Losartan prevents mesenteric vascular bed alterations in high-fat diet fed rats / Losartán previene las alteraciones del lecho vascular mesentérico en ratas alimentadas con dieta alta en grasas

Dysfunction of perivascular adipose tissue of mesenteric bed participates in the pathophysiology of high blood pressure linked to metabolic syndrome. Thus, it might consider a new therapeutic objective to take account in cardiovascular and metabolic diseases. Besides its antihypertensive effect, there is a growing interest on the pleiotropic actions of losartan, an angiotensin II type 1 (AT1) receptor antagonist. The aim of the study was to analyze the actions of losartan treatment on adiposity index and prostanoids release from mesenteric vascular bed and its relationship with blood pressure as well as homeostasis model of assessment of insulin resistance (HOMA-IR) in Sprague-Dawley rats under a high-fat (HF) diet for 8 weeks. Four groups were used: control (C), HF diet (HF, 50%, w/w bovine fat), losartan-treated (CL8, 30mg/kg/body weight/day in the drinking water) and losartan-treated HF diet (HFL, both treatments). A high-fat diet incremented systolic blood pressure, HOMA-IR, adiposity of mesenteric vascular bed and the release of vasoconstrictor prostanoids such as thromboxane (TX) B2 and prostaglandin (PG) F2α as well as PGE2, an inflammatory prostanoid in a context of insulin resistance and hypertension. We found a positive correlation between adiposity index and systolic blood pressure. Also, both parameters are positive correlated with the HOMA IR index. Moreover, we also found that these prostanoids release correlate with systolic blood pressure as well as with mesenteric vascular bed adiposity index. Losartan treatment prevented all these alterations and normalized the PGI2/TXA2 ratio in high-fat fed rats. We conclude that losartan may play beneficial actions on perivascular adipose tissue alterations and endothelial dysfunction through restoration of normal balance of vasoactive substances in this model

La disfunción del tejido adiposo perivascular del lecho mesentérico posee una participación en la fisiopatología de la hipertensión arterial relacionada con el síndrome metabólico. Por lo tanto, podría considerarse como un nuevo blanco terapéutico en las enfermedades cardiovasculares y metabólicas. Además de su efecto antihipertensivo, existe un interés creciente en las acciones pleiotrópicas de losartán, antagonista del receptor de angiotensina II. El objetivo del estudio fue analizar las acciones de losartán sobre el índice de adiposidad y la liberación de prostanoides del lecho vascular mesentérico y su relación con la presión arterial, así como en el índice HOMA-IR (modelo de evaluación homeostático de la resistencia a la insulina) en ratas con dieta alta en grasas. Observamos que la dieta alta en grasas incrementó la adiposidad del lecho vascular mesentérico y la liberación de prostanoides vasoconstrictores como tromboxano (TX) B2 y prostaglandina (PG) F2α, así como la PGE2, un prostanoide inflamatorio en el contexto de resistencia a la insulina e hipertensión. También encontramos una correlación positiva entre el índice de adiposidad y la presión arterial sistólica y ambos parámetros se correlacionan positivamente con el índice HOMA IR. Adicionalmente observamos que la liberación de estos prostanoides se correlaciona con la presión arterial sistólica, así como con el índice de adiposidad del lecho vascular mesentérico. El tratamiento con losartán previno todas estas alteraciones y normalizó la relación PGI2/TXA2 en ratas alimentadas con una dieta alta en grasa. Concluimos entonces que losartán puede ejercer acciones beneficiosas sobre las alteraciones del tejido adiposo perivascular y la disfunción endotelial a través de la restauración del equilibrio normal de sustancias vasoactivas en este modelo experimental

Losartan prevents mesenteric vascular bed alterations in high-fat diet fed rats.

Dysfunction of perivascular adipose tissue of mesenteric bed participates in the pathophysiology of high blood pressure linked to metabolic syndrome. Thus, it might consider a new therapeutic objective to take account in cardiovascular and metabolic diseases. Besides its antihypertensive effect, there is a growing interest on the pleiotropic actions of losartan, an angiotensin II type 1 (AT1) receptor antagonist. The aim of the study was to analyze the actions of losartan treatment on adiposity index and prostanoids release from mesenteric vascular bed and its relationship with blood pressure as well as homeostasis model of assessment of insulin resistance (HOMA-IR) in Sprague-Dawley rats under a high-fat (HF) diet for 8 weeks. Four groups were used: control (C), HF diet (HF, 50%, w/w bovine fat), losartan-treated (CL8, 30mg/kg/body weight/day in the drinking water) and losartan-treated HF diet (HFL, both treatments). A high-fat diet incremented systolic blood pressure, HOMA-IR, adiposity of mesenteric vascular bed and the release of vasoconstrictor prostanoids such as thromboxane (TX) B2 and prostaglandin (PG) F2α as well as PGE2, an inflammatory prostanoid in a context of insulin resistance and hypertension. We found a positive correlation between adiposity index and systolic blood pressure. Also, both parameters are positive correlated with the HOMA IR index. Moreover, we also found that these prostanoids release correlate with systolic blood pressure as well as with mesenteric vascular bed adiposity index. Losartan treatment prevented all these alterations and normalized the PGI2/TXA2 ratio in high-fat fed rats. We conclude that losartan may play beneficial actions on perivascular adipose tissue alterations and endothelial dysfunction through restoration of normal balance of vasoactive substances in this model.

Losartán y metformina previenen alteraciones en el tejido adiposo perivascular y en la liberación de prostanoides del lecho vascular mesentérico producidas por una dieta alta en grasa y sobrecarga de fructosa en ratas / Losartan and Metformin Prevent Abnormalities in Perivascular Adipose Tissue and in Mesenteric Vascular Bed Prostanoid Release Induced by High-fat High-fructose Diet in Rats

RESUMEN Objetivo: El objetivo de este trabajo fue analizar los efectos del losartán (30 mg/kg/día) y de la metformina (500 mg/kg/día) sobre el índice de adiposidad y la liberación de prostanoides del lecho vascular mesentérico, así como su relación con la presión arterial sistólica en un modelo de síndrome metabólico inducido por una dieta alta en grasa y sobrecarga de fructosa en ratas Sprague-Dawley macho durante 9 semanas. Material y métodos: Los lechos vasculares mesentéricos extraídos se incubaron y los prostanoides liberados se midieron por cromatografía líquida de alta eficiencia. La presión arterial sistólica fue medida por método indirecto. Resultados: La dieta alta en grasa y la sobrecarga de fructosa produjo aumentos significativos en la presión arterial sistólica y del índice de adiposidad del lecho vascular mesentérico. Por su parte, la dieta alta en grasa y sobrecarga de fructosa incrementó la liberación de prostanoides vasoconstrictores tanto del tromboxano B2 como de la prostaglandina F2alfa; y del marcador de inflamación, la prostaglandina E2. La relación PGI2/TXA2 se redujo significativamente. La administración de losartán como de metformina previnieron todas estas alteraciones. Conclusión: Ambos fármacos ejercen efectos beneficiosos sobre el tejido adiposo perivascular del lecho mesentérico, lo que mejora la disfunción endotelial inducida por un desbalance de sustancias vasoactivas.

ABSTRACT Objective: The aim of this study was to analyze the effects of losartan (30 mg/kg/day) and metformin (500 mg/kg/day) on the adiposity index and on mesenteric vascular bed prostanoid release, and their relationship with systolic blood pressure in a metabolic syndrome model induced by high-fat high fructose-diet in male Sprague-Dawley rats for 9 weeks. Methods: Mesenteric vascular beds were extracted and incubated and prostanoids were measured by high-performance liquid chromatography. Systolic blood pressure was measured by an indirect method. Results: High-fat high-fructose diet produced significant increase in systolic blood pressure and mesenteric vascular bed adiposity index and in the release of vasoconstricting prostanoids as thromboxane B2 and prostaglandin F2α and of prosta-glandin E2, a marker of inflammation. The PGI2/TXA2 ratio was significantly reduced. The administration of losartan and metformin prevented all these changes. Conclusion: Both drugs have beneficial effects on mesenteric perivascular adipose tissue by improving endothelial dysfunction induced by an imbalance of vasoactive substances.

Efectos del tungstato de sodio y sulfato de vanadilo sobre la liberación de prostanoides del lecho vascular mesentérico de ratas diabéticas / Effects of sodium tungstate and vanadyl sulphate on the liberation of prostanoids of the mesenteric vascular bed in diabetic rats

La pérdida del rol modulador del endotelio podría estar implicada en la patogénesis de las complicaciones vasculares diabéticas. Los compuestos de metales de transición tales como wolframio y vanadio se han propuesto como posibles agentes en el tratamiento de la diabetes al simular los efectos de la insulina. El lecho vascular mesentérico interviene en la resistencia vascular y constituye una fuente de compuestos vasoactivos como los prostanoides. El objetivo de este trabajo fue estudiar los efectos de los tratamientos con tungstato de sodio y sulfato de vanadilo sobre los parámetros metabólicos y la liberación de prostanoides del lecho vascular mesentérico en un modelo experimental de diabetes inducida por estreptozotocina. En ratas diabéticas se observó un aumento significativo de los niveles plasmáticos de glucosa, triglicéridos y colesterol total. Por su parte, se observó una reducción significativa en la liberación de los prostanoides vasodilatadores como la prostaciclina y la prostaglandina E2 y del vasoconstrictor tromboxano A2 por el lecho vascular mesentérico. Tanto el tungstato de sodio como el sulfato de vanadilo normalizaron la glucemia, la trigliceridemia y la colesterolemia en las ratas diabéticas. Por otra parte, solo el tratamiento con tungstato de sodio revirtió la reducción en la liberación de prostanoides vasodilatadores, mejorando en los animales diabéticos la relación prostaciclina/tromboxano, un indicador de disfunción vascular. En conclusión, a diferencia del sulfato de vanadilo, el tungstato de sodio demuestra ser más eficaz para controlar las alteraciones metabólicas y de la producción de prostanoides vasodilatadores observadas en la diabetes experimental inducida por estreptozotocina

The loss of the modulator role of the endothelium could be involved in the pathogenesis of diabetic vascular complications. Transition metal compounds, such as tungsten and vanadium, have been proposed as possible agents in the treatment of diabetes by simulating the effects of insulin. The mesenteric vascular bed intervenes in vascular resistance and is a source of vasoactive compounds, such as prostanoids. The aim of this work was to study the effects of sodium tungstate and vanadyl sulphate treatments on the metabolic parameters and the release of prostanoids of the mesenteric vascular bed in an experimental model of Streptozotocin-induced diabetes. In diabetic rats, a significant increase was observed in plasma levels of glucose, triglycerides and total cholesterol. On the other hand, there was a significant reduction in the release of vasodilator prostanoids, such as prostacyclin and prostaglandin E2 and vasoconstrictor thromboxane A2 through the mesenteric vascular bed. Both sodium tungstate and vanadyl sulphate normalised glycaemia, triglyceridaemia and cholesterolaemia in rats diabetics. On the other hand, only treatment with sodium tungstate reversed the reduction in the release of vasodilator prostanoids, improving in diabetic animals the prostacyclin/thromboxane ratio, an indicator of vascular dysfunction. In conclusion, unlike vanadyl sulphate, sodium tungstate is shown to be more effective in controlling metabolic changes and the production of vasodilator prostanoids observed in experimental diabetes induced by streptozotocin

Effects of sodium tungstate and vanadyl sulphate on the liberation of prostanoids of the mesenteric vascular bed in diabetic rats. / Efectos del tungstato de sodio y sulfato de vanadilo sobre la liberación de prostanoides del lecho vascular mesentérico de ratas diabéticas.

The loss of the modulator role of the endothelium could be involved in the pathogenesis of diabetic vascular complications. Transition metal compounds, such as tungsten and vanadium, have been proposed as possible agents in the treatment of diabetes by simulating the effects of insulin. The mesenteric vascular bed intervenes in vascular resistance and is a source of vasoactive compounds, such as prostanoids. The aim of this work was to study the effects of sodium tungstate and vanadyl sulphate treatments on the metabolic parameters and the release of prostanoids of the mesenteric vascular bed in an experimental model of Streptozotocin-induced diabetes. In diabetic rats, a significant increase was observed in plasma levels of glucose, triglycerides and total cholesterol. On the other hand, there was a significant reduction in the release of vasodilator prostanoids, such as prostacyclin and prostaglandin E2 and vasoconstrictor thromboxane A2 through the mesenteric vascular bed. Both sodium tungstate and vanadyl sulphate normalised glycaemia, triglyceridaemia and cholesterolaemia in rats diabetics. On the other hand, only treatment with sodium tungstate reversed the reduction in the release of vasodilator prostanoids, improving in diabetic animals the prostacyclin/thromboxane ratio, an indicator of vascular dysfunction. In conclusion, unlike vanadyl sulphate, sodium tungstate is shown to be more effective in controlling metabolic changes and the production of vasodilator prostanoids observed in experimental diabetes induced by streptozotocin.