RESUMO
The survival of pancreatic beta cells depends on the balance between external cytotoxic and protective molecular systems. The neuropeptide neurotensin (NT) has been shown to regulate certain functions of the endocrine pancreas including insulin and glucagon release. However, the mechanism of action of NT as well as the identification of receptors involved in the pancreatic functions of the peptide remained to be studied. We demonstrate here that NT is an efficient protective agent of pancreatic beta cells against cytotoxic agents. Both beta-TC3 and INS-1E cell lines and the mouse pancreatic islet cells express the three known NT receptors. The incubation of beta cells with NT protects cells from apoptosis induced either by staurosporine or by IL-1beta. In beta-TC3 cells, NT activates both MAP and PI-3 kinases pathways and strongly reduces the staurosporine or the Il-1beta-induced caspase-3 activity by a mechanism involving Akt activation. The NTSR2 agonist levocabastine displays the same protective effect than NT whereas the NTSR1 antagonist is unable to block the effect of NT suggesting the predominant involvement of the NTSR2 in the action of NT on beta cells. These results clearly indicate for the first time that NT is able to protect endocrine beta cells from external cytotoxic agents, a role well correlated with its release in the circulation after a meal.
Assuntos
Apoptose/efeitos dos fármacos , Citoproteção/efeitos dos fármacos , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/efeitos dos fármacos , Neurotensina/farmacologia , Animais , Caspase 3/metabolismo , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Células Secretoras de Insulina/enzimologia , Espaço Intracelular/efeitos dos fármacos , Espaço Intracelular/metabolismo , Camundongos , Ratos , Receptores de Neurotensina/genética , Receptores de Neurotensina/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: The aim of this study is to evaluate the feasibility and efficacy of Transcranial Doppler (TCD) in assessing cerebral perfusion changes in septic patients. METHODS: Using TCD, we measured the mean velocity in the middle cerebral artery (VmMCA, cm/sec) and calculated the pulsatility index (PI), resistance index (RI) and cerebral blood flow index (CBFi = 10*MAP/1.47(PI)) on the first day of patients' admission or on the first day of sepsis development; measurements were repeated on the second day. Sepsis was defined according to standard criteria. RESULTS: Forty-one patients without any known neurologic deficit treated in our 24-bed Critical Care Unit were assessed (Sepsis Group = 20, Control Group = 21). Examination was feasible in 91% of septic and 85% of non-septic patients (p = 0.89). No difference was found between the two groups in mean age, mean arterial pressure (MAP) or APACHE II score. The pCO2 values were higher in septic patients (46 ± 12 vs. 39 ± 4 mmHg p < 0.01). No statistically significant higher values of VmMCA were found in septic patients (110 ± 34 cm/sec vs. 99 ± 28 cm/sec p = 0.17). Higher values of PI and RI were found in septic patients (1.15 ± 0.25 vs. 0.98 ± 0.16 p < 0.01, 0.64 ± 0.08 vs. 0.59 ± 0.06 p < 0.01, respectively). No statistically significant lower values of CBFi were found in septic patients (497 ± 116 vs. 548 ± 110 p = 0.06). CONCLUSIONS: Our results suggest cerebral vasoconstriction in septic compared to non-septic patients. TCD is an efficient and feasible exam to evaluate changes in cerebral perfusion during sepsis.