Dietary L-tryptophan modulates agonistic behavior and brain serotonin in male dyadic contests of a cichlid fish.

Although some studies have investigated the effects of dietary L-tryptophan on agonistic behavior, research on adult fish specimens is still lacking. Moreover, submissive behaviors have been generally overlooked. We focused on agonistic behavior between males of the cichlid fish Cichlasoma dimerus, in dyadic encounters held in a novel context after being fed or not with an L-tryptophan enriched diet (TRP) for 2 weeks. We arranged three different dyads: control/control (control conditions: not TRP enriched), control/TRP, and TRP/TRP. We also registered the response of the brain serotonergic system in four brain regions. TRP/TRP dyads showed higher latencies to first attack, lower overall aggression, and lower proportions of bites and passive copings (submissive display) compared to control/control. TRP dominant males performed fewer bites with respect to controls, and subordinate males opposed to TRP males showed fewer passive copings. Higher serotonergic activities were found in subordinates' optic tectum and in the telencephalon and preoptic area/hypothalamus of TRP males. Altogether, results point out that dietary L-tryptophan reduced males' motivation to attack and dominant aggression, which consequently influenced subordinate agonistic repertory. In addition, males within TRP/TRP dyads showed a switch in their behavioral agonistic repertory. These behavioral outcomes were probably due to modifications at brain serotonergic functioning.

[Stability of prostaglandin E1 when fractioned into polypropylene syringes]. / Estabilidad de prostaglandina E1 fraccionada en jeringas de polipropileno.

UNLABELLED: Prostaglandin E1 is indicated for the temporary maintenance of patent ductus arteriosus in newborns with ductus-dependent congenital heart defects. Since the standard daily dose is smaller (0.2-0.4 ml) than one ampoule (1 ml), we performed a chemical stability study of prostaglandin E1 when it is fractioned into polypropylene syringes. Three concentrations were studied: 500 mg/ml (original), and 1:2 and 1:4 dilutions in sodium chloride 0.9%. Syringes were kept at 4 degrees C for 30 days. Prostaglandin E1 levels were determined by using high-pressure chromatography. In all three formulations, the concentrations underwent no statistically significant changes over time (p>0.05). CONCLUSION: PGE1 is chemically stable at 4 degrees C for 30 days when fractioned into polypropylene syringes, both in the original and the 1:2 and 1:4 diluted formulations.

Tempol-nebivolol therapy potentiates hypotensive effect increasing NO bioavailability and signaling pathway.

Nebivolol is a third generation beta blocker with endothelial nitric oxide synthase (eNOS) agonist properties. Considering the role of reactive oxygen species (ROS) in the uncoupling of eNOS, we hypothesized that the preadministration of an antioxidant as tempol, could improve the hypotensive response of nebivolol in normotensive animals increasing the nitric oxide (NO) bioavailability by a reduction of superoxide (O2(•-)) basal level production in the vascular tissue. Male Sprague Dawley rats were given tap water to drink (control group) or tempol (an antioxidant scavenger of superoxide) for 1 week. After 1 week, Nebivolol, at a dose of 3 mg/kg, was injected intravenously to the control group or to the tempol-treated group. Mean arterial pressure, heart rate, and blood pressure variability were evaluated in the control, tempol, nebivolol, and tempol nebivolol groups, as well as, the effect of different inhibitor as Nß-nitro-l-arginine methyl ester (L-NAME, a Nitric oxide synthase blocker) or glybenclamide, a KATP channel inhibitor. Also, the expression of α,ß soluble guanylate cyclase (sGC), phospho-eNOS, and phospho-vasodilator-stimulated phosphoprotein (P-VASP) were evaluated by Western Blot and cyclic guanosine monophosphate (cGMP) levels by an enzyme-linked immunosorbent assay (ELISA) commercial kit assay. We showed that pretreatment with tempol in normotensive rats produces a hypotensive response after nebivolol administration through an increase in the NO bioavailability and sGC, improving the NO/cGMP/protein kinase G (PKG) pathway compared to that of the nebivolol group. We demonstrated that tempol preadministration beneficiates the response of a third-generation beta blocker with eNOS stimulation properties, decreasing the basal uncoupling of eNOS, and improving NO bioavailability. Our results clearly open a possible new strategy therapeutic for treating hypertension.

Central insulin-angiotensin II interaction in blood pressure regulation in fructose overloaded rats.

The aim of the present study was to determine if insulin is able to modulate the pressor response to intracerebroventricularly administered angiotensin II in insulin resistant fructose overloaded rats. Male Sprague-Dawley rats were divided into two groups: 1) Control group (C) with tap water to drink for 6 weeks (n=36); and 2) fructose treated (F), with fructose solution (10% w/v) to drink for 6 weeks (n=36). On the day of the experiment, anesthetized male C and F rats were intracerebroventricularly infused with insulin (12 mU/h, n=15) or Ringer's solution as vehicle (n=15) for 2h. Immediately, changes in mean arterial pressure (MAP) in response to an intracerebroventricular subpressor dose of angiotensin II (5 pmol, n=10) or vehicle (n=5) were measured for 10 min. Then, hypothalami were removed and Akt and ERK1/2 phosphorylation levels were determined. In a subset of C (n=10) and F (n=20) animals, PD98059 (p44/42 MAPK inhibitor) or vehicle was administered intracerebroventricularly at a flow rate of 5 µl/min for 1 min. Ten minutes later, insulin (12 mU/h, n=5 for each group) or vehicle (Ringer's solution, only in the F group, n=5) was perfused for 2h at a flow rate of 4 µl/h, and cardiovascular parameters were measured every 15 min. Immediately, changes in MAP and HR in response to a subpressor dose of Ang II (5 pmol/2 µl) were evaluated for 10 min (n=5 for each group). In other subset of animals (n=6 for each group), AT1 and AT2 hypothalamic receptor levels were measured by Western blotting. Intracerebroventricular insulin pre-treatment increased the pressor response to angiotensin II in C rats. In F rats (with or without insulin pretreatment), the pressor response to angiotensin II was higher than that in vehicle pre-treated C animals, but similar to that observed in C after insulin infusion. In C rats phospho-ERK 1/2 hypothalamic levels significantly increased after angiotensin II injection in insulin pretreated animals compared to vehicle pre-treated rats, suggesting that MAPK activation might be involved in insulin potentiation of blood pressure response to angiotensin II in the brain. Phospho-ERK 1/2 hypothalamic levels were significantly increased in vehicle treated F rats compared to C, suggesting that basal MAPK activation might play a role in the enhanced response to angiotensin II observed in these animals. Finally, in F rats, either after vehicle or insulin infusion, angiotensin II injection was associated with a similar increase in phospho-ERK 1/2 hypothalamic levels, comparable to that observed after angiotensin II injection in insulin pre-treated C animals. ERK 1/2 blockade significantly reduced MAP in F rats compared to C. Moreover, ERK 1/2 inhibition completely abolished the Ang II pressor response in F rats and in insulin pre-treated C animals. All these findings suggest that insulin-angiotensin II interaction at hypothalamic level might be involved in the increase in blood pressure observed in the insulin resistant state.

Study of the evolution of blood and striatal levels of methyldopa: a microdialysis study in sinaortic denervated rats.

Pharmacokinetic of methyldopa (50 mg kg(-1)i.p.) was studied in anesthetized sham operated and sinoaortic denervated (SAD) rats by using the microdialysis technique. Vascular shunt probe was inserted into the carotid artery and concentric probe was placed in the striatum. Levels of methyldopa were measured by HPLC-EC. The number of animals in each group was six and normal distribution of the variables of the study was assumed. Peak concentrations in arterial blood of methyldopa were similar in both groups of rats but the elimination rate constant was 0.31+/-0.09 h(-1)for sham rats (n =6) and 1.28+/-0.31 h(-1)for SAD rats (n =6, P<0.05). Low levels of methyldopa and a more pronounced decrease were seen in striatum of sinoaortic denervated rats. In conclusion, by using a microdialysis technique, different kinetic profiles of methyldopa were observed in sham operated and sinoaortic denervated rats.

Pharmacokinetic study of methyldopa in aorta-coarctated rats using a microdialysis technique.

The pharmacokinetics of methyldopa (12.5, 25 and 50 mg kg(-1), i.p.) was studied in anesthetized sham-operated (SO) and abdominal aorta-coarctated (ACo) rats using a microdialysis technique. A non-linear relationship between the area under the curve (AUC) and dose was observed in SO rats. However, in ACo rats the AUC showed a proportional increase with dose. Abdominal aortic coarctation produced significant differences in the estimates of clearance (Cl) and the elimination rate constant from the dialysate (K(ed)) after the administration of 50 mg kg(-1)of methyldopa (K(ed)SO, 0.31 +/- 0.09; ACo, 0.66 +/- 0.09(*)h(-1): Cl SO, 30.8 +/- 10.1; ACo, 78.6 +/- 13.3(*)mlkg(-1)min(-1);n= 6,(*)P< 0.05 vs SO). In conclusion, this study, by using a microdialysis technique, suggests that abdominal aortic coarctation seems to produce changes in the pharmacokinetics of methyldopa in rats.

Pharmacokinetic and pharmacodynamic alterations of methyldopa in rats with aortic coarctation. A study using microdialysis.

A pharmacokinetic-pharmacodynamic study of methyldopa (MD) was made in anesthetized sham operated (SO) and aortic coarctated (ACo) rats by using a vascular shunt probe for arterial microdialysis and simultaneous blood pressure recording. Anesthetized Wistar rats were used 7 days after aortic coarctation or sham operation. A vascular shunt probe was inserted into the carotid artery and a concentric probe was placed into the striatum or posterior hypothalamus. MD and 3,4-dihydroxyphenylacetic acid (DOPAC) were determined in the dialysates by HPLC-EC. MD (50 mg kg(-1)i.p.) induced an increase of heart rate in SO (Delta HR: 108 +/- 22 bpm, n= 6) and in ACo rats (Delta HR: 55 +/- 10 bpm, n= 6, P< 0.05, one way ANOVA). Moreover, MD also reduced the mean arterial pressure (MAP) of SO rats (Delta MAP: -10 +/- 4 mmHg, n= 6) and ACo animals (Delta MAP: -51 +/- 9 mmHg, n= 6, P< 0.05, one way ANOVA). Analysis of the arterial blood dialysates showed a lower half-life of MD in ACo rats (t(1/2): 1.5 +/- 0.3 h, n= 6, P< 0.05, 't' test) than in SO rats (t(1/2): 3.7 +/- 1.0 h, n= 6). A low accumulation and a fast decay of striatal MD levels were seen in ACo rats. However, peak levels of drug were greater in the hypothalamic dialysates of ACo rats than in SO animals samples. On the other hand, MD also induced an increase of DOPAC levels in the hypothalamic dialysates of ACo rats. In conclusion, the aortic coarctation modifies the pharmacokinetic and cardiovascular effect of MD in the rat. The action of this drug on dopaminergic neurotransmission is also altered in the ACo animals.

Monitoreo terapéutico de indinavir en niños con infección HIV / Therapeutic monitoring of indinavir in children with HIV infection

El objetivo de este trabajo es realizar una evaluación de los resultados del monitoreo terapéutico (MT) de las concentraciones plasmáticas (Cp) de Indinavir, realizados durante la práctica clínica, en pacientes pediátricos que reciben TARV en esquemas que contienen Indinavir más Ritonavir. Métodos: fueron incluidos 13 pacientes en seguimiento ambulatorio en el Hospital de Pediatría Juan P. Garrahan, a los que se le realizaron dos determinaciones de Cp de Indinavir. Un valle y un pico (una hora posterior a la dosis). La dosis estimada que reciben los pacientes de 250 mg/m2/ 12 Hs. Resultados: ocho de los trece pacientes presentaron niveles subterapéuticos, de los cuales dos tuvieron niveles no detectables (mediana: o,73 ug/ml). El rango terapéutico propuesto por el Indinavir está entre 0,150 y 10 ug/mL. aunque estos valores fueron difinidos para la población adulta. Uno de los pacientes presentó niveles superiores a dicho rango (14,6 ug/ml). Conclusión: trabajos previos sugieren un régimen de 400 mg/m2 Indinavir más 125 mg/m2 Ritonavir cada 12 horas. Debido a que datos previos de pacientes de nuestro hospital habían mostrado que pautas similares podían resultar en niveles plasmáticos elevados asociados a manifestaciones tóxicas, la pauta inicial utilizada fue de 250 mg/m2 Indinavir más 100 mg/m2 Ritonavir cada doce horas. El MT de Indinavir mostró sin embargo que la administración de esta pauta resultó en niveles subterapéuticos. Aun cuando el Indinavir se asocia al Ritonavir la alta variabilidad observada en los niveles plasmáticos de Indinavir sugieren la necesidad de monitorizarlo.