Prevention of hypertension in patients with pre-hypertension: Protocol for the PREVER-prevention trial

Background: Blood pressure (BP) within pre-hypertensive levels confers higher cardiovascular risk and is an intermediate stage for full hypertension, which develops in an annual rate of 7 out of 100 individuals with 40 to 50 years of age. Non-drug interventions to prevent hypertension have had low effectiveness. In individuals with previous cardiovascular disease or diabetes, the use of BP-lowering agents reduces the incidence of major cardiovascular events. In the absence of higher baseline risk, the use of BP agents reduces the incidence of hypertension. The PREVER-prevention trial aims to investigate the efficacy, safety and feasibility of a population-based intervention to prevent the incidence of hypertension and the development of target-organ damage.Methods: This is a randomized, double-blind, placebo-controlled clinical trial, with participants aged 30 to 70 years, with pre-hypertension. The trial arms will be chlorthalidone 12.5 mg plus amiloride 2.5 mg or identical placebo. The primary outcomes will be the incidence of hypertension, adverse events and development or worsening of microalbuminuria and of left ventricular hypertrophy in the EKG. The secondary outcomes will be fatal or non-fatal cardiovascular events: myocardial infarction, stroke, heart failure, evidence of new sub-clinical atherosclerosis, and sudden death. The study will last 18 months. The sample size was calculated on the basis of an incidence of hypertension of 14% in the control group, a size effect of 40%, power of 85% and P alpha of 5%, resulting in 625 participants per group. The project was approved by the Ethics committee of each participating institution.Discussion: The early use of blood pressure-lowering drugs, particularly diuretics, which act on the main mechanism of blood pressure rising with age, may prevent cardiovascular events and the incidence of hypertension in individuals with hypertension. If this intervention shows to be effective and safe in a population-based perspective, it could be the basis for an innovative public health program to prevent hypertension in Brazil.Trial Registration: Clinical Trials NCT00970931. © 2011 Fuchs et al; licensee BioMed Central Ltd.

Participação da via alfa-2 adrenérgica no controle da secreção do hormônio do crescimento no período prépúbere em novilhas da raça Nelore

This study investigated GH secretion after clonidine (alpha-2 adrenergic agonist) treatment in pre-pubertal Nelore heifers. Clonidine (10 mg/kg, IV, 15 min samples for 4 h) was administrated in the same Nelore heifers at eight (n = 4), 12 (n = 5) and 15 (n = 4) months of age. The GH concentration was measured by radioimmunoassay (sensivity = 0.25 ng/mL, CV = 16%). At eight months, clonidine increased GH average concentration, total area of peaks, the total area of GH secretion and increased peak amplitude and reduced time to onset of peak (P < 0.05). At 15 months, the administration of clonidine increased the GH average concentration and at 12 months the increased occurred only in restricted intervals (P < 0.05). Clonidine injection stimulated GH secretion in prepubertal heifers and this effect was more evident in Nelore heifers at eight months compared to 12 and 15 months of age.

Involvement of the atrial natriuretic peptide in cardiovascular pathophysiology and its relationship with exercise

In this minireview we describe the involvement of the atrial natriuretic peptide (ANP) in cardiovascular pathophysiology and exercise. The ANP has a broad homeostatic role and exerts complex effects on the cardio-circulatory hemodynamics, it is produced by the left atrium and has a key role in regulating sodium and water balance in mammals and humans. The dominant stimulus for its release is atrial wall tension, commonly caused by exercise. The ANP is involved in the process of lipolysis through a cGMP signaling pathway and, as a consequence, reducing blood pressure by decreasing the sensitivity of vascular smooth muscle to the action of vasoconstrictors and regulate fluid balance. The increase of this hormone is associated with better survival in patients with chronic heart failure (CHF). This minireview provides new evidence based on recent studies related to the beneficial effects of exercise in patients with cardiovascular disease, focusing on the ANP. © 2012 de Almeida et al; licensee BioMed Central Ltd.

Analgésicos Tópicos

Background and objectives: Pain treatment involves the usage of common and opioid analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs) and adjuvant analgesics. Traditionally, these drugs are administered systemically or into the neuraxis. However, when analgesics are applied through these pathways, they are associated with significant side effects, which can hinder its use. Topical administration of analgesics is an alternative. The objective of this paper is to discuss topical analgesics, the mechanisms of action and clinical efficacy. Content: This is a review paper addressing the usage of the topical local anesthetics: capsaicin, clonidine, tricyclic antidepressants, ketamine, opioids and cannabinoids, discussing mechanism of action and effectiveness. Conclusions: Topical analgesics are promising as a strategy for pain treatment, as they are associated with lower incidence of side effects. The benefit of local anesthetics, NSAID's and capsaicin is well established. However, the efficacy of clonidine, tricyclic antidepressants, ketamine, opioids and cannabinoids is still questionable. Studies have shown that the multimodal approach is an alternative, but studies are needed to confirm this hypothesis. © 2012 Elsevier Editora Ltda.

Causes of resistant hypertension detected by a standardized algorithm

Resistant hypertension (RH) is characterized by blood pressure above 140 × 90 mm Hg, despite the use, in appropriate doses, of three antihypertensive drug classes, including a diuretic, or the need of four classes to control blood pressure. Resistant hypertension patients are under a greater risk of presenting secondary causes of hypertension and may be benefited by therapeutical approach for this diagnosis. However, the RH is currently little studied, and more knowledge of this clinical condition is necessary. In addition, few studies had evaluated this issue in emergent countries. Therefore, we proposed the analysis of specific causes of RH by using a standardized protocol in Brazilian patients diagnosed in a center for the evaluation and treatment of hypertension. The management of these patients was conducted with the application of a preformulated protocol which aimed at the identification of the causes of resistant hypertension in each patient through management standardization. The data obtained suggest that among patients with resistant hypertension there is a higher prevalence of secondary hypertension, than that observed in general hypertensive ones and a higher prevalence of sleep apnea as well. But there are a predominance of obesity, noncompliance with diet, and frequent use of hypertensive drugs. These latter factors are likely approachable at primary level health care, since that detailed anamneses directed to the causes of resistant hypertension are applied. © 2012 Livia Beatriz Santos Limonta et al.

Activation of central aα-adrenoceptors mediates salivary gland vasoconstriction

Objective: Peripheral treatment with the cholinergic agonist pilocarpine increases salivary gland blood flow and induces intense salivation that is reduced by the central injection of moxonidine (aα-adrenoceptors/ imidazoline agonist). In the present study, we investigated the effects of the intracerebroventricular (i.c.v.) injection of pilocarpine alone or combined with moxonidine also injected i.c.v. On submandibular/sublingual gland (SSG) vascular resistance. In addition, the effects of these treatments on arterial pressure, heart rate and on mesenteric and hindlimb vascular resistance were also tested. Design: Male Holtzman rats with stainless steel cannula implanted into lateral ventricle and anaesthetized with urethane + α-chloralose were used. Results: Pilocarpine (500 nmol/1 μl) injected i.c.v. Reduced SSG vascular resistance and increased arterial pressure, heart rate and mesenteric vascular resistance. Contrary to pilocarpine alone, the combination of moxonidine (20 nmol/1 μl) and pilocarpine injected i.c.v. Increased SSG vascular resistance, an effect abolished by the pre-treatment with the α2-adrenoceptor antagonist yohimbine (320 nmol/2 μl). The increase in arterial pressure, heart rate and mesenteric resistance was not modified by the combination of moxonidine and pilocarpine i.c.v. Conclusion: These results suggest that the activation of central α2- adrenoceptors may oppose to the effects of central cholinergic receptor activation in the SSG vascular resistance. © 2012 Elsevier Ltd. All rights reserved.

Ethopharmacological evaluation of the rat exposure test: A prey-predator interaction test

The rat exposure test (RET) is a prey (mouse)-predator (rat) situation that activates brain defensive areas and elicits hormonal and defensive behavior in the mouse. Here, we investigated possible correlations between the spatiotemporal [time spent in protected (home chamber and tunnel) and unprotected (surface) compartments and frequency of entries into the three compartments] and ethological [e.g., duration of protected and unprotected stretched-attend postures (SAP), duration of contact with the rat's compartment] measures (Experiment 1). Secondly, we investigated the effects of systemic treatment with pro- or anti-aversive drugs on the behavior that emerged from the factor analysis (Experiment 2). The effects of chronic (21 days) imipramine and fluoxetine on defensive behavior were also investigated (Experiment 3). Exp. 1 revealed that the time in the protected compartment, protected SAP and rat contacts loaded on factor 1 (defensive behavior), while the total entries and unprotected SAP loaded on factor 2 (locomotor activity). Exp. 2 showed that alprazolam (but not diazepam) selectively changed the defensive factor. Caffeine produced a mild proaversive-like effect, whereas yohimbine only decreased locomotor activity (total entries). Fluoxetine (but not imipramine) produced a weak proaversive-like effect. 5-HT1A/5-HT2 receptor ligands did not change any behavioral measure. In Exp. 3, chronic fluoxetine (but not imipramine) attenuated the defensive behavior factor without changing locomotion. Given that the defensive factor was sensitive to drugs known to attenuate (alprazolam and chronic fluoxetine) and induce (caffeine) panic attack, we suggest the RET as a useful test to assess the effects of panicolytic and panicogenic drugs. © 2012 Elsevier B.V.

Differential phosphorylation, desensitization, and internalization of α1A-adrenoceptors activated by norepinephrine and oxymetazoline

Loss of response on repetitive drug exposure (i.e., tachyphylaxis) is a particular problem for the vasoconstrictor effects of medications containing oxymetazoline (OXY), an α1-adrenoceptor (AR) agonist of the imidazoline class. One cause of tachyphylaxis is receptor desensitization, usually accompanied by phosphorylation and internalization. It is well established that a1A-ARs are less phosphorylated, desensitized, and internalized on exposure to the phenethylamines norepinephrine (NE), epinephrine, or phenylephrine (PE) than are the a1B and a1D subtypes. However, here we show in human embryonic kidney-293 cells that the low-efficacy agonist OXY induces G protein-coupled receptor kinase 2-dependent a1A-AR phosphorylation, followed by rapid desensitization and internalization (∼40% internalization after 5 minutes of stimulation), whereas phosphorylation of α1A-ARs exposed to NE depends to a large extent on protein kinase C activity and is not followed by desensitization, and the receptors undergo delayed internalization (∼35% after 60 minutes of stimulation). Native α1A-ARs from rat tail artery and vas deferens are also desensitized by OXY, but not by NE or PE, indicating that thisproperty of OXY is not limited to recombinant receptors expressed in cell systems. The results of the present study are clearly indicative of agonist-directed a1A-AR regulation. OXY shows functional selectivity relative to NE and PE at a1A-ARs, leading to significant receptor desensitization and internalization, which is important in view of the therapeutic vasoconstrictor effects of this drug and the varied biologic process regulated by α1A-ARs. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.

Role of brain nitric oxide in the cardiovascular control of bullfrogs

The goal of the present study was to determine if nitric oxide (NO) acting on the brain of bullfrog (Lithobates catesbeianus) is involved in arterial pressure and heart rate (HR) control by influencing sympathetic activity. We investigated the effect of intracerebroventricular injections of l-NMMA (a nonselective NO synthase inhibitor) on mean arterial blood pressure (MAP), HR and cutaneous vascular conductance (CVC) of pelvic skin after intravenous injection of α or β adrenergic blockers, prazosin or sotalol, respectively. Arterial pressure was directly measured by a telemetry sensor inserted in the aortic arch of animals. l-NMMA increased MAP, but did not change HR. This hypertensive response was inhibited by the pre-treatment with prazosin, but accentuated by sotalol. The effect of l-NMMA on MAP was also inhibited by i.v. injections of the ganglionic blocker, hexamethonium. Thus, NO acting on the brain of bullfrog seems to present a hypotensive effect influencing the sympathetic activity dependent on α and β adrenergic receptors in the periphery. © 2013 Elsevier Inc.

Noradrenergic neurotransmission within the bed nucleus of the stria terminalis modulates the retention of immobility in the rat forced swimming test

The bed nucleus of the stria terminalis (BNST) is a limbic structure that has a direct influence on the autonomic, neuroendocrine, and behavioral responses to stress. It was recently reported that reversible inactivation of synaptic transmission within this structure causes antidepressant-like effects, indicating that activation of the BNST during stressful situations would facilitate the development of behavioral changes related to the neurobiology of depression. Moreover, noradrenergic neurotransmission is abundant in the BNST and has an important role in the regulation of emotional processes related to the stress response. Thus, this study aimed to test the hypothesis that activation of adrenoceptors within the BNST facilitates the development of behavioral consequences of stress. To investigate this hypothesis, male Wistar rats were stressed (forced swimming, 15 min) and 24 h later received intra-BNST injections of vehicle, WB4101, RX821002, CGP20712, or ICI118,551, which are selective α1, α2, β1, and β2 adrenoceptor antagonists, respectively, 10 min before a 5-min forced swimming test. It was observed that administration of WB4101 (10 and 15 nmol), CGP20712 (5 and 10 nmol), or ICI118,551 (5 nmol) into the BNST reduced the immobility time of rats subjected to forced swimming test, indicating an antidepressant-like effect. These findings suggest that activation of α1, β1, and β2 adrenoceptors in the BNST could be involved in the development of the behavioral consequences of stress. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Slimmer or Fertile? Pharmacological Mechanisms Involved in Reduced Sperm Quality and Fertility in Rats Exposed to the Anorexigen Sibutramine

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

A role for histamine in cardiovascular regulation in late stage embryos of the red-footed tortoise, Chelonoidis carbonaria Spix, 1824

A chorioallantoic membrane artery in embryos of the red-footed tortoise, Chelonoidis carbonaria was occlusively cannulated for measurement of blood pressure and injection of drugs. Two age groups of embryos in the final 10 % of incubation were categorized by the ratio of embryonic body to yolk mass. All embryos first received cholinergic and β-adrenergic blockade. This revealed that β-adrenergic control was established in both groups whereas cholinergic control was only established in the older group immediately prior to hatching. The study then progressed as two series. Series one was conducted in a subset of embryos treated with histamine before or after injection of ranitidine, the antagonist of H2 receptors. Injection of histamine caused an initial phasic hypertension which recovered, followed by a longer lasting hypertensive response accompanied by a tachycardia. Injection of the H2 receptor antagonist ranitidine itself caused a hypotensive tachycardia with subsequent recovery of heart rate. Ranitidine also abolished the cardiac effects of histamine injection while leaving the initial hypertensive response intact. In series, two embryos were injected with histamine after injection of diphenhydramine, the antagonist to H1 receptors. This abolished the whole of the pressor response to histamine injection but left the tachycardic response intact. These data indicate that histamine acts as a non-adrenergic, non-cholinergic factor, regulating the cardiovascular system of developing reptilian embryos and that its overall effects are mediated via both H1 and H2 receptor types. © 2013 Springer-Verlag Berlin Heidelberg.

Glucose homoeostasis in rats exposed to acute intermittent hypoxia

Aim: Chronic exposure to intermittent hypoxia commonly induces the activation of sympathetic tonus and the disruption of glucose homoeostasis. However, the effects of exposure to acute intermittent hypoxia (AIH) on glucose homoeostasis are not yet fully elucidated. Herein, we evaluated parameters related to glucose metabolism in rats exposed to AIH. Methods: Male adult rats were submitted to 10 episodes of hypoxia (6% O2, for 45 s) interspersed with 5-min intervals of normoxia (21%), while the control (CTL) group was kept in normoxia. Results: Acute intermittent hypoxia rats presented higher fasting glycaemia, normal insulinaemia, increased lactataemia and similar serum lipid levels, compared to controls (n = 10, P < 0.05). Additionally, AIH rats exhibited increased glucose tolerance (GT) (n = 10, P < 0.05) and augmented insulin sensitivity (IS) (n = 10, P < 0.05). The p-Akt/Akt protein ratio was increased in the muscle, but not in the liver and adipose tissue of AIH rats (n = 6, P < 0.05). The elevated glycaemia in AIH rats was associated with a reduction in the hepatic glycogen content (n = 10, P < 0.05). Moreover, the AIH-induced increase in blood glucose concentration, as well as reduced hepatic glycogen content, was prevented by prior systemic administration of the β-adrenergic antagonist (P < 0.05). The effects of AIH on glycaemia and Akt phosphorylation were transient and not observed after 60 min. Conclusions: We suggest that AIH induces an increase in blood glucose concentration as a result of hepatic glycogenolysis recruitment through sympathetic activation. The augmentation of GT and IS might be attributed, at least in part, to increased β-adrenergic sympathetic stimulation and Akt protein activation in skeletal muscles, leading to a higher glucose availability and utilization. © 2013 Scandinavian Physiological Society.

Cross-talk with β2-adrenoceptors enhances ligand affinity properties from endothelial alpha1D-adrenoceptors that mediates carotid relaxation

Objectives Our main objectives were to investigate the affinity properties of endothelial and muscular α1D-adrenoceptors and to characterize the cross-talk between endothelial α1D- adrenoceptors and β2-adrenoceptors in rat carotid. Methods Relaxation and contraction concentration-response curves for phenylephrine (α1-adrenergic agonist) were obtained in carotid rings in absence or presence of increasing concentrations of BMY7378 (α 1D-adrenergic antagonist), combined or not with increasing concentration of ICI-118,551 (β2-adrenergic antagonist). Schild analysis was used to estimate the affinity constant from pA2 values of BMY7378. Key Findings BMY7378 produced an unsurmountable antagonism on phenylephrine-induced relaxation but a surmountable antagonism on phenylephrine-induced contraction. BMY7378 potency was higher in inhibiting the relaxation than the contraction induced by phenylephrine because the rightward shifts induced by BMY7378 were greater in the relaxation. The apparent pA 2 value for BMY7378 in phenylephrine-induced relaxation was greater than in contraction. When combined with ICI-118,551, BMY7378 yielded a surmountable antagonism on phenylephrine-induced relaxation and presented a pA2 value similar to that obtained in phenylephrine-induced contraction. Conclusions Endothelial α1D-adrenoceptors, which mediates rat carotid relaxation, present high ligand affinity because of the cross-talk with β2-adrenoceptors, which explains the higher potency of phenylephrine in inducing relaxation than contraction and the atypical unsurmountable antagonism produced by BMY7378 on phenylephrine-induced relaxation. © 2013 Royal Pharmaceutical Society.

Stress susceptibility in pigs supplemented with ractopamine

Ractopamine is a β-adrenergic agonist used as an energy repartitioning agent in the diets of finishing pigs. Most ractopamine studies are limited to evaluations of growth performance and meat quality, and there is little information on the effects of this additive on the behavior and welfare of pigs. Therefore, the objective of this study was to evaluate various indicators of stress caused by feeding diets containing ractopamine. One hundred seventy barrows and 170 gilts weighing 107.3 kg were allocated to 30 pens with 10 to 12 barrows or gilts per pen. Pigs were offered 1 of the 3 dietary treatments (0, 5, or 10 mg ractopamine/kg) for 28 d with 5 barrow pens and 5 gilt pens per treatment. Pigs were evaluated for behavior 3 d per week 1 wk before the initiation of the experiment and throughout the experiment. Each pig was classified into 1 of the 13 activities (drinking water, lying alone, lying in clusters, standing, nosing pig, sitting, feeding, biting pig, walking, exploring, running away, playing, and mounting pen mates) and also grouped into 1 of the 3 categories (calm, moving, and feeding themselves) based on those activities. At the end of the experiment, 3 pigs from each pen were slaughtered, and blood samples were collected during exsanguination to determine physiological indicators of stress (cortisol, lactate, and creatine-kinase enzymes). The incidence of skin and carcass lesions was determined at shoulder, loin, and ham. Ractopamine had no effect (P > 0.05) on pig behavior, total number of skin and carcass lesions, or blood concentrations of cortisol or lactate. However, there was an increase (P < 0.05) of creatine kinase concentrations in pigs receiving ractopaminesupplemented feed. This finding is consistent with the concept that ractopamine may cause muscular disorders, and this warrants further investigation. © 2013 American Society of Animal Science. All rights reserved.