Effects of ketamine plus fluoxetine on nNOS and CAPON expression in the prefrontal lobe of mentally depressed rats / 中国药理学通报

Aim To investigate the effect of ketamine plus fluoxetine on depressed behavior and the expres-sion of neuronal nitric oxide synthase (nNOS)and CA-PON in prefrontal lobe of mentally depressed rats at different time points,so as to study the possible mecha-nism of ketamine plus fluoxetine inducing antidepres-sant behavior.Methods Healthy adult male Sprague-Dawley rats,aged 2.5 ~3 months,weighing 220 ~270 g,were induced as the rodent model of depression by chronic unpredictable mild stress (CUMS).After the models of depression were established,96 of CUMS modeling successfully depressed rats were selected. Then they were randomly divided into four groups (n =24 each):the depressed group (group D,untreated group),ketamine group (group K,treated with intrap-eritoneal injection of ketamine 1 0 mg·kg -1 once a day for 3 days or 7 days),fluoxetine group (group F,trea-ted with gavage of fluoxetine 1 .8 mg·kg -1 once a day for 3 days or 7 days),or ketamine plus fluoxetine group (group KF,treated with intraperitoneal injection of ketamine 1 0 mg·kg -1 plus gavage of fluoxetine 1 .8 mg·kg -1 once a day for 3 days or 7 days).Open field test and sucrose preference test were performed 1 day before depression model was established,and 1 day before and after treatment.The rats were sacrificed 1 day after the last test for determination of the expres-sion of nNOS and CAPON protein (using immuno-his-tochemisity)and mRNA (by RT-PCR)in the prefron-tal lobe.Results After the models of depression were established,the total distance,rearing number and the sucrose preference percentage (SPP)were decreased significantly compared with those before (P 0.05 ).Compared with groups D and F,the total distance was prolonged,the number of rea-ring and SPP were significantly increased,the expres-sion of nNOS protein and mRNA was down-regulated and the expression of CAPON protein and mRNA was up-regulated in groups K and KF,with 3 days’treat-ment (P <0.05).Compared with group D,the total distance was prolonged,the number of rearing and SPP were significantly increased,the expression of nNOS protein and mRNA was down-regulated and the expres-sion of CAPON protein and mRNA was up-regulated in groups K,F and KF with 7 days’treatment (P <0.05).Compared with group F,the total distance was prolonged,the number of rearing and SPP were signifi-cantly increased,the expression of nNOS protein and mRNA was down-regulated and the expression of CA-PON protein and mRNA was up-regulated in group KF with 7 days’treatment (P <0.05).Conclusion Co-administration of antidepressant fluoxetine with ket-amine may induce a more pronounced antidepressant activity than treatment with each antidepressant alone and it can shorten the time to improve the depressive state through promoting the expression of CAPON and inhibiting nNOS activity in the prefrontal lobe of men-tally depressed rats.

Nasal and Exhaled Nitric Oxide in Allergic Rhinitis

OBJECTIVES: The primary aim of this study was to assess whether one can use levels of nasal nitric oxide (nNO) and exhaled nitric oxide (eNO) as a means of evaluation in allergic rhinitis. METHODS: We used a chemiluminescence analyzer to measure nNO and eNO in normal controls (n=34) and allergic rhinitis patients (n=35), and compared these measurements with various parameters of clinical symptoms and laboratory data. RESULTS: Mean nNO (389+/-119 ppb) in allergic rhinitis patients was significantly higher than normal controls (276+/-88 ppb). Without asthma, mean eNO (64.8+/-55.9 ppb) in allergic rhinitis patients was significantly higher than normal controls (33.0+/-24.0 ppb). In the persistent allergic rhinitis group, eNO concentration was significantly higher, while nNO concentration was significantly lower than the intermittent group. CONCLUSION: We can use nNO and eNO levels for evaluation of allergic rhinitis. However, we should consider the fact that nNO levels can be reduced, when symptoms are severe and long-lasting. Additionally, in allergic rhinitis, eNO can be elevated without asthma.

Expression of Cyclooxygenase-2 and Inducible Nitric Oxide Synthase in Colorectal Cancer

PURPOSE: Recently, it has been recognized that both cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) produce important endogeneous factors of human tumor progression. The aims of this study is to investigate the correlation between the expression of COX-2 and iNOS and to assess the clinicopathological significance of COX-2 and iNOS expression in patients with colorectal cancer. METHODS: One hundred and five patients, who underwent curative resection of colorectal cancer from 1994 to 1997 were analyzed retrospectively. The monoclonal antibody to the COX-2 and iNOS were used for the immunohistochemical analysis. RESULTS: In 105 patients the COX-2 and iNOS positive rate were 86.7% and 69.5% respectively. There was significant correlation between COX-2 and iNOS expression (r= 0.378, P<0.01), that is, the lesions which expressed high level of COX-2 also expressed iNOS highly. The proliferation index (Ki-67 labeling index) was correlated with iNOS (P=0.013), and the microscopic differentiation with COX-2 (P=0.004). However, the expression of COX-2 and iNOS proteins did not correlate with any other clinicopathological parameters including patient survival. CONCLUSIONS: Although the pattern of positive expression was similar in both enzymes, the expression of both enzymes was not related to prognosis in patients with colorectal cancer. But COX-2 and iNOS seems to have a role not only in carcinogenesis but also tumor cells proliferation. To evaluate the exact role of these enzymes, further studies of the apoptosis and cancer metastasis and of links between the cancer related factors of COX-2 and iNOS are warranted.

Hemodynamic Effect of Nitric Oxide Inhalation in the Acute Hypoxic Pulmonary Hypertension Induced Newborn Piglet

Purposes : Nitric oxide (NO) is classified as toxic gas in native states, but in most biologic systems NO acts as a messenger molecule. NO is known as endothelium derived relaxing factor that modulates tone of vascular smooth muscle. Inhaled NO has been reported to act as a selective pulmonary vasodilator and we expect that NO inhalation can be used as a successful treatment modality in the management of persistent pulmonary hypertension of the newborn. We used the newborn piglet to create acute hypoxic pulmonary hypertension and examined the hemodynamic effect of inhlaled NO and dose-response characteristics in different concentrations of NO in this model. The aims of this study were to investigate the feasibility and safety of administering NO to a neonatal model and to get a useful informations about clinical applications of administering NO. METHODS: Nine 2-to 9-d-old piglets with an average weight of 3.1+/-0.86kg were anesthetized, intubated and instrumented in order to measure the hemodynamic variables. NO in nitrogen in a concentration of 800 ppm in 47 liter sylinder was obtained and injected into the inspiratory line of a time-cycled pressure-limited neonatal ventilator after reducing of pressure using 3 staged regulator. Gas mixture in downstream of the injection site was analyzed for NO and NO2 using electrochemical analyzer. Statistical analyses were done using with SAS software ver. 6.04. RESULTS: Baseline hemodynamic parameters in normoxic breathing such as mean systemic arterial pressure, mean pulmonary arterial pressure, systemic vascular resistance, pulmonary vascular resistance and cardiac index were 79+/-18mmHg, 16+/-4mmHg, 0.20+/-0.09mmHg, mL-1, min, kg, 0.04+/-0.02mmHg, mL-1, min, kg, and 399+/-201mL/min/kg respectively. Inhaling 20 and 80 ppm NO during ventilation at FIO2 0.21 did not produce any significant changes in hemodynamic indices. Pulmonary hypertension was induced by reducing the fraction of inspired oxygen to 0.10 to 0.15 and arterial oxygen saturation between 35 and 45%. The hypoxic challenge caused a significant increase in pulmonary arterial pressure, pulmonary vascular resistance and the ratio of pulmonary to systemic vascular resistance of 105% (P<0.001), 92% (P<0.02), 72% (P<0.01) respectively. Systemic arterial pressure increased by 20% (P<0.05), but systemic vascular resistance and cardiac index were not changed significantly. Inhaled NO was then administered in concentrations of 10, 20, 40, 80, and 100 parts per million in random order. All concentrations of NO were associated with a rapid decrease in pulmonary arterial pressure and pulmonary vascular resistance (P<0.02, P<0.001). The ratios of pulmonary to systemic vascular resistance decreased with all levels of inhaled NO (P<0.05). There was no significant difference between the different doses of NO in their effects. There was no significant increase in circulating methemoglobin, and the NO2 levels in the inspiratory limb of ventilator never exceeded 1.5 ppm. Plasma nitrite and nitrate increased in a dose-dependent manner (P<0.05). CONCLUSIONS: In acute hypoxic pulmonary hypertension induced newborn piglets NO inhalation with all the varying concentrations led to reduction of pulmonary arterial pressure promptly and safely without significant increase of methemoglobin and NO2 levels.