Combined aliskiren and L-arginine treatment has antihypertensive effects and prevents vascular endothelial dysfunction in a model of renovascular hypertension

Angiotensin II is a key player in the pathogenesis of renovascular hypertension, a condition associated with endothelial dysfunction. We investigated aliskiren (ALSK) and L-arginine treatment both alone and in combination on blood pressure (BP), and vascular reactivity in aortic rings. Hypertension was induced in 40 male Wistar rats by clipping the left renal artery. Animals were divided into Sham, 2-kidney, 1-clip (2K1C) hypertension, 2K1C+ALSK (ALSK), 2K1C+L-arginine (L-arg), and 2K1C+ALSK+L-arginine (ALSK+L-arg) treatment groups. For 4 weeks, BP was monitored and endothelium-dependent and independent vasoconstriction and relaxation were assessed in aortic rings. ALSK+L-arg reduced BP and the contractile response to phenylephrine and improved acetylcholine relaxation. Endothelium removal and incubation with N-nitro-L-arginine methyl ester (L-NAME) increased the response to phenylephrine in all groups, but the effect was greater in the ALSK+L-arg group. Losartan reduced the contractile response in all groups, apocynin reduced the contractile response in the 2K1C, ALSK and ALSK+L-arg groups, and incubation with superoxide dismutase reduced the phenylephrine response in the 2K1C and ALSK groups. eNOS expression increased in the 2K1C and L-arg groups, and iNOS was increased significantly only in the 2K1C group compared with other groups. AT1 expression increased in the 2K1C compared with the Sham, ALSK and ALSK+L-arg groups, AT2 expression increased in the ALSK+L-arg group compared with the Sham and L-arg groups, and gp91phox decreased in the ALSK+L-arg group compared with the 2K1C and ALSK groups. In conclusion, combined ALSK+L-arg was effective in reducing BP and preventing endothelial dysfunction in aortic rings of 2K1C hypertensive rats. The responsible mechanisms appear to be related to the modulation of the local renin-angiotensin system, which is associated with a reduction in endothelial oxidative stress.

Effects of acute administration of selective serotonin reuptake inhibitors on sympathetic nerve activity

Serotonergic mechanisms have an important function in the central control of circulation. Here, the acute effects of three selective serotonin (5-HT) reuptake inhibitors (SSRIs) on autonomic and cardiorespiratory variables were measured in rats. Although SSRIs require 2-3 weeks to achieve their full antidepressant effects, it has been shown that they cause an immediate inhibition of 5-HT reuptake. Seventy male Wistar rats were anesthetized with urethane and instrumented to record blood pressure, heart rate, renal sympathetic nerve activity (RSNA), and respiratory frequency. At lower doses, the acute cardiovascular effects of fluoxetine, paroxetine and sertraline administered intravenously were insignificant and variable. At middle and higher doses, a general pattern was observed, with significant reductions in sympathetic nerve activity. At 10 min, fluoxetine (3 and 10 mg/kg) reduced RSNA by -33±4.7 and -31±5.4%, respectively, without changes in blood pressure; 3 and 10 mg/kg paroxetine reduced RSNA by -35±5.4 and -31±5.5%, respectively, with an increase in blood pressure +26.3±2.5; 3 mg/kg sertraline reduced RSNA by -59.4±8.6%, without changes in blood pressure. Sympathoinhibition began 5 min after injection and lasted approximately 30 min. For fluoxetine and sertraline, but not paroxetine, there was a reduction in heart rate that was nearly parallel to the sympathoinhibition. The effect of these drugs on the other variables was insignificant. In conclusion, acute peripheral administration of SSRIs caused early autonomic cardiovascular effects, particularly sympathoinhibition, as measured by RSNA. Although a peripheral action cannot be ruled out, such effects are presumably mostly central.

Sertraline inhibits formalin-induced nociception and cardiovascular responses

The objective of the present study was to determine the antihyperalgesic effect of sertraline, measured indirectly by the changes of sciatic afferent nerve activity, and its effects on cardiorespiratory parameters, using the model of formalin-induced inflammatory nociception in anesthetized rats. Serum serotonin (5-HT) levels were measured in order to test their correlation with the analgesic effect. Male Wistar rats (250-300 g) were divided into 4 groups (N = 8/per group): sertraline-treated group (Sert + Saline (Sal) and Sert + Formalin (Form); 3 mg·kg-1·day-1, ip, for 7 days) and saline-treated group (Sal + Sal and Sal + Form). The rats were injected with 5 percent (50 µL) formalin or saline into the right hind paw. Sciatic nerve activity was recorded using a silver electrode connected to a NeuroLog apparatus, and cardiopulmonary parameters (mean arterial pressure, heart rate and respiratory frequency), assessed after arterial cannulation and tracheotomy, were monitored using a Data Acquisition System. Blood samples were collected from the animals and serum 5-HT levels were determined by ELISA. Formalin injection induced the following changes: sciatic afferent nerve activity (+50.8 ± 14.7 percent), mean arterial pressure (+1.4 ± 3 mmHg), heart rate (+13 ± 6.8 bpm), respiratory frequency (+4.6 ± 5 cpm) and serum 5-HT increased to 1162 ± 124.6 ng/mL. Treatment with sertraline significantly reduced all these parameters (respectively: +19.8 ± 6.9 percent, -3.3 ± 2 mmHg, -13.1 ± 10.8 bpm, -9.8 ± 5.7 cpm) and serum 5-HT level dropped to 634 ± 69 ng/mL (P < 0.05). These results suggest that sertraline plays an analgesic role in formalin-induced nociception probably through a serotonergic mechanism.

Efeitos da crioterapia, estimulação elétrica transcutânea e da sua associação na atividade elétrica do nervo femoral em ratos / Effects of cryotherapy, transcutaneous electrical stimulation and their combination on femoral nerve electrical activity in rats

CONTEXTUALIZAÇÃO: Relatos clínicos sugerem que a associação terapêutica entre crioterapia (CRIO) e estimulação elétrica transcutânea (TENS) favorece analgesia local. OBJETIVO: Avaliar a atividade elétrica do nervo femoral (ANF), em repouso e durante a aplicação isolada, e associada de TENS e CRIO em ratos. MÉTODOS: Foram utilizados nove ratos (Wistar) adultos com peso de ±300g. Após anestesia (Uretana, 1mg/g i.p.), o nervo femoral direito foi isolado para registro da ANF basal e durante as modalidades analgésicas. Depois da fixação dos eletrodos no terço inferior da coxa direita, foram aplicadas TENS (50Hz, 10mÅ) por cinco minutos, CRIO isolada e terapia associada (TA) por dez minutos. Os registros contínuos da ANF foram realizados por meio de um amplificador de potenciais de ação, avaliados posteriormente no primeiro, quinto e décimo minuto em unidades arbitrárias (Ua). Utilizaram-se a análise de variância (ANOVA) uma via e o teste de Dunnett como post-hoc. Valores expressos como média ±EPM e as diferenças fixadas em p<0,05. RESULTADOS: A atividade do nervo femoral aumentou (p<0,01) na TENS (0,358±0,09Ua) e na TA (0,230±0,07Ua) e ficou inalterada após CRIO (0,063±0,003Ua), em relação ao basal inicial (0,009±0,0003Ua). No quinto minuto, observou-se uma significante (p<0,05) atenuação da ANF na modalidade TA (0,144±0,027Ua) versus TENS isolada (0,324±0,089Ua). CONCLUSÕES: A associação entre as modalidades analgésicas não-invasivas CRIO e TENS atenua significativamente os efeitos produzidos pela TENS isoladamente sobre a ANF de ratos anestesiados.

BACKGROUND: Clinical reports suggest that the therapeutic association between cryotherapy (CRYO) and transcutaneous electrical stimulation (TENS) favors local analgesia. OBJECTIVE: To evaluate the electrical activity of the femoral nerve (FNA), at rest and during single and combined application of TENS and CRYO, in rats. METHODS: Nine adult Wistar rats weighting ±300g were used in this study. After inducing anesthesia (Urethane, 1mg/g i.p.), the right femoral nerve was isolated in order to record the FNA at baseline and during the therapeutic modalities. After attaching the electrodes to the lower third of the right thigh, TENS (50Hz, 10mÅ) was applied for five minutes, and CRYO and the combined therapy (CT) for ten minutes. The FNA was recorded continuously by means of an action potential amplifier and the recordings from the first, fifth and tenth minutes were subsequently evaluated using arbitrary units (aU). One-way analysis of variance (ANOVA) was used, with Dunnett's test as post-hoc analysis. The values were expressed as the mean ±SEM and differences were established at p<0.05. RESULTS: The femoral nerve activity increased (p<0.01) after TENS (0.358±0.09aU) and CT (0.230±0.07aU) and was unchanged after CRYO (0.063±0.003aU), in relation to the baseline (0.009±0.0003aU). In the fifth minute, we observed significant (p<0.05) attenuation of FNA in the CT (0.144±0.027aU) in relation to TENS alone (0.324±0.089aU). CONCLUSIONS: The association between CRYO and TENS noninvasive analgesia significantly attenuates the effects produced by TENS alone on the FNA of anesthetized rats.