Espironolactona ou clonidina como quarto fármaco na hipertensão resistente? / Spironolactone or clonidine as the fourth drug to treat resistant hypertension?

A hipertensão arterial resistente (HAR) é definida como a ausência de controle pressórico nas medidas de pressão arterial (PA) de consultório a despeito do uso de três ou mais anti-hipertensivos em doses adequadas, incluindo-se preferencialmente um diurético, ou o controle pressórico atingido às custas do uso de quatro ou mais medicamentos. O uso de espironolactona, um antagonista dos receptores de aldosterona, como quarto fármaco no tratamento da HAR é indicado pelas principais diretrizes sobre o assunto, e tem a sua eficácia comprovada em ensaios clínicos e meta análises. Um estudo comparou o uso de clonidina, um agonista adrenérgico alfa-2, como quarto fármaco para tratamento da HAR em comparação com a espironolactona. Embora o desfecho primário (taxa de controle da PA no consultório ou na medida ambulatorial da PA) tenha sido similar com as duas medicações, a espironolactona mostrou maior redução na PA de 24h quando comparada à clonidina. Neste contexto, a clonidina pode ser uma alternativa à espironolactona, particularmente em grupos específicos de pacientes que tenham contraindicação ao uso de espironolactona, como os que apresentam hipercalemia ou doença renal crônica pré dialítica.

Resistant Hypertension (RH) is defined as the absence of blood pressure (BP) control despite the use of three antihypertensive drugs in adequate doses, or the achievement of BP control with the use of four or more medications. The use of spironolactone, an antagonist of aldosterone receptors, as the fourth medication in the treatment of RH is recommended by current Management of Hypertension Guidelines, and its efficacy has been proved in clinical trials and meta-analysis. One clinical trial compared the use of clonidine, an adrenergic alpha-2 agonist, versus spironolactone as an option as the fourth drug in the treatment of RH. The results showed similar rates of the primary outcome (BP control at the office and at ambulatory monitoring) with both drugs, although spironolactone promoted greater reduction in 24h BP when compared with clonidine. In this context, clonidine can be used as an alternative to spironolactone, particularly among specific groups of patients that have contraindications to the use of spironolactone, such as patients with hyperkalemia or end stage renal disease.

Opposing roles of CB1 and CB2 cannabinoid receptors in the stimulant and rewarding effects of cocaine.

BACKGROUND AND PURPOSE: The endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) bind to CB1 and CB2 cannabinoid receptors in the brain and modulate the mesolimbic dopaminergic pathway. This neurocircuitry is engaged by psychostimulant drugs, including cocaine. Although CB1 receptor antagonism and CB2 receptor activation are known to inhibit certain effects of cocaine, they have been investigated separately. Here, we tested the hypothesis that there is a reciprocal interaction between CB1 receptor blockade and CB2 receptor activation in modulating behavioural responses to cocaine. EXPERIMENTAL APPROACH: Male Swiss mice received i.p. injections of cannabinoid-related drugs followed by cocaine, and were then tested for cocaine-induced hyperlocomotion, c-Fos expression in the nucleus accumbens and conditioned place preference. Levels of endocannabinoids after cocaine injections were also analysed. KEY RESULTS: The CB1 receptor antagonist, rimonabant, and the CB2 receptor agonist, JWH133, prevented cocaine-induced hyperlocomotion. The same results were obtained by combining sub-effective doses of both compounds. The CB2 receptor antagonist, AM630, reversed the inhibitory effects of rimonabant in cocaine-induced hyperlocomotion and c-Fos expression in the nucleus accumbens. Selective inhibitors of anandamide and 2-AG hydrolysis (URB597 and JZL184, respectively) failed to modify this response. However, JZL184 prevented cocaine-induced hyperlocomotion when given after a sub-effective dose of rimonabant. Cocaine did not change brain endocannabinoid levels. Finally, CB2 receptor blockade reversed the inhibitory effect of rimonabant in the acquisition of cocaine-induced conditioned place preference. CONCLUSION AND IMPLICATIONS: The present data support the hypothesis that CB1 and CB2 receptors work in concert with opposing functions to modulate certain addiction-related effects of cocaine. LINKED ARTICLES: This article is part of a themed section on 8th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc.

Carbohydrate-enriched diet predispose to anxiety and depression-like behavior after stress in mice.

OBJECTIVES: Obesity is a chronic disease frequently associated with serious co-morbidities, such as diabetes type II, metabolic syndrome, and psychiatric disorders. Little is known, however, regarding the behavioral consequences of modified diet constituents and the propensity to development of stress related disorders. Thus, the aim of this study was to verify whether chronic exposure to a normocaloric/high-carbohydrate diet will modify the animal's behavior after different stressful stimuli. METHODS: BALB/c mice were fed for 12 weeks with a standard chow diet or high refined carbohydrate-containing diet (HC). Following this period, independent groups of animals were exposed to different stress paradigms: 1 - two hours of restraint stress followed by exposure to the Elevated Plus Maze test (EPM) 24 hours later; 2 - The contextual fear conditioning (CFC) test and 3 - the tail suspension test (TST). RESULTS: Despite no change on total body weight, animals fed with HC diet showed increase in serum leptin levels and higher adiposity compared to diet control group. In behavioral tests, animals from HC diet group displayed reduction in the percentage of entries into the open arms of the EPM, evaluated 24 hours after restraint stress, suggesting an anxiogenic-like effect. It is also observed increase in aversive memory in the CFC test and depressive-like behavior in TST. DISCUSSION: Our results suggest that a moderate obesity, induced by high refined carbohydrate diet, may facilitate the development of anxiety and depressive-like behaviors after the stress. The mechanisms responsible for such effects remain to be elucidated.