RESUMEN
BACKGROUND: This study addresses the question of whether psychosocial functioning measured by the Personal and Social Performance (PSP) Scale is related to various psychopathological measures in a cohort of patients with schizophrenia. METHODS: The 'Neuroleptic Strategy Study' (NeSSy) performed at 14 German hospitals between 2010 and 2013 compared two treatment strategies instead of individual drugs. Secondary end-points were the two PSP scales as well as measures of quality of life (SF-36) and the Positive and Negative Syndrome Scale (PANSS). RESULTS: 149 patients were randomised. There was no difference between the two treatment strategies (first-generation versus second-generation antipsychotics) with regard to the PSP. There were differences in doctors' assessments regarding psychosocial functioning compared with patients' own assessments. Furthermore, there were relationships between the PSP and quality of life, level of skills (ICF), and severity of disease (PANSS), level of sexual activities and poor well-being under antipsychotic medication but not with cognitive changes. CONCLUSIONS: The findings on psychosocial functioning of patients with schizophrenia related to severity and skill level could be confirmed. Further findings were the correlation between psychosocial functioning and quality of life, well-being under treatment, and sexuality what emphasizes the substantial importance of a reduced psychosocial functioning.
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Antipsicóticos/uso terapéutico , Funcionamiento Psicosocial , Esquizofrenia/tratamiento farmacológico , Psicología del Esquizofrénico , Adulto , Método Doble Ciego , Femenino , Humanos , Masculino , Calidad de VidaRESUMEN
The relative bioavailability of different prednisolone (CAS 50-24-8) tablet formulations (Prednisolon Ferring 2, 5, and 20 mg) was investigated in comparison to a reference formulation. The study was performed in a GCP/ICH-conform manner using a randomized cross-over design in 13 healthy volunteers. With respect to the pharmacokinetic parameters Cmax (maximal prednisolone concentration), AUC0-12 h (area under the concentration-time curve until 12 h after drug intake), AUC0-infinity (area under the concentration-time curve until infinity), and t1/2 (elimination half-life time), 10 x 2 mg prednisolone tablets did not show any relevant differences as compared to the reference (1 x 20 mg) meaning that the 90% confidence intervals were within the given 0.80-1.25 limits for the decision of bioequivalence. Although not statistically significant, tmax (time to reach the maximal prednisolone plasma concentration) was 11 min shorter regarding the test preparation as compared to the reference. The pharmacokinetic parameters of 4 x 5 prednisolone tablets were also well in accordance with the reference. The most important parameters Cmax, AUC and t1/2 were within the defined limits for the acceptance of bioequivalence and, in addition, tmax did not show any significant differences. The 20 mg prednisolone tablet formulation showed almost identical parameters of Cmax, AUC, t1/2 und tmax in comparison to the reference substance. Taken together, the results of the bioavailability parameters indicate the bioequivalence of the three prednisolone test preparations as compared to the reference.
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Antiinflamatorios/farmacocinética , Prednisolona/farmacocinética , Adulto , Antiinflamatorios/efectos adversos , Antiinflamatorios/química , Área Bajo la Curva , Disponibilidad Biológica , Cromatografía Líquida de Alta Presión , Estudios Cruzados , Método Doble Ciego , Femenino , Humanos , Masculino , Prednisolona/efectos adversos , Prednisolona/química , Reproducibilidad de los Resultados , Comprimidos , Equivalencia TerapéuticaRESUMEN
BACKGROUND: Dopamine D(2)-like receptors are involved in the physiological response of renal haemodynamics to amino-acid infusion. The present study was performed to investigate whether domperidone, a D(2)-like receptor antagonist, modulates the pathological hyperfiltration in experimental diabetes mellitus. METHODS: Renal function was studied in anaesthetized rats 2 weeks after induction of moderate diabetes mellitus by streptozotocin, and in non-diabetic controls. Rats in both groups continuously received domperidone or vehicle via drinking water. Following infusion of Ringer's saline for measurement of baseline values, an i.v. amino-acid load was applied to investigate the renal functional reserve. RESULTS: In vehicle-treated diabetic rats baseline glomerular filtration rate and renal plasma flow were significantly higher compared with controls (1.10+/- 0.04 vs. 0.83+/-0.02 (P<0.004) and 4.83+/-0.26 vs 3.32+/-0.24 ml/min/100 g body weight (bw) (P<0.001) respectively). Domperidone completely normalized glomerular filtration rate and renal plasma flow in diabetic rats to values observed in vehicle-treated controls (0.81+/-0.07 (P=0.740) and 3.35+/- 0.30 ml/min/100 g bw (P=0.889) respectively). In the clearance experiments, arterial blood pressure, urinary flow rate and sodium excretion did not significantly differ when comparing the four groups. However, in conscious rats, urinary flow rate and sodium excretion were significantly higher in diabetic rats compared with non-diabetic controls. In both non-diabetic groups, amino-acid infusion induced a significant glomerular hyperfiltration that was completely absent in diabetic rats, and restored by domperidone treatment. In conscious vehicle-treated diabetic rats urinary albumin excretion was enhanced (449.0+/-47.7 vs. 185.7+/- 18.1 microg/24 h in non-diabetic rats (P<0.001)) and significantly lowered in diabetic rats by domperidone treatment (109.8+/-15.4 microg/24 h (P<0.001)). CONCLUSION: The data suggest that dopaminergic mechanisms are involved in the changes in renal haemodynamics during early experimental diabetes mellitus in rats.
Asunto(s)
Diabetes Mellitus Experimental/fisiopatología , Domperidona/farmacología , Antagonistas de los Receptores de Dopamina D2 , Tasa de Filtración Glomerular/efectos de los fármacos , Animales , Glucemia/metabolismo , Antagonistas de Dopamina/farmacología , Tasa de Filtración Glomerular/fisiología , Hemodinámica/efectos de los fármacos , Hemodinámica/fisiología , Riñón/irrigación sanguínea , Riñón/efectos de los fármacos , Riñón/fisiopatología , Masculino , Ratas , Ratas Sprague-Dawley , Flujo Sanguíneo Regional/efectos de los fármacos , Circulación Renal/efectos de los fármacos , Factores de TiempoRESUMEN
AIMS: In rodents, blockade of dopamine D2-like receptors abolishes both the physiological increase in glomerular filtration rate (GFR) induced by amino acids and the pathological hyperfiltration in experimental diabetes mellitus. This study addressed the contribution of dopamine D2-like receptors to changes in renal haemodynamics after amino acid infusion in humans. METHODS: Twelve healthy volunteers participated in this double-blind, randomized, cross-over study. GFR and renal blood flow (RPF) were assessed by renal clearance of inulin and p-aminohippuric acid (PAH), respectively. Following infusion of 0.45% saline at baseline, an electrolyte-balanced solution of mixed amino acids (10%) was infused. Prior to the experiments, the subjects received orally either placebo, or sulpiride (10 mg kg-1), a centrally and peripherally acting D2-like receptor antagonist, or domperidone (1 mg kg-1) which affects only peripheral D2-like receptors. RESULTS: In the placebo series, amino acid infusion significantly increased GFR and RPF by up to 15.8 +/- 5.3% and 14.4 +/- 6.1%, respectively, while mean blood pressure and heart rate remained unchanged. Pretreatment with domperidone only marginally altered the renal response to amino acids (maximal increase by 13.2 +/- 5.6 and 11.9 +/- 4.0% in GFR and RPF, respectively), while sulpiride completely abolished the renal haemodynamic changes induced by amino acids. Total and fractional urinary sodium excretion as well as urinary osmolality were similar at baseline and increased in response to amino acids, to the same extent, in all series. No changes in renal dopamine excretion occurred. CONCLUSION: The results indicate that in man dopamine D2-like receptors are involved in the renal haemodynamic response to amino acid infusion. Whether dopamine D2-like receptor blockade diminishes glomerular hyperfiltration in pathological states requires clinical investigations.
Asunto(s)
Aminoácidos/farmacología , Antagonistas de Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2 , Tasa de Filtración Glomerular/efectos de los fármacos , Adulto , Presión Sanguínea/efectos de los fármacos , Estudios Cruzados , Domperidona/farmacocinética , Domperidona/farmacología , Dopamina/orina , Antagonistas de Dopamina/farmacocinética , Método Doble Ciego , Interacciones Farmacológicas , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Masculino , Tasa de Depuración Metabólica , Receptores de Dopamina D2/metabolismo , Flujo Plasmático Renal/efectos de los fármacos , Sulpirida/farmacocinética , Sulpirida/farmacologíaRESUMEN
Two prednisolone (CAS 50-24-8) formulations (Prednisolone 50 mg Ferring tablets as the test preparation and tablets of a reference preparation) were investigated in 13 healthy volunteers in order to prove bioequivalence between these preparations. A single oral dose of 50 mg was given using a randomized, two-way cross-over design with a wash-out period of one week. Blood samples for determination of prednisolone plasma concentrations were collected up to 15 h following drug administration. Additionally, in vitro tests were performed with tablets from the same lots to determine dissolution characteristics. Prednisolone concentrations were measured by means of validated HPLC with UV-detection. Maximum concentrations (Cmax) of 1020.9 +/- 57.8 and 1053.3 +/- 55.7 ng/ml were achieved for the test and the reference preparation, respectively. The AUC0-infinity was 212.2 +/- 13.2 micrograms.min/ml (test preparation) and 222.2 +/- 14.3 micrograms.min/ml (reference preparation). The 90% confidence intervals of the test to reference ratios were within the range of 80-125% with 97.8-101.3% for Cmax and 98.1-100.4% for AUC0-infinity. The time to reach maximum plasma concentration (tmax) tended to be lower (-25%) in the test (39.6 +/- 6.4 min) as compared to the reference preparation (52.8 +/- 9.0 min). Interestingly, this difference correlated well with the observation of a more rapid dissolution rate of the test preparation by some 10 min. Both prednisolone formulations were well tolerated. Based on the results obtained in this study, (1) bioequivalence between the test and the reference preparation was clearly demonstrated and (2) a positive correlation between dissolution rate observed in vitro and tmax as measured in vivo was found.
Asunto(s)
Antiinflamatorios/farmacocinética , Prednisolona/farmacocinética , Adulto , Antiinflamatorios/administración & dosificación , Antiinflamatorios/efectos adversos , Área Bajo la Curva , Estudios Cruzados , Femenino , Humanos , Masculino , Prednisolona/administración & dosificación , Prednisolona/efectos adversos , Solubilidad , Equivalencia TerapéuticaRESUMEN
The present study was designed to investigate, in human subjects, urinary dopamine excretion under different conditions of sodium and water homeostasis. In a cross-over trial, ten healthy volunteers were subjected to low-salt (LS; dietary salt restriction, sodium chloride (NaCl) intake <5 g per day), normal-salt (NS; normal food ad libitum), and high-salt (HS; normal food plus NaCl 100 mg/kg per day) regimens for 8 days in a randomized order. On day 7, urine was collected for 24 h. The variations in urinary sodium excretion reflected the dietary salt intake (LS: 16.3+/-4.7; NS: 144.1+/-18.2; HS: 221.9+/-12.9 mmol 24 h(-1) 1.73 m(-2)), but were not accompanied by significant changes in urinary dopamine excretion. On day 8, clearance studies showed that an acute oral water load of 1500 ml did not alter glomerular filtration rate or renal plasma flow but significantly increased urinary flow rate without affecting dopamine excretion. Assuming that excreted dopamine is not metabolized or reabsorbed during the tubular passage, both the unchanged urinary dopamine output in spite of 14-fold variations in sodium excretion and its independence of an acute water load argue against the hypothesis that dopamine in the tubular lumen acts as a natriuretic and/or diuretic factor in humans.
Asunto(s)
Dopamina/orina , Sodio en la Dieta/farmacología , Agua/administración & dosificación , Administración Oral , Adulto , Estudios Cruzados , Diuresis/efectos de los fármacos , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Valores de Referencia , Análisis de Regresión , Flujo Plasmático Renal/efectos de los fármacosRESUMEN
In the present study we investigated the renal hemodynamic effects of dopamine D(3) receptor activation by R(+)-7-hydroxy-dipropylaminotetraline (7-OH-DPAT) in thiopental-anesthetized Sprague-Dawley rats. In clearance experiments infusion of 7-OH-DPAT (0.01-1.0 microg. kg(-1). min(-1)) dose-dependently elevated glomerular filtration rate (GFR) without affecting mean arterial blood pressure (MAP). In renal blood flow experiments 7-OH-DPAT infusion (1.0 microg. kg(-1). min(-1)) increased GFR by 16 +/- 2%, associated with an unexpected fall in renal blood flow by 20 +/- 3% and a significant elevation of renal vascular resistance by 18 +/- 3%. The renal hemodynamic changes were not influenced by pretreatment with the D(2)-receptor antagonist S(-)-sulpiride but were completely abolished during D(3) receptor inhibition by 5,6-dimethoxy-2-(di-n-propylamino)indane (U-99194A). In micropuncture experiments 7-OH-DPAT (1.0 microg. kg(-1). min(-1)) significantly elevated stop-flow pressure measured in the early proximal tubules and reduced hydrostatic pressure at the first branching point of the efferent arteriole without altering MAP. We conclude from these data that pharmacological activation of dopamine D(3) receptors affects renal hemodynamics in anesthetized rats by preferential postglomerular vasoconstriction.
Asunto(s)
Glomérulos Renales/irrigación sanguínea , Receptores de Dopamina D2/fisiología , Vasoconstricción/fisiología , Animales , Agonistas de Dopamina/farmacología , Antagonistas de Dopamina/farmacología , Antagonistas de los Receptores de Dopamina D2 , Hemodinámica/efectos de los fármacos , Hemodinámica/fisiología , Indanos/farmacología , Masculino , Punciones , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D2/agonistas , Circulación Renal/efectos de los fármacos , Circulación Renal/fisiología , Tetrahidronaftalenos/farmacologíaRESUMEN
It is well accepted that dopamine receptors play an important role in the regulation of cardiovascular and kidney function. Most of the knowledge on the renal actions of dopamine has been accumulated focussing on the prototypes of the two known dopamine receptor subfamilies, i.e. D1 and D2. The dopamine D3 receptor is a member of the D2-like subfamily and has been intensively studied in the neurosciences. Recently, the peripheral actions of this receptor subtype have also raised considerable interest as well because its effects on kidney function appear to be different from that of the other dopamine receptors. This short overview will summarize the data reported and add new results on the role of D3 receptors in the regulation of renal function as well as their potential pathophysiological implications.
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Riñón/fisiología , Riñón/fisiopatología , Receptores de Dopamina D2/fisiología , Animales , Humanos , Riñón/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3 , Circulación Renal , Tetrahidronaftalenos/farmacología , Distribución TisularAsunto(s)
Enfermedades Cardiovasculares/tratamiento farmacológico , Diuréticos/uso terapéutico , Edema/tratamiento farmacológico , Furosemida/uso terapéutico , Enfermedades Cardiovasculares/etiología , Diuréticos/efectos adversos , Diuréticos/farmacocinética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Edema/etiología , Furosemida/efectos adversos , Furosemida/farmacocinética , HumanosRESUMEN
Late endosomes and the Golgi complex maintain their cellular localizations by virtue of interactions with the microtubule-based cytoskeleton. We study the transport of mannose 6-phosphate receptors from late endosomes to the trans-Golgi network in vitro. We show here that this process is facilitated by microtubules and the microtubule-based motor cytoplasmic dynein; transport is inhibited by excess recombinant dynamitin or purified microtubule-associated proteins. Mapmodulin, a protein that interacts with the microtubule-associated proteins MAP2, MAP4, and tau, stimulates the microtubule- and dynein-dependent localization of Golgi complexes in semi-intact Chinese hamster ovary cells. The present study shows that mapmodulin also stimulates the initial rate with which mannose 6-phosphate receptors are transported from late endosomes to the trans-Golgi network in vitro. These findings represent the first indication that mapmodulin can stimulate a vesicle transport process, and they support a model in which the microtubule-based cytoskeleton enhances the efficiency of vesicle transport between membrane-bound compartments in mammalian cells.
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Dineínas/metabolismo , Endosomas/metabolismo , Microtúbulos/metabolismo , Proteínas/metabolismo , Receptor IGF Tipo 2/metabolismo , Proteínas de Transporte Vesicular , Animales , Transporte Biológico , Células CHO/efectos de los fármacos , Células CHO/metabolismo , Proteínas Portadoras/metabolismo , Bovinos , Cricetinae , Citoplasma/metabolismo , Complejo Dinactina , Aparato de Golgi/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Proteínas de la Membrana/metabolismo , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Microtúbulos/efectos de los fármacos , Nocodazol/farmacología , Proteínas Nucleares , Paclitaxel/farmacología , Proteínas de Unión al ARN , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Solubles de Unión al Factor Sensible a la N-Etilmaleimida , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
Methemoglobinemia may occur after the administration of various drugs, including some local anesthetics. We report a patient with chronic renal failure and ischemic heart disease who developed clinically significant methemoglobinemia after an axillary block with bupivacaine and additional injection of lidocaine in the operative field. Although the two local anesthetics usually do not cause methemoglobinemia, we suspect that the displacement of lidocaine from protein binding by bupivacaine, in combination with metabolic acidosis and treatment with other oxidants, was the reason for the development of methemoglobinemia.
Asunto(s)
Anestésicos Locales/efectos adversos , Axila/inervación , Bupivacaína/efectos adversos , Lidocaína/efectos adversos , Metahemoglobinemia/inducido químicamente , Bloqueo Nervioso/efectos adversos , Acidosis/complicaciones , Álcalis/uso terapéutico , Anestésicos Locales/administración & dosificación , Antídotos/uso terapéutico , Bupivacaína/administración & dosificación , Interacciones Farmacológicas , Femenino , Humanos , Cuidados Intraoperatorios , Fallo Renal Crónico/complicaciones , Lidocaína/administración & dosificación , Metahemoglobinemia/tratamiento farmacológico , Azul de Metileno/uso terapéutico , Persona de Mediana Edad , Isquemia Miocárdica/complicaciones , Oxidantes/uso terapéutico , Unión Proteica/efectos de los fármacos , Bicarbonato de Sodio/uso terapéuticoRESUMEN
A sensitive and rapid method for measuring simultaneously adenosine, S-adenosylhomocysteine and S-adenosylmethionine in renal tissue, and for the analysis of adenosine and S-adenosylhomocysteine concentrations in the urine is presented. Separation and quantification of the nucleosides are performed following solid-phase extraction by reversed-phase ion-pair high-performance liquid chromatography with a binary gradient system. N6-Methyladenosine is used as the internal standard. This method is characterized by an absolute recovery of over 90% of the nucleosides plus the following limits of quantification: 0.25-1.0 nmol/g wet weight for renal tissue and 0.25-0.5 microM for urine. The relative recovery (corrected for internal standard) of the three nucleosides ranges between 98.1 +/- 2.6% and 102.5 +/- 4.0% for renal tissue and urine, respectively (mean +/- S.D., n = 3). Since the adenosine content in kidney tissue increases instantly after the onset of ischemia, a stop freezing technique is mandatory to observe the tissue levels of the nucleosides under normoxic conditions. The resulting tissue contents of adenosine, S-adenosylhomocysteine and S-adenosylmethionine in normoxic rat kidney are 5.64 +/- 2.2, 0.67 +/- 0.18 and 46.2 +/- 1.9 nmol/g wet weight, respectively (mean +/- S.D., n = 6). Urine concentrations of adenosine and S-adenosylhomocysteine of man and rat are in the low microM range and are negatively correlated with urine flow-rate.
Asunto(s)
Adenosina/orina , Cromatografía Líquida de Alta Presión/métodos , S-Adenosilmetionina/orina , Adenosina/metabolismo , Animales , Humanos , Riñón/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , S-Adenosilhomocisteína/metabolismo , S-Adenosilhomocisteína/orina , S-Adenosilmetionina/metabolismo , Espectrofotometría UltravioletaRESUMEN
The modulation of the renal response to exogenous dopamine by renal denervation (DNX) and dopamine receptor antagonists was investigated in thiopental-anesthetized Sprague-Dawley rats. Experiments were performed after reaching stable systemic hemodynamics and urinary flow rate. These conditions were obtained with an infusion rate of approximately 1.2% of body weight per hour. In the vehicle group (VHC) i.v. infusion of dopamine (1, 3 and 9 microg kg(-1) min(-1) significantly increased glomerular filtration rate (GFR), assessed by renal clearance of [3H]inulin, by 14+/-1.5, 16+/-1.6 and 31+/-2.6%, respectively. Infusion of 1 and 3 microg kg(-1) min(-1) dopamine did not change systemic hemodynamics while the highest dose elevated heart rate, potentially contributing to the GFR increase. The specific D1 receptor antagonist SCH 23390 (10 microg kg(-l) min(-1) i.v.) did not affect the GFR response to dopamine infusion. In contrast, domperidone (DOM; 8 microg kg(-1) min(-1) i.v.), a specific, peripherally acting D2 antagonist, attenuated the glomerular hyperfiltration induced by the three doses of dopamine to 11+/-1.7, 13+/-2.2 and 16+/-2.6%, respectively. DNX diminished the GFR response to dopamine infusion to almost the same extent (11+/-2.8, 10+/-2.2 and 17+/-2.6%, respectively) as did DOM. When DNX animals were treated with DOM, the GFR responses to dopamine were further attenuated to non-significant increases. These additive effects of DOM and DNX suggest that two different mechanisms are involved. Both DNX and SCH 23390 decreased sodium excretion at baseline whereas DOM enhanced it. Under the present experimental condition, neither D1 nor D2 receptor blockade affected the natriuretic and diuretic response to dopamine. Whereas D1 receptors do not appear to be involved, both D2 receptors and renal nerves play a role in the renal hemodynamic response to dopamine, indicating involvement of both pre- and postsynaptical dopamine receptors.
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Antagonistas de Dopamina/farmacología , Dopamina/farmacología , Riñón/efectos de los fármacos , Animales , Benzazepinas/farmacología , Desnervación , Domperidona/farmacología , Tasa de Filtración Glomerular/efectos de los fármacos , Riñón/inervación , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D1/fisiología , Receptores de Dopamina D2/fisiologíaRESUMEN
The present investigation was undertaken to determine the effect of various ions on the characteristics of S-adenosylhomocysteine (SAH) hydrolase from bovine kidney. The binding sites of [3H]-adenosine to purified SAH hydrolase were not influenced by phosphate, magnesium, potassium, sodium, chloride or calcium ions at physiological cytosolic concentrations. To test whether NAD+ in the SAH hydrolase is essential for adenosine binding, we prepared the apoenzyme by removing NAD+ with ammonium sulfate. The resulting apoenzyme did not exhibit any [3H]-adenosine binding. Since the apoenzyme was enzymatically inactive, it is suggested that adenosine binds to the active site and not to an allosteric site of the intact enzyme. The kinetics of the hydrolysis and the synthesis of SAH catalyzed by the enzyme SAH hydrolase were measured in the presence and absence of phosphate and magnesium. Phosphate increased the Vmax for both synthesis and hydrolysis. However, only the affinity of adenosine for SAH synthesis was significantly enhanced from 10.1+/-1.3 microM to 5.4+/-0.5 microM by phosphate. This effect was already maximal at a phosphate concentration of 1 mM. All other tested ions were without effect on the enzyme activity. Our results show that phosphate at physiological concentrations shifts the thermodynamic equilibrium of SAH hydrolase in the direction of SAH synthesis. These findings imply that SAH-sensitive transmethylation reactions are inhibited during renal hypoxia when intracellular levels of phosphate, adenosine, and SAH are elevated.
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Adenosina/metabolismo , Hidrolasas/metabolismo , Riñón/enzimología , Adenosilhomocisteinasa , Animales , Sitios de Unión , Calcio/farmacología , Bovinos , Cloruros/farmacología , Hidrolasas/química , Hidrolasas/aislamiento & purificación , Iones , Cinética , Magnesio/farmacología , Fosfatos/farmacología , Potasio/farmacología , Sodio/farmacologíaRESUMEN
Renal dopamine has been proposed to be involved in the regulation of glomerular filtration rate (GFR). Because inhibition of dopamine D2 receptors abolishes the renal hyperfiltration due to amino acid load, we tested the hypothesis that pharmacological activation of D2-like receptors mimicked this renal response. In anesthetized rats, quinpirole (0.3 microgram . 100 g-1 . min-1), an agonist for receptors of the D2-like family, caused an increase in GFR by 20 +/- 2%, which corresponded to that provoked by infusion of an 10% amino acid solution. The D2 receptor antagonist S(-)-sulpiride that acts both centrally and peripherally completely abolished the renal hemodynamic response to quinpirole and to amino acids whereas domperidone, a peripherally acting D2 receptor antagonist, inhibited this hyperfiltration only in part. Urinary dopamine excretion increased in response to amino acid infusion whether GFR increased or not. We conclude that, in anesthetized rats, dopamine D2 receptors contribute to the amino acid-induced hyperfiltration and that both central and peripheral receptors might be involved, whereas dopamine excreted into the urine does not appear to play a functional role in this renal hemodynamic response.
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Aminoácidos/farmacología , Tasa de Filtración Glomerular/efectos de los fármacos , Receptores de Dopamina D2/fisiología , Animales , Domperidona/farmacología , Masculino , Quinpirol/farmacología , Ratas , Ratas Sprague-Dawley , Sulpirida/farmacologíaRESUMEN
We report here the identification and characterization of a human 76kDa membrane protein that is found predominantly in endosomes. This protein is related to the Saccharomyces cerevisiae EMP70 gene product, a precursor protein whose 24kDa cleavage product (p24a) was found in yeast endosome-enriched membrane fractions (Singer-Krüger et al., 1993. J. Biol. Chem. 268, 14376-14386). Northern blot analysis indicated that p76 mRNA is highly expressed in human pancreas but could be detected in all tissues examined. p76 is highly conserved throughout evolution, as related proteins have also been detected in Caenorhabditis elegans and Arabidopsis thaliana. This family of proteins has a relatively divergent, hydrophilic N-terminal domain and a well-conserved, highly hydrophobic C-terminal domain which contains nine potential membrane-spanning domains. Transiently expressed, myc-tagged human p76 appears to be localized to endosomes by virtue of its apparent colocalization with transferrin receptors and some mannose 6-phosphate receptors. Furthermore, p76 adopts a type-I topology within the membrane, with its hydrophilic N-terminus facing the lumen of cytoplasmic membranes. The structural features of p76 suggest that it may function as a channel or small molecule transporter in intracellular compartments throughout phylogeny. 1998 Elsevier Science B.V.
Asunto(s)
Secuencia Conservada , Endosomas/química , Proteínas de la Membrana , Secuencia de Aminoácidos , Secuencia de Bases , Membrana Celular/química , Clonación Molecular , Humanos , Proteínas de la Membrana/análisis , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Datos de Secuencia Molecular , Peso Molecular , Especificidad de Órganos , Páncreas/química , Filogenia , ARN Mensajero/análisis , Análisis de Secuencia de ADN , Homología de Secuencia de AminoácidoRESUMEN
DGAP1 of Dictyostelium discoideum is a cell cortex associated 95 kDa protein that shows homology to both RasGTPase-activating proteins (RasGAPs) and RasGAP-related proteins. When tested for RasGAP activity, recombinant DGAP1 protein did not promote the GTPase activity of human H-Ras or of Dictyostelium RasG in vitro. Instead, DGAP1 bound to Dictyostelium Rac1A and human Rac1, but not to human Cdc42. DGAP1 preferentially interacted with the activated GTP-bound forms of Rac1 and Rac1A, but did not affect the GTPase activities. Since Rho-type GTPases are implicated in the formation of specific F-actin structures and in the control of cell morphology, the microfilament system of mutants that either lack or overexpress DGAP1 has been analysed. DGAP1-null mutants showed elevated levels of F-actin that was organised in large leading edges, membrane ruffles or numerous large filopods. Expression of actin fused to green fluorescent protein (GFP) was used to monitor the actin dynamics in these cells, and revealed that the F-actin cytoskeleton of DGAP1-null cells was rapidly re-arranged to form ruffles and filopods. Conversely, in DGAP1-overexpressing cells, the formation of cellular projections containing F-actin was largely suppressed. Measurement of cell migration demonstrated that DGAP1 expression is inversely correlated with the speed of cell motility.