Endothelial expression of the receptor for advanced glycation end products in experimental diabetes / Expresión endotelial del receptor para productos finales de glicación avanzada en diabetes experimental

The receptor for advanced glycation end products (RAGE) is implicated in the pathogenesis of several chronic diseases including diabetes. The interaction between RAGE and advanced glycation end products (AGEs) promotes gene expression, enhances the release of proinflammatory molecules and causes the generation of oxidative stress in numerous cell types. The aim of this investigation was to evaluate the effect of enalapril and losartan on RAGE expression in abdominal aortic endothelium of rats with experimentally induced diabetes. Male Sprague-Dawley rats, weighing approximately 150 - 200 g, were used. Diabetes was induced in 30 rats by intravenous administration of a single dose of 55 mg/kg body weight of streptozotocin (ETZ). The following groups were studied: control (n=10), diabetic (n=10), losartan-treated diabetic (n=10) and enalapril-treated diabetic (n=10) rats. RAGE expression in aortic endothelium was determined by indirect immunofluorescence. A significant increase in RAGE expression was observed in diabetic animals versus controls (p<0.001), there was a decrease in RAGE expression, in animals treated with losartan versus controls (p<0.01) and in those treated with enalapril (p<0.05) versus control and versus diabetes + vehicle. In conclusion, in the experimental model of ETZ-induced diabetes, there is an increase in RAGE expression at the level of the abdominal aortic endothelium, which can be reversed by treatment with losartan and/or enalapril, two drugs that block the renin-angiotensin system, suggesting its involvement in the molecular events related to vascular damage during diabetes.

El receptor para productos finales de glicación avanzada (RAGE) está implicado en la patogénesis de varias enfermedades crónicas incluyendo la diabetes. La interacción entre RAGE y los productos finales de glicación avanzada (AGEs), promueve la expresión génica, potencia la liberación de moléculas proinflamatorias y provoca la generación de estrés oxidativo en numerosos tipos de células. El objetivo de esta investigación fue evaluar el efecto del enalapril y el losartán sobre la expresión de RAGE en el endotelio de la aorta abdominal de ratas con diabetes inducida experimentalmente. Se utilizaron ratas Sprague-Dawley machos, con un peso aproximado de entre 150 - 200 g. La diabetes se indujo en 30 ratas mediante la administración intravenosa de una sola dosis de 55 mg/Kg de peso corporal de estreptozotocina (ETZ). Se estudiaron los siguientes grupos: ratas control (n=10), diabéticas (n=10), diabéticas tratadas con losartán (n=10) y diabéticas tratadas con enalapril (n=10). La expresión de RAGE en el endotelio aórtico se determinó por inmunofluorescencia indirecta. Se observó un incremento significativo en la expresión de RAGE en los animales diabéticos versus los controles (p<0.001), hubo una disminución en la expresión de RAGE, en los animales tratados con losartán versus los controles (p<0.01) y en los tratados con enalapril (p<0.05) versus control y versus diabetes + vehículo. En conclusión, en el modelo experimental de diabetes inducida por ETZ, existe un incremento en la expresión de RAGE a nivel del endotelio de la aorta abdominal, la cual puede revertirse mediante el tratamiento con losartán y/o enalapril, dos fármacos bloqueadores del sistema renina-angiotensina, lo cual sugiere la participación del mismo en los acontecimientos moleculares relacionados con el daño vascular durante la diabetes.

Improved histoarchitectural changes with angiotensin receptor blockers in early testicular and cauda toxicity in rats / Mejora de los cambios en la histoarquitectura con bloqueadores de receptores de angiotensina en la toxicidad precoz testicular y de cauda en ratas

SUMMARY: Reproductive dysfunction is a complication for many diseases and toxins. Its early diagnosis and treatment are immensely important. Here the morphological histoarchitecture changes in early testicular and cauda toxicity before and after treatment with angiotensin receptor blockers were evaluated. Low-grade testicular damage was induced using thioacetamide (TAA, 50 mg/kg/day) intraperitoneally for two weeks in rats. The rats were randomly divided into four groups (n = 8) treated daily orally for three weeks as follows: Normal control (distilled water), TAA (positive control), TAA+candesartan (0.2 mg/kg) and TAA+losartan (7.5 mg/kg). Serum testosterone and testicular malondialdehyde and glutathione were measured. The changes in histoarchitecture of testis and cauda epididymis were evaluated by hematoxylin and eosin for general structure, Masson's trichrome for collagen, periodic acid Schiff for basement membrane, and caspase-3 and proliferating cell nuclear antigen (PCNA) for immunohistochemical analysis. The TAA-rats showed decreases of serum testosterone and testicular glutathione, increases in testicular malondialdehyde, degenerative changes and apoptosis in germ cells, thickening of tubular basal lamina and increases in expression of caspase 3, and decreases in expression of PCNA. The ARBs (candesartan and losartan) significantly reversed these changes with non-significant differences in-between. Treatment with ARBs (candesartan and losartan) significantly reversed TAA-induced low-grade testicular and cauda toxicity in rats. This could be potentially useful for early treatment of male patients with occupational toxicant-induced reproductive dysfunction especially if they are using ARBs for other comorbidities.

RESUMEN: La disfunción reproductiva es una complicación por muchas enfermedades y toxinas. Su diagnóstico y tratamiento tempranos son inmensamente importantes. Aquí se evaluaron los cambios morfológicos en la histoarquitectura en la toxicidad precoz testicular y cauda antes y después del tratamiento con bloqueadores de receptores de angiotensina. Se indujo daño testicular de bajo grado usando tioacetamida (TAA, 50 mg / kg / día) por vía intraperitoneal durante dos semanas en ratas. Las ratas se dividieron aleatoriamente en cuatro grupos (n = 8) tratados diariamente por vía oral durante tres semanas de la siguiente manera: control normal (agua destilada), TAA (control positivo), TAA + candesartan (0,2 mg / kg) y TAA + losartán (7,5 mg / kg). Se midieron la testosterona sérica, el malondialdehído testicular y el glutatión. Los cambios en la histoarquitectura de los testículos y la epidermis de la cauda se evaluaron mediante Hematoxilina y Eosina para determinar la estructura general, con tricrómicro de Masson para el colágeno, ácido periódico de Schiff para la membrana basal y la caspasa-3 y el antígeno nuclear de células proliferantes (PCNA) para análisis inmunohistoquímico. Las ratas TAA mostraron disminución de la testosterona sérica y glutatión testicular, aumentos en el malondialdehído testicular, cambios degenerativos y apoptosis en células germinales, engrosamiento de la lámina basal tubular y aumentos en la expresión de la caspasa 3, y disminución en la expresión de PCNA. Los ARB (candesartán y losartán) revirtieron significativamente estos cambios con diferencias no significativas en el medio. El tratamiento con BRA (candesartán y losartán) revirtió significativamente la toxicidad testicular y cauda inducida por TAA en ratas. Esto podría ser potencialmente útil para el tratamiento temprano de pacientes con disfunción reproductiva inducida por tóxicos ocupacionales, especialmente si están usando BRA para otras comorbilidades.

Diuretics are Similar to Losartan on Echocardiographic Target-Organ Damage in Stage I Hypertension. PREVER-Treatment Study / Diuréticos são Similares à Losartana na Avaliação Ecocardiográfica de Lesão a Órgãos-Alvo no Estágio I da Hipertensão. Estudo PREVER-Treatment

Abstract Blood pressure (BP)-lowering therapy improves left ventricular (LV) parameters of hypertensive target-organ damage in stage II hypertension, but whether there is a drug-class difference in echocardiographic parameters in stage I hypertension patients is less often studied. In the PREVER treatment study, where individuals with stage I hypertension were randomized for treatment with diuretics (chlorthalidone/amiloride) or losartan, 110 participants accepted to participate in a sub-study, where two-dimensional echocardiograms were performed at baseline and after 18 months of antihypertensive treatment. As in the general study, systolic BP reduction was similar with diuretics or with losartan. Echocardiographic parameters showed small but significant changes in both treatment groups, with a favorable LV remodeling with antihypertensive treatment for 18 months when target blood pressure was achieved either with chlorthalidone/amiloride or with losartan as the initial treatment strategy. In conclusion, even in stage I hypertension, blood pressure reduction is associated with improvement in echocardiographic parameters, either with diuretics or losartan as first-drug regimens.

Resumo A terapia de redução da pressão arterial (PA) melhora os parâmetros do ventrículo esquerdo (VE) na lesão a órgãos-alvo causada pela condição hipertensiva na hipertensão de estágio II; no entanto, se existem ou não diferenças relacionadas à classe de medicamentos nos parâmetros ecocardiográficos de pacientes com hipertensão estágio I é menos frequentemente estudado. No estudo PREVER-treatment, em que indivíduos com hipertensão estágio I foram randomizados para tratamento com diuréticos (clortalidona/amilorida) ou losartana, 110 participantes aceitaram participar de um subestudo, no qual foram realizados ecocardiogramas bidimensionais basais e após 18 meses de tratamento anti-hipertensivo. Como no estudo geral, a redução da PA sistólica foi semelhante com diuréticos ou com losartana. Os parâmetros ecocardiográficos mostraram pequenas mas significativas alterações em ambos os grupos de tratamento, com um remodelamento favorável do VE com tratamento anti-hipertensivo por 18 meses, quando a pressão arterial alvo foi atingida com clortalidona/amilorida ou com losartana como estratégia inicial de tratamento. Em conclusão, mesmo na hipertensão estágio I, a redução da pressão arterial está associada à melhora nos parâmetros ecocardiográficos tanto com o uso de diuréticos ou losartana como primeiro esquema de tratamento farmacológico.

Losartan improves alveolar bone dynamics in normotensive rats but not in hypertensive rats

Abstract Hypertension is one of the main causes of premature death in the world; also, it is associated with several bone alterations. Preclinical studies have demonstrated delayed alveolar bone healing in hypertensive rats. However, losartan has been favorable for consolidation of bone grafts and reduction in active periodontitis. Therefore, losartan is suggested to be effective in bone formation stages, as well as in the synthesis of matrix proteins and mineralization. Objectives: To evaluate the alveolar bone dynamics in hypertensive rats treated with losartan by laser confocal microscopy and histological analysis. Methodology: Thirty-two rats, 16 spontaneously hypertensive rats (SHR) and 16 Wistar albinus rats, treated or not with losartan (30 mg/kg/day) were used. Calcein fluorochrome at 21 days and alizarin red fluorochrome at 49 days were injected in rats (both 20 mg/kg). The animals were submitted to euthanasia 67 days after treatment, and then the right maxilla was removed for laser confocal microscopy analysis and the left maxilla for histological analysis. Results: This study showed a greater calcium marking in normotensive animals treated with losartan in relation to the other groups. Laser confocal microscopy parameters showed higher values of bone volume formed, mineralized surface, active surface of mineralization and bone formation rate in normotensive animals treated with losartan. However, a smaller mineralized surface was observed in all hypertensive animals. Conclusion: Losartan can improve bone mineralization parameters under normal physiological conditions, but the same anabolic effect does not occur under hypertension.

Comparison of the efficacy of losartan, hydrocortisone and acetylsalicylic acid (ASA) in preventing the development of fibrous scar tissue in skeletal muscle / Comparação da eficácia de losartana, hidrocortisona e ácido acetilsalicílico (AAS) na prevenção do desenvolvimento de tecido cicatricial fibroso nos músculos esqueléticos / Comparación de la eficacia de losartán, hidrocortisona y ácido acetilsalicílico (AAS) en la prevención del desarrollo de tejido cicatricial fibroso en los músculos esqueléticos

OBJECTIVE: To analyze fibrous scar tissue inhibition capacity with the use of losartan, hydrocortisone and acetylsalicylic acid. METHOD: The sample consisted of 120 male heterogeneic Wistar rats with a muscle laceration model. The rats were divided into four groups of 30 animals each: control group, losartan group, ASA group and hydrocortisone group. The animals were anesthetized and a 2.5 cm longitudinal incision was made in the left thoracolumbar paravertebral region. The muscles were subjected to a Grade III lesion caused by applying Kelly hemostatic forceps for 60 seconds, followed by sectioning with scissors. The skin was sutured with 3-0 nylon monofilament thread. The animals were placed in individual cages with plenty of food and water. The losartan group received losartan diluted in water at a dose of 0.1 mg/mL (10 mg/kg/day), the ASA Group received a 3 mg/mL ASA solution (300 mg/kg/day), and the hydrocortisone group received a 0.2 mg/mL hydrocortisone solution (20 mg/kg/day). RESULTS: The control, losartan, hydrocortisone and aspirin groups had a fibrotic area of 0.95 ± 0.35 mm, 0.55 ± 0.34 mm, 0.93 ± 0.33 mm, and 0.66 ± 0.36 mm, respectively. We observed a significantly smaller fibrotic area in the losartan group compared to the control (p=0.01) and hydrocortisone (p=0.01) groups. There were no significant differences among the other groups. CONCLUSION: The healing of striated skeletal muscle produced less fibrous scar tissue when exposed to losartan in comparison to the control group or the hydrocortisone group. Level of Evidence I; Randomized double-blind placebo-controlled study.

OBJETIVO: Analisar a capacidade de inibição de formação de tecido cicatricial fibroso com losartana, hidrocortisona e AAS. MÉTODOS: A amostra consistiu em 120 ratos Wistar heterogênicos machos com modelo de laceração muscular. Os ratos foram distribuídos em quatro grupos de 30 animais: grupo controle, grupo losartana, grupo AAS e grupo hidrocortisona. Os animais foram anestesiados e submetidos a uma incisão em sentido longitudinal de 2,5 cm de extensão na região paravertebral toracolombar esquerda, e os músculos sofreram uma lesão grau III com pinça hemostática de Kelly durante 60 segundos e posterior secção com tesoura. A pele foi suturada com nylon monofilamentar 3-0. Os animais foram colocados em gaiolas individuais, com água e alimento à vontade. O grupo losartana recebeu losartana diluída em água na dose de 0,1 mg/ml (10 mg/kg/dia), o grupo AAS recebeu solução de AAS 3 mg/ml (300 mg/kg/dia), o grupo hidrocortisona recebeu solução de hidrocortisona 0,2 mg/ml (20 mg/kg/ dia). RESULTADOS: Os grupos controle, losartana, hidrocortisona e AAS apresentaram área fibrótica de0,95 ± 0,35 mm, 0,55 ± 0,34 mm, 0,93 ± 0,33 mm, 0,66 ± 0,36 mm, respectivamente. Observou-se área fibrótica significativamente menor do grupo losartana em comparação com o grupo controle (p = 0,01) e hidrocortisona (p = 0,01). Nos demais grupos não houve diferença significativa. CONCLUSÃO: A cicatrização do músculo estriado esquelético produziu menos tecido cicatricial fibroso quando exposto à losartana do que quando comparado com o grupo controle ou o grupo hidrocortisona. Nível de Evidência I; Estudo duplo-cego randomizado controlado por placebo.

OBJETIVO: Analizar la capacidad de inhibición de formación de tejido cicatricial fibroso con losartán, hidrocortisona y AAS (ácido acetilsalicílico). MÉTODOS: La muestra consistió en 120 ratas Wistar heterogéneas machos con modelo de laceración muscular. Las ratas fueron distribuidas en cuatro grupos de 30 animales: grupo control; grupo losartán; grupo AAS y grupo hidrocortisona. Los animales fueron anestesiados y sometidos a una incisión longitudinal de 2,5 cm de extensión en la región paravertebral toracolumbar izquierda y los músculos sufrieron una lesión de grado III con pinza hemostática de Kelly durante 60 segundos y posterior sección con tijera. La piel se suturó con monofilamento de nylon 3-0. Los animales fueron dispuestos en jaulas individuales con abundante comida y agua. El grupo losartán recibió losartán diluido en agua a una dosis de 0,1 mg/ml (10 mg/kg/día), el grupo AAS recibió solución de AAS de 3 mg/ml (dosis 300 mg/kg/día), el grupo hidrocortisona recibió solución hidrocortisona de 0,2 mg/ml (20 mg/kg/día). RESULTADOS: Los grupos control, losartán, hidrocortisona y AAS mostraron área fibrótica de 0,95 ± 0,35 mm, 0,55 ± 0,34 mm, 0,93 ± 0,33 mm, 0,66 ± 0,36 mm, respectivamente. Se observó área fibrótica significativamente menor del grupo losartán en comparación con el grupo control (p = 0,01) e hidrocortisona (p = 0,01). En los demás grupos no hubo diferencias significativas. CONCLUSIÓN: La cicatrización del músculo estriado esquelético produjo menos tejido cicatricial fibroso cuando fue expuesto a losartán que cuando fue comparado con el grupo control o el grupo hidrocortisona. Nivel de Evidencia I; Estudio doble ciego aleatorio controlado por placebo.

Participation of hepatic α/β-adrenoceptors and AT1 receptors in glucose release and portal hypertensive response induced by adrenaline or angiotensin II

It has been previously demonstrated that the hemodynamic effect induced by angiotensin II (AII) in the liver was completely abolished by losartan while glucose release was partially affected by losartan. Angiotensin II type 1 (AT1) and adrenergic (∝1- and β-) receptors (AR) belong to the G-proteins superfamily, which signaling promote glycogen breakdown and glucose release. Interactive relationship between AR and AT1-R was shown after blockade of these receptors with specific antagonists. The isolated perfused rat liver was used to study hemodynamic and metabolic responses induced by AII and adrenaline (Adr) in the presence of AT1 (losartan) and ∝1-AR and β-AR antagonists (prazosin and propranolol). All antagonists diminished the hemodynamic response induced by Adr. Losartan abolished hemodynamic response induced by AII, and AR antagonists had no effect when used alone. When combined, the antagonists caused a decrease in the hemodynamic response. The metabolic response induced by Adr was mainly mediated by ∝1-AR. A significant decrease in the hemodynamic response induced by Adr caused by losartan confirmed the participation of AT1-R. The metabolic response induced by AII was impaired by propranolol, indicating the participation of β-AR. When both ARs were blocked, the hemodynamic and metabolic responses were impaired in a cumulative effect. These results suggested that both ARs might be responsible for AII effects. This possible cross-talk between β-AR and AT1-R signaling in the hepatocytes has yet to be investigated and should be considered in the design of specific drugs.

Influence of antihypertensive drugs on aortic and coronary effects of Ang-(1-7) in pressure-overloaded rats

This study investigated the influence of antihypertensive drugs, such as angiotensin-converting enzyme inhibitors (ACEIs), AT1 receptor blockers (ARBs), voltage-gated L-type calcium channel blockers, and mineralocorticoid receptor antagonists (MRAs), on the effects of angiotensin-(1-7) [Ang-(1-7)] on aorta and coronary arteries from pressure-overloaded rats. Pressure overload was induced by abdominal aortic banding (AB). To evaluate the role of antihypertensive drugs on the effect of Ang-(1-7), AB male Wistar rats weighing 250–300 g were treated with vehicle or low doses (5 mg·kg-1·day-1, gavage) of losartan, captopril, amlodipine, or spironolactone. Isolated aortic rings and isolated perfused hearts under constant flow were used to evaluate the effect of Ang-(1-7) in thoracic aorta and coronary arteries, respectively. Ang-(1-7) induced a significant relaxation in the aorta of sham animals, but this effect was reduced in the aortas of AB rats. Chronic treatments with losartan, captopril or amlodipine, but not with spironolactone, restored the Ang-(1-7)-induced aorta relaxation in AB rats. The coronary vasodilatation evoked by Ang-(1-7) in sham rats was blunted in hypertrophic rats. Only the treatment with losartan restored the coronary vasodilatory effect of Ang-(1-7) in AB rat hearts. These data support a beneficial vascular effect of an association of Ang-(1-7) and some antihypertensive drugs. Thus, this association may have potential as a new therapeutic strategy for cardiovascular diseases.

Candesartan, rather than losartan, improves motor dysfunction in thioacetamide-induced chronic liver failure in rats

Minimal hepatic encephalopathy is more common than the acute syndrome. Losartan, the first angiotensin-II receptor blocker (ARB), and candesartan, another widely-used ARB, have protected against developing fibrogenesis, but there is no clear data about their curative antifibrotic effects. The current study was designed to examine their effects in an already-established model of hepatic fibrosis and also their effects on the associated motor dysfunction. Low-grade chronic liver failure (CLF) was induced in 3-month old Sprague-Dawley male rats using thioacetamide (TAA, 50 mg·kg−1·day−1) intraperitoneally for 2 weeks. The TAA-CLF rats were randomly divided into five groups (n=8) treated orally for 14 days (mg·kg−1·day−1) as follows: TAA (distilled water), losartan (5 and 10 mg/kg), and candesartan (0.1 and 0.3 mg/kg). Rats were tested for rotarod and open-field tests. Serum and hepatic biochemical markers, and hepatic histopathological changes were evaluated by H&E and Masson's staining. The TAA-CLF rats showed significant increases of hepatic malondialdehyde, hepatic expression of tumor necrosis factor-α (TNF-α), and serum ammonia, alanine aminotransferase, γ-glutamyl transferase, TNF-α, and malondialdehyde levels as well as significant decreases of hepatic and serum glutathione levels. All treatments significantly reversed these changes. The histopathological changes were moderate in losartan-5 and candesartan-0.1 groups and mild in losartan-10 and candesartan-0.3 groups. Only candesartan significantly improved TAA-induced motor dysfunction. In conclusion, therapeutic antifibrotic effects of losartan and candesartan in thioacetamide-induced hepatic fibrosis in rats are possibly through angiotensin-II receptor blocking, antioxidant, and anti-inflammatory activities. Improved motor dysfunction by candesartan could be attributed to better brain penetration and slower "off-rate" from angiotensin-II receptors. Clinical trials are recommended.

Avaliação dos eixos ECA / ANG II / AT1 e ECA-2 / ANG (1-7) / MAS em fibroblastos de gengiva e ligamento periodontal humanos estimulados por IL-1ß e sua contribuição na produção e regulação de citocinas e quimiocinas / Evaluation ACE /ANG II /AT1 and ACE-2 /ANG (1-7) /MAS axis in gingival and periodontal ligament human fibroblasts stimulated with IL-1ß and its contribution in the production of cytokines and chemokines

O Sistema renina-angiotensina (SRA) tem sido relatado como um importante modulador de processos inflamatórios e imunológicos, incluindo a doença periodontal (DP). Estudos sugerem neste sistema um eixo alternativo (ECA-2 /ANG(1-7) /MAS) que atuaria como um contra-regulador de efeitos mediados pelo clássico eixo (ECA /ANGII /AT1). Sabe-se que bactérias periodontopatogênicas, como a Porphyromonas gingivalis (Pg), possuem componentes bioativos de membrana (ex. lipopolissacarídeos-LPS) capazes de induzir uma forte resposta imune no hospedeiro devido à liberação de citocinas nas células, entre elas Interleucina (IL)- 1ß. Neste contexto, fibroblastos são as células mais abundantes nos tecidos periodontais e possuem em sua superfície celular receptores necessários para o reconhecimento da invasão bacteriana, ativando cascatas intracelulares, que levam à produção de citocinas. O objetivo deste estudo foi verificar se os eixos ECA/ ANGII/ AT1 e ECA-2/ ANG(1-7)/ MAS contribuem para a produção e/ ou regulação de citocinas inflamatórias (CI) por fibroblastos de gengiva humana (HGF) e ligamento periodontal humano (HPLF) estimulados por IL-1ß. Após o pré-tratamento com Losartan e Ang (1-7) ou silenciamento mediado por RNA de interferência (RNAi) de AT1, HGF e HPLF foram estimulados por IL-1ß por 3 horas (RNAm) ou 24 horas (proteína). Expressão de RNAm para AT1, MAS, ECA, ECA-2, IL-1ß, TNF-α, IL-6, IL-8, IL-10, TGF-ß, CXCL12, RANK-L e OPG foram avaliados por RT-qPCR e das proteínas IL-6, IL-8, ECA e ECA-2 por ELISA. Foi realizado também Western Blot para detecção de AT1 e ECA nos extratos celulares e dosagem de nitrito no sobrenadante das culturas. Ambos os subtipos de fibroblastos mostraram aumento da expressão de RNAm para AT1, IL-1ß, IL-6, IL-8, TNF-α e OPG, quando estimulados por IL-1ß. No entanto, apenas em HPLF foi observado aumento para MAS, ECA e TGF-ß. Losartan e Ang (1-7) não modularam o transcrito, a secreção de CI e nem a produção de nitrito no sobrenadante das culturas, tanto em HGF como em HPLF. O silenciamento do receptor AT1 reduziu a secreção de IL-6 e IL-8 induzida por IL-1ß em cultura de HGF e HPLF e aumentou a expressão gênica de OPG somente em HGF. Estes resultados sugerem que o silenciamento de AT1, mas não o bloqueio farmacológico deste receptor pelo antagonista Losartan, em HGF e HPLF, pode controlar a produção de IL-6 e IL-8, que por sua vez contribuem para a patogênese periodontal.(AU)

The renin-angiotensin system (RAS) has been reported as an important modulator of inflammatory and immune responses, including periodontal disease (PD). Studies suggest an alternative axis as part of this system (ACE-2 / ANG (1-7) / MAS) that would act as counter-regulatory to the classical axis (ECA / ANGII / AT1). It is known that periodontal bacteria such as Porphyromonas gingivalis (Pg) have bioactive components in their membrane (such as lipopolysaccharide-LPS) capable of inducing a strong immune response in the host due to the release of cytokines in cells, including interleukin (IL) - 1ß. In this regard, fibroblasts are the most abundant cells in periodontal tissues and receptors needed for the recognition of bacterial invasion by activating intracellular cascades that lead to cytokine production. The aim of this study was to determine whether the axes ACE / ANGII / AT1 and ACE-2 / ANG (1-7) / MAS contribute to the production and / or regulation of inflammatory cytokines (IC) by fibroblasts of human gingiva (HGF) and human periodontal ligament (HPLF) stimulated IL-1ß. After pre-treatment with Losartan, Ang (1-7) or silencing mediated by RNA interference (RNAi) of AT1, HGF and HPLF were stimulated by IL-1ß for 3 hours (RNAm) or 24 hours (protein). Expression mRNA for AT1, MAS, ACE, ACE-2, IL-1ß, TNF-α, IL-6, IL-8, IL-10, TGF-ß, CXCL12, RANK-L and OPG was assessed by RT- qPCR and proteins IL-6, IL-8, ACE and ACE-2 by ELISA. Western Blot for the detection of AT1 and ECA and dosage of nitrite was also performed. Experiments stimulated by IL-1ß showed a positive control for gene expression AT1, IL-1ß, IL-6, IL-8, TNF-α and OPG in HGF and HPLF and MAS, ACE and TGF-ß only HPLF. Losartan and Ang (1-7) did not modulate the transcription and secretion of IC and no nitrite production in the culture supernatant of HGF and HPLF. The silencing AT1 reduced IL-6 secretion and IL-8 induced by IL- ß in cultured HGF and HPLF and increased OPG gene expression only HGF. These results suggest that silencing AT1, but not pharmacological blockade of this receptor by Losartan in HPLF and HGF, can control the production of IL-6 and IL-8, which in turn contribute to the pathogenesis of periodontal disease.(AU)

Renin-angiotensin system blockers regulate the metabolism of isolated fat cells in vitro

Due to the presence of the renin-angiotensin system (RAS) in tissues and its specific influence on white adipose tissue, fat cells are possible targets of pharmacological RAS blockers commonly used as anti-hypertensive drugs. In the present study, we investigated the effects of different RAS blockers on fat cell metabolism, more specifically on lipolysis, lipogenesis and oxidation of energy substrates. Isolated primary adipocytes were incubated with different RAS blockers (aliskiren, captopril and losartan) in vitro for 24 h and lipolysis, lipogenesis and glucose oxidation capacities were determined in dose-response assays to a β-adrenergic agonist and to insulin. Although no change was found in lipolytic capacity, the RAS blockers modulated lipogenesis and glucose oxidation in a different way. While captopril decreased insulin-stimulated lipogenesis (−19% of maximal response and −60% of insulin responsiveness) due to reduced glucose derived glycerol synthesis (−19% of maximal response and 64% of insulin responsiveness), aliskiren increased insulin-stimulated glucose oxidation (+49% of maximal response and +292% of insulin responsiveness) in fat cells. Our experiments demonstrate that RAS blockers can differentially induce metabolic alterations in adipocyte metabolism, characterized by a reduction in lipogenic responsiveness or an increase in glucose oxidation. The impact of RAS blockers on adipocyte metabolism may have beneficial implications on metabolic disorders during their therapeutic use in hypertensive patients.

Angiotensin II Modulates p130Cas of Podocytes by the Suppression of AMP-Activated Protein Kinase

Angiotensin II (Ang II) induces the pathological process of vascular structures, including renal glomeruli by hemodynamic and nonhemodynamic direct effects. In kidneys, Ang II plays an important role in the development of proteinuria by the modification of podocyte molecules. We have previously found that Ang II suppressed podocyte AMP-activated protein kinase (AMPK) via Ang II type 1 receptor and MAPK signaling pathway. In the present study, we investigated the roles of AMPK on the changes of p130Cas of podocyte by Ang II. We cultured mouse podocytes and treated them with various concentrations of Ang II and AMPK-modulating agents and analyzed the changes of p130Cas by confocal imaging and western blotting. In immunofluorescence study, Ang II decreased the intensity of p130Cas and changed its localization from peripheral cytoplasm into peri-nuclear areas in a concentrated pattern in podocytes. Ang II also reduced the amount of p130Cas in time and dose-sensitive manners. AMPK activators, metformin and AICAR, restored the suppressed and mal-localized p130Cas significantly, whereas, compound C, an AMPK inhibitor, further aggravated the changes of p130Cas. Losartan, an Ang II type 1 receptor antagonist, recovered the abnormal changes of p130Cas suppressed by Ang II. These results suggest that Ang II induces the relocalization and suppression of podocyte p130Cas by the suppression of AMPK via Ang II type 1 receptor, which would contribute to Ang II-induced podocyte injury.

Renin-Angiotensin System Blockade Associated with Statin Improves Endothelial Function in Diabetics / Bloqueio do Sistema Renina-Angiotensina Associado a Estatina Melhora a Função Endotelial em Diabéticos

Abstract Background: Studies suggest that statins have pleiotropic effects, such as reduction in blood pressure, and improvement in endothelial function and vascular stiffness. Objective: To analyze if prior statin use influences the effect of renin-angiotensin-aldosterone system inhibitors on blood pressure, endothelial function, and vascular stiffness. Methods: Patients with diabetes and hypertension with office systolic blood pressure ≥ 130 mmHg and/or diastolic blood pressure ≥ 80 mmHg had their antihypertensive medications replaced by amlodipine during 6 weeks. They were then randomized to either benazepril or losartan for 12 additional weeks while continuing on amlodipine. Blood pressure (assessed with ambulatory blood pressure monitoring), endothelial function (brachial artery flow-mediated dilation), and vascular stiffness (pulse wave velocity) were evaluated before and after the combined treatment. In this study, a post hoc analysis was performed to compare patients who were or were not on statins (SU and NSU groups, respectively). Results: The SU group presented a greater reduction in the 24-hour systolic blood pressure (from 134 to 122 mmHg, p = 0.007), and in the brachial artery flow-mediated dilation (from 6.5 to 10.9%, p = 0.003) when compared with the NSU group (from 137 to 128 mmHg, p = 0.362, and from 7.5 to 8.3%, p = 0.820). There was no statistically significant difference in pulse wave velocity (SU group: from 9.95 to 9.90 m/s, p = 0.650; NSU group: from 10.65 to 11.05 m/s, p = 0.586). Conclusion: Combined use of statins, amlodipine, and renin-angiotensin-aldosterone system inhibitors improves the antihypertensive response and endothelial function in patients with hypertension and diabetes.

Resumo Fundamentos: Estudos sugerem que as estatinas possuem efeitos pleotrópicos, como melhora da função endotelial, da rigidez vascular e redução da pressão arterial. Objetivo: Analisar se o uso prévio de estatina influenciou o efeito sobre a pressão arterial, a função endotelial e a rigidez vascular de drogas inibidoras do sistema renina-angiotensina-aldosterona. Métodos: Pacientes hipertensos e diabéticos com pressão arterial de consultório sistólica ≥ 130 mmHg e/ou diastólica ≥ 80 mmHg tiveram suas medicações anti-hipertensivas substituídas por anlodipino durante 6 semanas. Em seguida, foram randomizados para associação de benazepril ou losartana por mais 12 semanas. Pressão arterial (através da monitorização ambulatorial da pressão arterial), função endotelial (dilatação mediada por fluxo da artéria braquial) e rigidez vascular (velocidade da onda de pulso) foram avaliados antes e após o tratamento combinado. Neste trabalho, uma análise post-hoc foi realizada para comparar pacientes que vinham (grupo CE) ou não (grupo SE) em uso de estatina. Resultados: O grupo CE apresentou maior redução na pressão arterial sistólica nas 24 horas (134 para 122 mmHg, p = 0,007) e na dilatação mediada por fluxo da artéria braquial (6,5 para 10,9%, p = 0,003) quando comparado com o grupo SE (137 para 128 mmHg, p = 0,362, e 7,5 para 8,3%, p = 0,820). Não houve diferença estatisticamente significante na velocidade de onda de pulso (grupo CE 9,95 para 9,90 m/s, p = 0,650 e grupo SE 10,65 para 11,05 m/s, p = 0,586). Conclusão: O uso combinado de estatinas, anlodipino e inibidores do sistema renina-angiotensina-aldosterona melhora a resposta anti-hipertensiva e a função endotelial em pacientes hipertensos e diabéticos.

Bloqueio do receptor AT1 da Angiotensina II reduz o número de folículos antrais em ratas com obesidade induzida por dieta de cafeteria / Blockade of AT1 receptor of Angiotensin II reduces the number of antral follicles in female rats with obesity induced by cafeteria diet

OBJETIVO: Avaliar o desenvolvimento folicular em ratas Wistar com obesidade induzida por dieta de cafeteria (DCAF) submetidas à administração de losartan (LOS), um antagonista do receptor AT1 da Angiotensina II. MÉTODOS: Aos 21 dias de vida, as ratas foram separadas aleatoriamente em dois grupos: controle (CTL), que recebeu ração padrão, e cafeteria (CAF), que recebeu a DCAF, altamente palatável e calórica. Aos 70 dias de vida, início da idade reprodutiva, animais do grupo CAF foram subdivididos em dois grupos (n=15/grupo): CAF, que recebeu água, e CAF+LOS, que recebeu 30 mg/kg de peso corporal (PC) de LOS por gavagem durante 30 dias. O grupo CTL também recebeu água por gavagem. Aos 100 dias de vida foi realizada a eutanásia dos animais e o PC e das gorduras retroperitoneal, perigonadal e subcutânea foi avaliado. Os ovários direitos foram retirados para contagem do número dos diferentes tipos de folículos ovarianos. As concentrações plasmáticas dos hormônios folículo-estimulantes (FSH), luteinizante (LH), prolactina (PRL) e progesterona foram avaliadas. Os resultados foram expressos como média±erro padrão da média. Para análise estatística, foi utilizado one-way ANOVA, seguido pelo pós-teste de Newman-Keuls (p<0,05). RESULTADOS: O PC e das gorduras, assim como o número de folículos antrais, foi elevado no grupo CAF em relação ao CTL. Todavia, as concentrações de FSH e LH foram mais baixas entre os animais CAF. A administração de LOS reduziu o PC e das gorduras retroperitoneal e subcutânea, bem como o número de folículos antrais. O tratamento com LOS atenuou a redução das concentrações de FSH e de LH. As concentrações de progesterona e PRL foram semelhantes entre os grupos estudados. CONCLUSÃO: O uso de LOS pode favorecer o desenvolvimento folicular em fêmeas obesas e pode possibilitar sua utilização como fármaco coadjuvante no tratamento da infertilidade associada à obesidade. .

PURPOSE: To evaluate the follicular development of female Wistar rats with obesity induced by the cafeteria diet, submitted to the administration of losartan (LOS), an antagonist of the AT1 receptor of Angiotensin II. METHODS: At weaning (21 days of age), female Wistar rats were randomly divided, into two groups: control (CTL) that received standard chow and cafeteria (CAF) that received a cafeteria diet, a highly palatable and highly caloric diet. At 70 days of age, at the beginning of the reproductive age, animals of the CAF group were subdivided into two groups (n=15/group): CAF, that received water, and CAF+LOS, that received LOS for 30 days. The CTL group also received water by gavage. At 100 days of age, the animals were euthanized and body weight (BW) as well as the retroperitoneal, perigonadal and subcutaneous fat weights were analyzed. The right ovaries were isolated for counting the number of primary, secondary, antral and mature follicles. Plasma levels of FSH, LH, prolactin and progesterone hormones were analyzed. The results were expressed as mean±standard error of the mean. Data were analyzed statistically by one-way ANOVA followed by the Newman-Keuls post-test (p<0.05). RESULTS: BW and fat weight, as well as the number of antral follicles, were higher in the CAF group compared to the CTL group. However, FSH and LH levels were lower in CAF animals compared to CTL animals. LOS administration attenuated the reduction of FSH and LH levels. Progesterone and PRL levels were similar among groups. CONCLUSION: LOS could improve follicular development in obese females and could be used as an adjunctive drug in the treatment of infertility associated with obesity. .

Functional Vascular Study in Hypertensive Subjects with Type 2 Diabetes Using Losartan or Amlodipine / Estudo Vascular Funcional em Hipertensos com Diabetes Tipo 2 em uso de Losartana ou Anlodipina

Background: Antihypertensive drugs are used to control blood pressure (BP) and reduce macro- and microvascular complications in hypertensive patients with diabetes. Objectives: The present study aimed to compare the functional vascular changes in hypertensive patients with type 2 diabetes mellitus after 6 weeks of treatment with amlodipine or losartan. Methods: Patients with a previous diagnosis of hypertension and type 2 diabetes mellitus were randomly divided into 2 groups and evaluated after 6 weeks of treatment with amlodipine (5 mg/day) or losartan (100 mg/day). Patient evaluation included BP measurement, ambulatory BP monitoring, and assessment of vascular parameters using applanation tonometry, pulse wave velocity (PWV), and flow-mediated dilation (FMD) of the brachial artery. Results: A total of 42 patients were evaluated (21 in each group), with a predominance of women (71%) in both groups. The mean age of the patients in both groups was similar (amlodipine group: 54.9 ± 4.5 years; losartan group: 54.0 ± 6.9 years), with no significant difference in the mean BP [amlodipine group: 145 ± 14 mmHg (systolic) and 84 ± 8 mmHg (diastolic); losartan group: 153 ± 19 mmHg (systolic) and 90 ± 9 mmHg (diastolic)]. The augmentation index (30% ± 9% and 36% ± 8%, p = 0.025) and augmentation pressure (16 ± 6 mmHg and 20 ± 8 mmHg, p = 0.045) were lower in the amlodipine group when compared with the losartan group. PWV and FMD were similar in both groups. Conclusions: Hypertensive patients with type 2 diabetes mellitus treated with amlodipine exhibited an improved pattern of pulse wave reflection in comparison with those treated with losartan. However, the use of losartan may be associated with independent vascular reactivity to the pressor effect. .

Fundamento: A escolha dos fármacos anti-hipertensivos no tratamento de hipertensos diabéticos tem como objetivos o controle da pressão arterial (PA) e a redução das complicações macro/microvasculares. Objetivos: O objetivo deste estudo foi comparar as alterações vasculares funcionais em pacientes hipertensos e diabéticos tipo 2 após seis semanas de anlodipina ou losartana. Métodos: Pacientes com diagnóstico prévio de hipertensão arterial e diabetes melito tipo 2 foram randomizados e divididos em dois grupos, sendo avaliados na sexta semana de uso de losartana 100 mg/dia ou anlodipina 5 mg/dia, com medida da PA, realização de monitoração ambulatorial da pressão arterial e testes para avaliação de parâmetros vasculares, como tonometria de aplanação, velocidade de onda de pulso (VOP) e dilatação mediada por fluxo (DMF) da artéria braquial. Resultados: Foram incluídos 42 pacientes, 21 em cada grupo, com predominância do sexo feminino (71%) nos dois grupos. Os grupos anlodipina e losartana apresentaram média de idade semelhante (54,9 ± 4,5 e 54,0 ± 6,9 anos, respectivamente) e sem diferença estatística na média da PA (145 ± 14/84 ± 8 e 153 ± 19/90 ± 9 mmHg). O augmentation index (30 ± 9% × 36 ± 8%, p = 0,025), assim como a augmentation pressure (16 ± 6 mmHg × 20 ± 8 mmHg, p = 0,045) foram menores no grupo anlodipina que no grupo losartana. Os valores obtidos para VOP e DMF foram semelhantes nos dois grupos. Conclusões: Em hipertensos e diabéticos tipo 2, o uso de anlodipina demonstrou um padrão de reflexão da onda de pulso mais favorável nesse grupo, mas o uso de losartana pode estar associado com ações vasculares independentes do efeito pressórico. .

Dissociação da resposta anti-hipertensiva e metabólica à losartana e espironolactona em ratos com síndrome metabólica experimental / Dissociation of antihypertensive and metabolic response to losartan and spironolactone in experimental rats with metabolic sindrome

INTRODUÇÃO: O tratamento da hipertensão arterial (HA) em indivíduos com síndrome metabólica (SM) é um desafio, uma vez que terapias não medicamentosas são de difícil implementação e o tratamento farmacológico ideal não está totalmente estabelecido. OBJETIVO: Avaliar o bloqueio do sistema renina angiotensina aldosterona (SRAA) na pressão arterial (PA), na função e na morfologia renais em modelo experimental de SM induzida por dieta hiperlipídica. MÉTODOS: Ratos Wistar receberam ração hiperlipídica a partir da quarta semana de vida, por 20 semanas. Os grupos tratados receberam Losartana ou Espironolactona a partir da oitava semana de vida. Avaliou-se semanalmente o peso corporal e a PA de cauda por pletismografia. Ao final do experimento, foram realizados testes de tolerância oral à glicose, perfil lipídico, clearance de creatinina, medida direta da PA, análise morfométrica renal. RESULTADOS: A administração de dieta hiperlipídica se associou ao desenvolvimento de SM, caracterizada por acúmulo central de gordura, hipertensão arterial, hiperglicemia e hipertrigliceridemia. Nesse modelo não foram observadas alterações da histomorfometria renal. O bloqueio do receptor AT1 da angiotensina II (Ang II) preveniu o desenvolvimento da HA. O bloqueio mineralocorticoide não apresentou eficácia anti-hipertensiva, porém, associou-se à redução da gordura abdominal. CONCLUSÃO: A dissociação da resposta anti-hipertensiva aos bloqueios dos receptores da Ang II e mineralocorticoide indica a participação da Ang II na gênese da HA associada à obesidade. A redução da obesidade central com a Espironolactona sugere a presença de efeito adipogênico mineralocorticoide.

INTRODUCTION: The treatment of arterial hypertension (AH) in patients with metabolic syndrome (MS) is a challenge, since non drug therapies are difficult to implement and optimal pharmacological treatment is not fully established. OBJECTIVE: To assess the blockade of the rennin angiotensin aldosterone system (RAAS) in blood pressure (BP) in renal function and morphology in an experimental model of MS induced by high fat diet. METHODS: Wistar rats were fed on high fat diet from the fourth week of life, for 20 weeks. The groups received Losartan or Spironolactone from the eighth week of life. We weekly evaluated the body weight and BP by tail plethysmography. At the end of the experiment oral glucose tolerance, lipid profile, creatinine clearance tests, and the direct measurement of BP were performed. A morphometric kidney analysis was performed. RESULTS: The administration of high-fat diet was associated with the development of MS, characterized by central fat accumulation, hypertension, hyperglycemia and hypertriglyceridemia. In this model there were no changes in renal histomorphometry. The blockade of angiotensin II (Ang II) receptor AT1 prevented the development of hypertension. The mineralocorticoid blockage did not have antihypertensive efficacy but was associated with reduction of abdominal fat. CONCLUSION: The dissociation of the antihypertensive response to the blockades of Ang II receptors and mineralocorticoid indicates the involvement of Ang II in the pathogenesis of hypertension associated with obesity. Reduction of central obesity with Spironolactone suggests the presence of mineralocorticoid adipogenic effect.

Gadolinium increases the vascular reactivity of rat aortic rings

Gadolinium (Gd) blocks intra- and extracellular ATP hydrolysis. We determined whether Gd affects vascular reactivity to contractile responses to phenylephrine (PHE) by blocking aortic ectonucleoside triphosphate diphosphohydrolase (E-NTPDase). Wistar rats of both sexes (260-300 g, 23 females, 7 males) were used. Experiments were performed before and after incubation of aortic rings with 3 µM Gd. Concentration-response curves to PHE (0.1 nM to 0.1 mM) were obtained in the presence and absence of endothelium, after incubation with 100 µM L-NAME, 10 µM losartan, or 10 µM enalaprilat. Gd significantly increased the maximum response (control: 72.3 ± 3.5; Gd: 101.3 ± 6.4 percent) and sensitivity (control: 6.6 ± 0.1; Gd: 10.5 ± 2.8 percent) to PHE. To investigate the blockade of E-NTDase activity by Gd, we added 1 mM ATP to the bath. ATP reduced smooth muscle tension and Gd increased its relaxing effect (control: -33.5 ± 4.1; Gd: -47.4 ± 4.1 percent). Endothelial damage abolished the effect of Gd on the contractile responses to PHE (control: 132.6 ± 8.6; Gd: 122.4 ± 7.1 percent). L-NAME + Gd in the presence of endothelium reduced PHE contractile responses (control/L-NAME: 151.1 ± 28.8; L-NAME + Gd: 67.9 ± 19 percent AUC). ATP hydrolysis was reduced after Gd administration, which led to ATP accumulation in the nutrient solution and reduced ADP concentration, while adenosine levels remained the same. Incubation with Gd plus losartan and enalaprilat eliminated the pressor effects of Gd. Gd increased vascular reactivity to PHE regardless of the reduction of E-NTPDase activity and adenosine production. Moreover, the increased reactivity to PHE promoted by Gd was endothelium-dependent, reducing NO bioavailability and involving an increased stimulation of angiotensin-converting enzyme and angiotensin II AT1 receptors.

The effect of anti-hypertensive drugs on the obstructive pancreatitis in rats / Efeitos de fármacos anti-hipertensivos sobre pancreatite obstrutiva em ratos

PURPOSE: To investigate the effect of ACE inhibitor, lisinopril and AT1 blocker, losartan, on the obstructive pancreatitis in rat. METHODS: Acute pancreatitis in rats (n=21) was induced for a common hepatic duct were ligated proximal to its entry into the pancreas and the common bile - pancreatic duct were also ligated near its junction with the duodenum, under ether anesthesia, after which the abdomen were closed. The animals was divided in tree groups, being two treated and control group. The animals was treated with Losartan and Lisinopril at the dose of 10µg/Kg body weight per day, i.p., in a proportional volume, for five days, before and after treatement. RESULTS: The inflammation, collagen deposition in the pancreas of treated animals were smaller, suggesting that the use of antihypertensive agents interfered positively in the depletion of the injury of the pancreas. Scythe showed a correlation between activity of pancreatic stellate cells (PSCs) lower in treated animals when compared to control. CONCLUSION: The pancreatic stellate cells strength are involved in collagen production during acute pancreatitis and why antihypertensive drugs such as lisinopril and losartan may possibly have beneficial effects in reducing pancreatic fibrosis in models of experimental obstructive pancreatitis.

OBJETIVO: Investigar o efeito de um inibidor da ECA, lisinopril e bloqueador AT1, losartan, a pancreatite obstrutiva em ratos. MÉTODOS: Pancreatite aguda em ratos (n = 21) foi induzida por um ducto hepático comum foram ligados proximal à sua entrada no pâncreas e da bílis comum - ducto pancreático também foram ligados perto de sua junção com o duodeno, sob anestesia com éter, após o que abdome foram fechadas. Os animais foram divididos em três grupos, sendo dois tratados eo grupo controle. Os animais foram tratados com lisinopril e losartan na dose de 10µg/Kg de peso corporal por dia, IP, em um volume proporcional, por cinco dias, antes e depois do tratamento com. RESULTADOS: A inflamação, deposição de colágeno no pâncreas de animais tratados foram menores, sugerindo que o uso de agentes anti-hipertensivos interferiram positivamente na diminuição da lesão do pâncreas. Este estudo mostrou uma correlação entre a atividade das células pancreáticas estreladas (CSP) menor nos animais tratados quando comparados ao control. CONCLUSÃO: A força das células pancreáticas estreladas está envolvida na produção de colágeno durante a pancreatite aguda e por medicamentos anti-hipertensivos, tais como lisinopril e losartan pode eventualmente ter efeitos benéficos na redução da fibrose do pâncreas em modelos experimentais de pancreatite obstrutiva.

Control of hypertension; efficacy and safety of losartan and atenolol alone and in combination

To compare the efficacy and tolerability of Losartan and Atenolol in alone and combination in treatment of hypertension. Comparative study. Medical out patients department of Jinnah Postgraduate Medical Centre Karachi from January 2007 to June 2007. There were 60 patients previously untreated with mild and moderate essential hypertensions were registered for study. The selected patients were divided into three groups. Group A was given atenolol, Group B was given Losartan, and Group C was given both drugs. The target blood pressure was 120-140/80-90 mmHg. There were 42 males and 18 females with age range 25-65 years. The mean baseline score of groups A, B and C were showed systolic blood pressure 182 +/- 19, 174 +/- 20 and 168 +/- 12 respectively. The diastolic blood pressure was 104.5 +/- 11, 102.5 +/- 9 and 104.5 +/- 10 respectively. The difference in mean systolic and diastolic blood pressure was not significant statistically as P=0.06 and 0.76 respectively. After 4 months of treatment with atenolol, systolic blood pressure decreased to 147 +/- 17, and diastolic blood pressure fell to 87 +/- 4. Losartan decreased systolic blood pressure 138 +/- 13 and diastolic blood pressure 87 +/- 4 in 4 months of treatment. The combined therapy decreased systolic blood pressure 115 +/- 4.6 and diastolic blood pressure 75 +/- 4.7. The effect of treatments on systolic and diastolic blood pressure was significantly different as [p<0.001] and [p 0.036] respectively. Side effects observed in 2 [10%] patients from group C, 8 [40%] in group A and 4 [20%] in group B. Combination therapy proved more effective in controlling hypertension than mono therapy and also fewer side effects. Patients showed better control on combination therapy as compared to mono therapy. Losartan proved a little better in controlling hypertension then atenolol and was more expensive. Patients showed better results with combination therapy for hypertension compared to individual drug

Endogenous angiotensin II modulates nNOS expression in renovascular hypertension

Nitric oxide (NO) influences renal blood flow mainly as a result of neuronal nitric oxide synthase (nNOS). Nevertheless, it is unclear how nNOS expression is modulated by endogenous angiotensin II, an inhibitor of NO function. We tested the hypothesis that the angiotensin II AT1 receptor and oxidative stress mediated by NADPH oxidase contribute to the modulation of renal nNOS expression in two-kidney, one-clip (2K1C) hypertensive rats. Experiments were performed on male Wistar rats (150 to 170 g body weight) divided into 2K1C (N = 19) and sham-operated (N = 19) groups. nNOS expression in kidneys of 2K1C hypertensive rats (N = 9) was compared by Western blotting to that of 2K1C rats treated with low doses of the AT1 antagonist losartan (10 mg·kg-1·day-1; N = 5) or the superoxide scavenger tempol (0.2 mmol·kg-1·day-1; N = 5), which still remain hypertensive. After 28 days, nNOS expression was significantly increased by 1.7-fold in the clipped kidneys of 2K1C rats and by 3-fold in the non-clipped kidneys of 2K1C rats compared with sham rats, but was normalized by losartan. With tempol treatment, nNOS expression increased 2-fold in the clipped kidneys and 1.4-fold in the non-clipped kidneys compared with sham rats. The changes in nNOS expression were not followed by changes in the enzyme activity, as measured indirectly by the cGMP method. In conclusion, AT1 receptors and oxidative stress seem to be primary stimuli for increased nNOS expression, but this up-regulation does not result in higher enzyme activity.

Roles of mitogen-activated protein kinases and angiotensin II in renal development

Experimental and clinical evidence suggests that angiotensin II (AII) participates in renal development. Renal AII content is several-fold higher in newborn rats and mice than in adult animals. AII receptors are also expressed in higher amounts in the kidneys of newborn rats. The kidneys of fetuses whose mother received a type 1 AII receptor (AT1) antagonist during gestation present several morphological alterations. Mutations in genes that encode components of the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis. Morphological changes were detected in the kidneys of 3-week-old angiotensin-deficient mice. Mitogen-activated protein kinases (MAPKs) are important mediators that transduce extracellular stimuli to intracellular responses. The MAPK family comprises three major subgroups, namely extracellular signal-regulated protein kinase (ERK), c-jun N-terminal kinases (JNK), and p38 MAPK (p38). Important events in renal growth during nephrogenesis such as cellular proliferation and differentiation accompanied by apoptosis on a large scale can be mediated by MAPK pathways. A decrease in glomerulus number was observed in embryos cultured for 48 and 120 h with ERK or p38 inhibitors. Many effects of AII are mediated by MAPK pathways. Treatment with losartan during lactation provoked changes in renal function and structure associated with alterations in AT1 and type 2 AII (AT2) receptors and p-JNK and p-p38 expression in the kidney. Several studies have shown that AII and MAPKs play an important role in renal development. However, the relationship between the effects of AII and MAPK activation on renal development is still unclear.