Effects of chronic administration of tamsulosin and tadalafil, alone or in combination, in rats with bladder outlet obstruction induced by chronic nitric oxide deficiency

Purpose The aim of this study was to define if tadalafil causes detrusor muscle impairment and to observe the effect of combination of tadalafil with tamsulosin on the lower urinary tract of rats with bladder outlet obstruction (BOO) induced by chronic nitric oxide deficiency. Materials and Methods Thirty-one male rats were randomized to following groups: 1 - control; 2 - L-Nitroarginine methyl ester (L-NAME); 3 - Tamsulosin + L-NAME, 4 Tadalafil+L-NAME; and 5 - Tamsulosin + Tadalafil + L-NAME. At the end of the treatment period (30 days), all animals were submitted to urodynamic study. Results The administration of L-NAME increased the number of non-voiding contractions (NVC) (1.04 ± 0.22), volume threshold (VT) (1.86 ± 0.35), and micturition cycle (MC) (1.34 ± 0.11) compared with control (0.52 ± 0.06, 0.62 ± 0.06, and 0.67 ± 0.30), respectively. The administration of tamsulosin reduced the number of NVC (0.57 ± 0.42) and VT (0.76 ± 0.24 ) compared with L-NAME group. Co-treatment with tadalafil decreased the number of VT (0.85 ± 0.53) and MC (0.76 ± 0.22) compared with L-NAME group. The combination of tamsulosin with tadalafil improved the number of NVC (0.56 ± 0.18), VT (0.97 ± 0.52) and MC (0.68 ± 0.30) compared with L-NAME group. Conclusion In rats with BOO induced by chronic nitric oxide deficiency, tadalafil did not cause impairment in detrusor muscle and seems to have an addictive effect to tamsulosin because the combination decreased non voiding contractions as well the number of micturition cycles. .

Effect of acute administration of sildenafil to rats with detrusor overactivity induced by chronic deficiency of nitric oxide

Purpose Recently, the effect of phosphodiesterase inhibitors (PDE5i) in the lower urinary tract symptoms (LUTS) associated to benign prostatic hyperplasia have been studied thoroughly. However, it remains unclear how the PDE5i improve LUTS. Therefore, the aim of the present study was to evaluate the potential of acute administration of the PDE5i sildenafil to improve detrusor overactivity (DO) induced by Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME), an nitric oxide sinthase (NOS) inhibitor, in rats. Materials and Methods Twenty-seven MALE adult Wistar Rats were divided into the following groups: (1) control, (2) L-NAME, (3) sildenafil alone, and (4) L-NAME + sildenafil. The NOS blocker L-NAME (20 mg/rat/day) was given in the drinking water. Sildenafil (100µg/kg) was administrated intravenously (i.v.) acutely, diluted in cremophor, propylene glycol and water. All animals underwent to anesthetized cystometograms. Results The chronic and systemic administration of L-NAME markedly increased the number of non voiding contractions (2.62 (± 0.89)), and frequency of micturition (1.97 (± 0.78)), as well increased volume threshold (2.83 mL (± 1.64)) compared with control group, the number of non voiding contractions (1.17 (± 0.75)), frequency of micturition (1.08 (± 0.65)) and volume threshold (1.16 mL (± 0.38)), p < 0.001, p = 0.01, and p = 0.04, respectively. Sildenafil infusion decreased the number of micturition cycles significantly from the baseline to end point (-0.93 (± 0.34)) in nitric oxide (NO) deficient animals compared with sildenafil infusion alone (control) in animals with normal NO level (0.13 (± 0.25)), p = 0.03. Conclusion Systemic reduction of nitric oxide causes detrusor overactivity and acute infusion of sildenafil reduces the number of micturition cycles in chronic NO-deficient rats. .

Hipertensión y edema pulmonar de altura: Rol de la disfunción endotelial y de la programación fetal / Pulmonary hypertensión and lung edema at high altitude: Role of endothelial dysfunction and fetal programming

La altura constituye un fascinante laboratorio natural para la investigación médica. Si bien al principio el objetivo de la investigación en la altura fue la comprensión de los mecanismos de adaptación del organismo a la hipoxia y la búsqueda de tratamientos para las enfermedades relacionadas con la altura, durante la última década el alcance de esta investigación se ha ampliado considerablemente. Dos importantes observaciones han generado las bases para el crecimiento del alcance científico de la investigación en la altura. Primero, el hecho de que el edema pulmonar agudo de la altura constituye un modelo único para estudiar los mecanismos fundamentales de la hipertensión pulmonar y el edema pulmonar en humanos. Segundo, que la hipoxia ambiental asociada con la exposición a la altura facilita la detección de disfunción vascular pulmonar y sistémica en un estadio precoz. Aquí revisaremos los estudios que, capitalizando estas observaciones, han llevado a la descripción de nuevos mecanismos subyacentes del edema pulmonar y de la hipertensión pulmonar, y a la primera demostración directa de la existencia de una programación fetal sobre la disfunción vascular en humanos.

High altitude constitutes an exciting natural laboratory for medical research. While initially, the aim of high-altitude research was to understand the adaptation of the organism to hypoxia and find treatments for altitude-related diseases, over the past decade or so, the scope of this research has broadened considerably. Two important observations led to the foundation for the broadening of the scientific scope of high-altitude research. First, high-altitude pulmonary edema (HAPE) represents a unique model which allows studying fundamental mechanisms of pulmonary hypertension and lung edema in humans. Secondly, the ambient hypoxia associated with high-altitude exposure facilitates the detection of pulmonary and systemic vascular dysfunction at an early stage. Here, we review studies that, by capitalizing on these observations, have led to the description of novel mechanisms underpinning lung edema and pulmonary hypertension and to the first direct demonstration of fetal programming of vascular dysfunction in humans.

Rosuvastatin prevents proteinuria and renal inflammation in nitric oxide-deficient rats

OBJECTIVE: The aim of the present study was to assess the effects of rosuvastatin on renal injury and inflammation in a model of nitric oxide deficiency. METHODS: Male Wistar rats were randomly divided into four groups (n = 10/group) and treated for 28 days with saline (CTRL); 30 mg/kg/day L-NAME (L-name); L-NAME and 20 mg/kg/day rosuvastatin (L-name+ROS-20); or L-NAME and 2 mg/kg/day rosuvastatin (L-name+ROS-2). Systolic blood pressure was measured by plethysmography in the central artery of the tail. The serum total cholesterol, triglycerides, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, creatinine, nitric oxide, interleukin-6, and tumor necrosis factor alpha levels were analyzed. Urine samples were taken to measure the albumin: urinary creatinine ratio. Kidneys were sectioned and stained with hematoxylin/eosin and Masson's trichrome. Immunohistochemical analysis of the renal tissue was performed to detect macrophage infiltration of the glomeruli. RESULTS: The systolic blood pressure was elevated in the L-name but not the L-name+rosuvastatin-20 and L-name+rosuvastatin-2 groups. The L-name group had a significantly reduced nitric oxide level and an increased interleukin-6 and tumor necrosis factor alpha level, albumin: urinary creatinine ratio and number of macrophages in the renal glomeruli. Rosuvastatin increased the nitric oxide level in the L-name+rosuvastatin-2 group and reduced the interleukin-6 and tumor necrosis factor alpha levels, glomerular macrophage number and albumin:urinary creatinine ratio in the L-name+rosuvastatin-20 and L-name+rosuvastatin-2 groups. CONCLUSION: Rosuvastatin treatment reduced glomerular damage due to improvement in the inflammatory pattern independent of the systolic blood pressure and serum lipid level. These effects may lead to improvements in the treatment of kidney disease.

Oxidative stress and nitric oxide deficiency in inflammation of chronic renal failure. Possible preventive role of L-arginine and multiple antioxidants

To evaluate the effect of L-arginine and multiple antioxidants on the inflammatory cytokines level, renal functions, blood pressure and dyslipidemia in chronic renal failure [CRF] rats. This study was carried out between December 2007 and November 2008 in the Department of Physiology, Faculty of Medicine, King Saud University, Kingdom of Saudi Arabia. Chronic renal failure was induced in 40 rats by renal mass reduction [RMR] and 10 rats were sham operated. Renal mass reduction rats were treated for 12 weeks by L-arginine and/or a mixture of antioxidants [L-carnitine, Catechin, Vitamins E and C] and the effect of the treatments on plasma cytokines, soluble intercellular adhesion molecule-1 [sICAM-1], nitrate [NO2] and nitrites [NO3], lipid profile, blood pressure, and renal function was examined. Chronic renal failure increased plasma Interleukin [IL]-1alpha, IL-1beta, IL-6, tumor necrosis factor-alpha, soluble intercellular adhesion molecule-1 [sICAM-1] levels and decreased anti-inflammatory cytokines IL-4 and 10 levels. In addition, hypertension, and dyslipidemia were found. L-arginine treatment improved kidney functions, decreased systolic blood pressure and decreased inflammatory cytokines levels. Antioxidants administration decreased inflammatory cytokines and sICAM-1 levels and increased IL-4 levels. Combined use of L-arginine and the antioxidants mixture were very effective in their tendency to recover normal values of kidney functions, plasma cytokines, sICAM-1, blood pressure, NO2/NO3, cholesterol and triglycerides concentrations. Restoration of the pro-oxidant/ antioxidants balance with increased NO bio-availability counteracts inflammation, renal impairment and dyslipidemia in CRF. This may open new perspectives for the role of antioxidants and NO precursors in the treatment of uremia and its complications

Defecto en la homeostasis del óxido nítrico: Mecanismo común subyacente de la insulino-resistencia, la hiperactividad simpática y la morbi-mortalidad cardiovascular / Defective nitric oxide homeostasis: Common underlying mechanism between insulin resistance, sympathetic overactivity and cardiovascular morbidity and mortality

La incidencia de la obesidad y de la resistencia a la insulina con sus complicaciones asociadas, como la hipertensión arterial y el aumento de la morbi-mortalidad cardiovascular, alcanzan hoy en día proporciones epidémicas y representan un problema mayor de salud pública. En los últimos años se ha demostrado que la administración de insulina, además de sus efectos metabólicos, posee efectos cardiovasculares importantes. El sistema nervioso simpático y el sistema L-arginina - óxido nítrico son los mediadores centrales de estas acciones cardiovasculares de la insulina. Mostramos, gracias a estudios realizados en animales y en humanos, que no sólo un déficit de la síntesis del óxido nítrico (NO), sino también un aumento exagerado en su producción representan un defecto subyacente central de las anomalías metabólicas, cardiovasculares y del sistema nervioso simpático que caracterizan a la insulino resistencia. Mostramos cómo estos resultados establecen el fundamento científico para la utilización de sustancias farmacológicas capaces de liberar de manera prolongada cantidades fisiológicas de NO o de inhibidores de su sobreproducción como futuros tratamientos para la resistencia a la insulina y sus complicaciones asociadas.

Obesity, insulin resistance and associated cardiovascular complications are reaching epidemic proportions worldwide and represent a major public health problem. Over the past decade, evidence has accumulated indicating that insulin administration, in addition to its metabolic effects, also has important cardiovascular actions. The sympathetic nervous system and the L-arginine-nitric oxide pathway are the central players in the mediation of insulin's cardiovascular actions. Based on recent animal and human research, we demonstrate that both defective and augmented NO synthesis represent a central defect triggering many of the metabolic, vascular and sympathetic abnormalities characteristic of insulin-resistant states. These observations provide the rationale for the use of pharmaceutical drugs releasing small and physiological amounts of NO and/or inhibitors of NO overproduction as a future treatment for insulin resistance and associated comorbidities.

Obstructive sleep apnoea/hypopnoea syndrome and hypertension

The obstructive sleep apnoea/hypopnoea syndrome [OSAHS] is a common disorder, affecting around 2-4% of the middle-aged population. There is a strong association between OSAHS and hypertension, based on animal, large epidemiological and interventional studies. The epidemiological studies have shown a dose-response relationship between apnoea/hypopnoea index [AHI] and the risk of developing hypertension. Different mechanisms may have a role in the process of elevated blood pressure in OSAHS. Sympathetic activity is increased in OSAHS patients during sleep and wakefulness. This increase in sympathetic activity is probably due to activation of baroreflexes and chemoreflexes by frequent arousals and hypoxaemia a result of apnoea or hypopnoea events. Continuous positive airway pressure [CPAP] has been shown to reduce sympathetic stimulation and blood pressure in OSAHS patients. Altered endothelial function may also have a role in the pathogenesis of hypertension in OSAHS subjects. Reduction of nitric oxide [NO] production and increase in the formation of free radicals may be responsible for the impairment of the vasodilatation of micro-vasculature in these subjects as a result of hypoxaemia. It has been shown that effective CPAP therapy has a reversible effect on endothelial dysfunction

El lactitol incrementa el glutation reducido y disminuye el óxido nítrico en ratas Sprague-Dawley / Lactitol increases reduced glutathione and decreases nitric oxide in Sprague Dawley rats

Existe un creciente uso de los alcohol-azúcares como el lactitol en la industria de los alimentos. El estrés oxidativo juega un papel importante en la génesis de patologías digestivas que van desde inflamación hasta cáncer. El propósito de este estudio fue determinar el efecto del lactitol sobre el malondialdehído (MDA), óxido nítrico (NO), glutation reducido (GSH), ácido ascórbico y ácido dehidroascórbico como marcadores del balance oxidación/antioxidación. Para ello se utilizaron 80 ratas macho Sprague-Dawley divididas en cuatro grupos , tres experimentales de 20 animales, a los cuales se les administró por sonda orogástrica, lactitol en dosis de 0,3; 1,0 y 5,0 g/Kg/día durante 12 semanas y un grupo control que recibió solución salina fisiológica por el mismo período de tiempo. El lactitol administrado en dosis de 0,3; 1,0 y 5,0 g/Kg/día produjo un incremento significativo (P<0,05) del GSH (326,5 ± 13,0 µg/ml; 328,5 ± 9,2 µg/ml y 398,2 ± 11,8 µg/ml) al ser comparado con sus respectivos valores basales (285,8 ± 4,0 µg/ml; 280,0 ± 6,2 µg/ml y 279,5 ± 9,1 µg/ml). El lactitol a dosis de 5 g/Kg/día produjo el más alto incremento de la concentración de GSH y al mismo tiempo provocó una disminución significativa del los niveles de NO (33,0 ± 1,2 µM) cuando se comparó con su concentración basal (46,2 ± 2,8 µM). No fueron observados cambios significativos sobre el resto de los marcadores del balance oxidación/antioxidación. Aunque el lactitol es un alcohol-azúcar que no se absorbe a nivel del tracto gastrointestinal, es posible que los productos finales obtenidos luego de su metabolismo por las bacterias intestinales, induzcan efectos sistémicos que pueden afectar el balance oxidación/antioxidación a favor de la antioxidación.

Sugar alcohols such as lactitol are increasingly being used in the food industry. Tissue oxidative stress is an important contributor to the genesis of inflammatory bowel disease and cancer. The purpose of this study was to determine the effect of lactitol on malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), dehydroascorbic and ascorbic acid as redox markers. Eighty Sprague Dawley rats were divided into four groups; three experimental groups which received lactitol through an oral catheter at doses of 0.3; 1.0; 5 g/kg/day and an experimental group to which saline solution was administered during 12 weeks. Lactitol at doses of 0.3; 1.0; 5 g/kg/day produced a significant increase (P<0.05) on GSH (326.5 ± 13.0 µg/ml; 328.5 ± 9.2 µg/ml y 398.29 ± 11.8 µg/ml respectively) when compared with their respective basal values (285.8 ± 4.0 µg/ml; 280.0 ± 6.2 µg/ml y 279.5 ± 9.1 µg/ml). Lactitol dose of 5g/kg/day produced the highest increase on GSH levels and at the same time elicited a significant decrease on NO levels (33.0 ± 1.2 µM) when compared with basal values (46.2 ± 2.8 µM). No significant changes were observed on the remaining redox markers. Although lactitol is a sugar alcohol that is not absorbed in the small bowel, it is possible that its metabolisms end products, under intestinal bacterial effects, alter the redox balance in favor of antioxidants.

Endotelio vascular e hipertensión arterial / Hypertension and vascular endothelial

El endotelio funciona como receptor efector frente a cada estímulo físico o químico liberando las sustancias necesarias para mantener las homeostasis y funciones vasculares. Esto se logra mediante un delicado balance entre la liberación de sustancias que ejercen efectos funcionales antagónicos. Un desbalance de estos factores genera disfunción endotelial. El estrés oxidativo constituye una alteración que permite explicar la generación de hipertensión arterial en diversas patologías y asocia a una menor biodisponibilidad del vasodilatador óxido nítrico que produce el endotelio; su ocurrencia es debida en parte a la activación de la enzima NADPH oxidasa, principal fuente de anión superóxido de la pared vascular y mediador de agentes vasocontrictores. Esto deriva en un predominio de las fuerzas vasoconstrictoras de la pared vascular. Se presentan los mecanismos que pueden dar cuenta del papel del endotelio en el desarrollo de hipertensión arterial, aplicando estos conceptos al análisis de la hipertensión presente en algunos ejemplos clínicos.

Value of serum nitric oxide in patients with coronary artery disease before and after percutaneous transluminal coronary angioplasty with or without stent

Our study was planned to assess the value of plasma NO as an early marker for endothelial injury and to detect its relation to the severity of coronary artery disease and its relation to restenosis after PCI. This study included [51] patients; [14] were normal control group [Group I]; and [37] patients were diseased [Group II], whom classified into three subgroups; subgroup [A] patients with single vessel disease [15 patients], subgroup [B] patients with two vessels disease [15 patients], subgroup [C] multi-vessels disease included [7 patients]. All patients subjected to coronary angiography with or without intervention [PTCA only, PTCA + stent or without stent]. [21] Patients accepted and respected follow-up by coronary angiography after 4 months. NO serum level was done before PCI and after 4 months in those accepted follow-up. Mean NO serum level on control group was 83 micro mol/L, while mean plasma NO serum level in subgroup [A] [34.8 +/- 10.3 micro mol/L], [17.5 +/- 3.5 micro mol/L] in subgroup [B]; and [8.9 +/- 2.2 micro mol/L in subgroup [C]. This revealed a highly significant decrease than control group, with P-value <0.05, <0.0005 and <0.0005 respectively when compared mean NO serum level in control group with each subgroup. On comparing the mean values of plasma NO level of subgroups [A, B, C]; to each other there was more or less gradual mathematical decrease in NO serum level between the subgroups, with highly significant P-values. Comparing the mean level of plasma NO of restenosis cases before and after PCI in each subgroup [A, B and C], we found a significant decrease in plasma NO level after PCI than before PCI. Endothelial dysfunction is an important contributing factor in CAD and it is associated with NO deficiency which can be considered as one of the endothelial markers for CAD. The more the degree of endothelial dysfunction, the more the deficiency of NO, the more the severity of CAD. Restenosis is a multi-factorial subject requiring a lot of work and lack of NO is related at least in part to the development of restenosis after angioplasty. We can suggest that if plasma NO level after PCI is reduced at least 30% of its initial level before PCI, most probably restenosis has occurred

Role of nitric oxide in essential hypertension and its relationship to ventricular hypertrophy

Patients with essential hypertension exhibit blunted endothelium dependent vasodilator response, which is largely attributable to reduced bioavailability of nitric oxide [NO]. Therefore, this study was designed to estimate, more directly, nitric oxide production in patients with essential hypertension and to examine the possible association between NO and left ventrivular [LV] and vascular hypertrophy. The level of serum total nitrite and nitrate, the stable end products of NO oxidation, was measured in 40 hypertensive patients [group I] and 15 control subjects [group II]. Hypertensive patients were divided according to LV geometry into 21 patients with left ventricular hypertrophy [LVH] [group Ia] and 19 patients with normal LV geometry [group Ib]. Serum total nitrite and nitrate level was significantly lower in patients with essential hypertension compared to normal controls [25.07 +/- 8.78 micro mol/L verses 39.36 +/- 7.07 micro mol/L] [p<0.001]. It was significantly lower in patients with LVH compared to patients without LVH [20.50 +/- 8.07 micro mol/L versus 30.11 +/- 6.60 micro mol/L] [p<0.001]. There was a significant negative correlation between serum total nitrite and nitrate level and LVMI, IVS and PWT [p<0.001]. This study also showed a significant positive correlation between LVMI and carotid, femoral and aortic media to lumen [M/L] ratio [p<0.001]. Serum total nitrite and nitrate level was significantly lower in patients with higher M/L ratio and there was a significant negative correlation between serum total nitrite and nitrate level and carotid, femoral and aortic M/L ratio [p<0.01, p<0.001 and p<0.05 respectively]. It was concluded that NO level is reduced in patients with essential hypertension and that this reduced level has a role in the pathogenesis of left ventricular and vascular hy[ertrophy in patients with essential hyptertension