Small peptides patterned after the N terminus of the synaptosomal protein of 25 kDa, a member of the protein complex implicated in Ca 2ϩ -dependent neuronal exocytosis, inhibit in vitro the release of neuromodulators involved in pain signaling, suggesting an in vivo analgesic activity. Here, we report that compound DD04107 (palmitoyl-EEMQRR-NH 2 ), a 6-mer palmitoylated peptide that blocks the inflammatory recruitment of ion channels to the plasma membrane of nociceptors and the release of calcitonin gene-related peptide from primary sensory neurons, displays potent and long-lasting in vivo antihyperalgesia and antiallodynia in chronic models of inflammatory and neuropathic pain, such as the complete Freund's adjuvant, osteosarcoma, chemotherapy, and diabetic neuropathic models. Subcutaneous administration of the peptide produced a dose-dependent antihyperalgesic and antiallodynic activity that lasted Ն24 h. The compound showed a systemic distribution, characterized by a bicompartmental pharmacokinetic profile. Safety pharmacology studies indicated that the peptide is largely devoid of side effects and substantiated that the in vivo activity is not caused by locomotor impairment. Therefore, DD04107 is a potent and long-lasting antinociceptive compound that displays a safe pharmacological profile. These findings support the notion that neuronal exocytosis of receptors and neuronal algogens pivotally contribute to chronic inflammatory and neuropathic pain and imply a central role of peptidergic nociceptor sensitization to the pathogenesis of pain.
Objetivo: Identificar los factores de riesgo asociados con la mortalidad a las seis semanas. Diseño: Estudio prospectivo multicéntrico. Ámbito: 26 UCI de Andalucía. Pacientes o participantes: Pacientes ingresados en UCI por neumonía grave por SARS COV 2 en el periodo de tiempo comprendido entre el 8 de marzo y el 30 de mayo. Intervenciones: Ninguna. Variables de interés principales: características demográficas, clínicas y escalas de gravedad. Se analizaron tratamientos de soporte, fármacos y la mortalidad. Resultados: 495 pacientes fueron incluidos, 73 fueron excluidos por incompletos. 422 pacientes fueron incluidos en el análisis final. La mediana de edad fue de 63 años, 305 (72,3%) eran hombres. La mortalidad en la UCI fue: 144/422 34%; mortalidad a los 14 días: 81/422 (19,2%); mortalidad a los 28 días: 121/422 (28,7%); mortalidad a las 6 semanas 152/422 36,5%. Los factores asociados con la mortalidad a los 42 días fueron la edad, APACHE II, SOFA >6 y LDH al ingreso > 470 U/L, uso de vasopresores, necesidad de técnicas de reemplazo de la función renal, porcentaje de linfocitos a las 72 horas del ingreso en UCI < 6,5%, y trombocitopenia, mientras que el uso de lopinavir/ritonavir fue identificado como un factor protector. Conclusiones: La edad, gravedad y fracaso orgánico junto con la necesidad de terapias de soporte fueron identificadas como factores predictores de mortalidad a las seis semanas.
Background and purpose: The delayed onset of certain effects of antagonists of b-adrenoceptors (b-blockers), such as lowering arterial blood pressure (several days), cannot be explained solely by their effects on b-adrenoceptors, an action that occurs within minutes. Although several mechanisms have been proposed, none of them explain this temporal delay. This work aimed at providing a new explanation based on the interference of these drugs with the functional accumulation of catecholamines within neurosecretory vesicles. Experimental approach: We used the simultaneous on-line monitoring of catecholamine and labetalol release from bovine isolated chromaffin cells and from rat perfused adrenal glands, as well as single cell amperometry, intracellular electrochemistry, patch amperometry and HPLC. Key results: Using amperometry, three b-blockers, labetalol, atenolol and propranolol, reduced the quantal size of secretory events in chromaffin cells, accompanied by a slowing down of exocytosis. By patch amperometry, we found that treatment with b-blockers also increases the chromaffin vesicle volume, thereby creating a functional dilution of catecholamines. Experiments with intracellular electrochemistry show that vesicles cannot uptake new catecholamines. There was progressive accumulation of labetalol in secretory vesicles of bovine adrenal chromaffin cells, and this b-blocker was co-released with catecholamines from rat and bovine chromaffin tissues. Conclusions and implications:We propose that b-blockers are progressively concentrated into sympathetic secretory vesicles, and interfere with the storage of catecholamines and are co-released with the natural transmitters, resulting in a decrease in the sympathetic tone. This could explain the delayed onset of the hypotensive effects of b-blockers. (2010) Keywords: amperometry; chromaffin cells; patch amperometry; secretion; catecholamines; b-adrenoceptor; labetalol; propranolol; atenolol Abbreviations: b-blocker, b-adrenoceptor antagonist; CgB, chromogranin B; DMPP, dimethylphenyl piperazinium; Imax, maximal intensity of amperometrical spikes; m, ascending slope of spikes; Q, spike charge; t1/2, spike width at a half height British Journal of Pharmacology
Chromaffin granules are similar organelles to the large dense core vesicles (LDCV) present in many secretory cell types including neurons. LDCV accumulate solutes at high concentrations (catecholamines, 0.5-1 M; ATP, 120-300 mM; or Ca(2+), 40 mM (Bulenda and Gratzl Biochemistry 24:7760-7765, 1985). Solutes seem to aggregate to a condensed matrix to elude osmotic lysis. The affinity of solutes for LDCV matrix is responsible for the delayed release of catecholamines during exocytosis. The aggregation of solutes occurs due to a specific H(+) pump denominated V-ATPase that maintains an inner acidic media (pH ≈5.5). This pH gradient against cytosol is also responsible for the vesicular accumulation of amines and Ca(2+). When this gradient is reduced by modulation of the V-ATPase activity, catecholamines and Ca(2+) are moved toward the cytosol. In addition, some drugs largely accumulate inside LDCV and not only impair the accumulation of natural solutes, but also act as false neurotransmitters when they are co-released with catecholamines. There is much experimental evidence to conclude that the physiological modulation of vesicle pH and the manipulation of intravesicular media with drugs affect the LDCV cargo and change the kinetics of exocytosis. Here, we will present some experimental data demonstrating the participation of drugs in the kinetics of exocytosis through changes in the composition of vesicular media. We also offer a model to explain the regulation of exocytosis by the intravesicular media that conciliate the experimentally obtained data.
Near-infrared spectroscopy (NIRS) could be a useful continuous, non-invasive technique for monitoring the effect of partial pressure of carbon dioxide (PaCO 2 ) fluctuations in the cerebral circulation during ventilation. The aim of this study was to examine the efficacy of NIRS to detect acute changes in cerebral blood flow following PaCO 2 fluctuations after confirming the autoregulation physiology in piglets. Fourteen piglets (o72 h of life) were studied. Mean arterial blood pressure, oxygen saturation, pH, glycemia, hemoglobin, electrolytes, and temperature were monitored. Eight animals were used to evaluate brain autoregulation, assessing superior cava vein Doppler as a proxy of cerebral blood flow changing mean arterial blood pressure. Another 6 animals were used to assess hypercapnia generated by decreasing ventilatory settings and complementary CO 2 through the ventilator circuit and hypocapnia due to increasing ventilatory settings. Cerebral blood flow was determined by jugular vein blood flow by Doppler and continuously monitored with NIRS. A decrease in PaCO 2 was observed after hyperventilation (47.6±2.4 to 29.0±4.9 mmHg). An increase in PaCO 2 was observed after hypoventilation (48.5±5.5 to 90.4± 25.1 mmHg). A decrease in cerebral blood flow after hyperventilation (21.8 ± 10.4 to 15.1 ± 11.0 mL/min) and an increase after hypoventilation (23.4 ± 8.4 to 38.3 ± 10.5 mL/min) were detected by Doppler ultrasound. A significant correlation was found between cerebral oxygenation and Doppler-derived parameters of blood flow and PaCO 2 . Although cerebral NIRS monitoring is mainly used to detect changes in regional brain oxygenation, modifications in cerebral blood flow following experimental PaCO 2 changes were detected in newborn piglets when no other important variables were modified.
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