of ATP-gamma-S and U46169, a purinergic, and TXA2 agonists, respectively, mimicked +I and +V. The results indicate that ATP is the paracrine inotropic mediator while thromboxane A2 is the vasoconstrictor mediator. Thus, the +I and +V distinct effects by intracoronary Ang II indicate that its diverse mechanism of action along the coronary vascular tree may be due to a functionally heterogeneous endothelium.
Assuntos
Angiotensina II/administração & dosagem , Vasos Coronários/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Comunicação Parácrina/efeitos dos fármacos , Animais , Cardiotônicos/administração & dosagem , Vasos Coronários/fisiologia , Relação Dose-Resposta a Droga , Técnicas In Vitro , Masculino , Contração Miocárdica/fisiologia , Comunicação Parácrina/fisiologia , RatosRESUMO
La hipertensión inducida por el embarazo es una complicación presente en 5 por ciento a 10 por ciento de los embarazos y es causa importante de morbilidad materna y fetal. En este trabajo se evalúa la relación de los niveles séricos de lipoproteínas (muy baja, baja y alta densidad), durante el segundo y tercer trimestre, con el desarrollo de la hipertensión inducida por el embarazo, en 55 embarzadas, menores de 25 años, que atendieron la consulta prenatal del Hospital General del Oeste "Dr. José Gregorio Hernández", en el lapso comprendido entre julio de 1999 y julio de 2000. La hipertensión se presentó en 8 embarazadas con preeclampsia leve y 1 con preeclampsia severa. En este grupo de hipertensas, la media y la desviación estándar de los valores de lipoproteínas con muy baja densidad, expresados en mg/dL, fueron 45 ± 14 contra 33 ± 10 en las normotensas o controles. Los mismos valores en las de baja densidad fueron: 158 ± 46, contra 137 ± 37 en los controles. Los valores de las de alta densidad fueron: 56 ± 14 contra 59 ± 11 en los controles. Las concentraciones séricas elevadas de las lipoproteínas de muy baja densidad, acompañadas de disminución de los niveles de alta densidad, se relacionan con el desarrollo de la hipertensión inducida por el embarazo.
Assuntos
Humanos , Feminino , Gravidez , Feto , Hipertensão/complicações , Lipoproteínas HDL , Lipoproteínas LDL , Pré-Eclâmpsia , Medicina , VenezuelaRESUMO
In isolated guinea pig hearts saline perfused at constant flow, adenosine A(1), A(2A), and A(3) (A(x)) agonists covalently bound to a large polymer (Pol; 2,000 kDa) were intracoronarily administered, and three effects were studied: dromotropic, vascular and inotropic. The rank order of potencies were the following: dromotropic (Pol-A(2A)Pol-A(1)>Pol-A(3)) and vascular and inotropic (Pol-A(2A)> or =Pol-A(1)Pol-A(3)), where the rank order of potency for Pol-A(x) depends on the part of the coronary vascular network involved; i.e., there is a vascular heterogeneity. The large size of Pol-A(x) prevents extravascular diffusion and causes it to act solely in the endothelial luminal surface. This implies their cardiac effects are due to endothelial mediators. Inhibition of nitric oxide (NO) and prostaglandin (PG) synthesis with N(G)-nitro-l-arginine methyl ester and indomethacin, respectively, show that the three cardiac effects of Pol-A(1) were mediated by NO and PG, whereas for Pol-A(2A) and Pol-A(3) the mediator was mainly NO but not PG. These results suggest that if Pol-A(x) activated the corresponding endothelial A(x)-receptor subtype, a different mediator would be produced.