Expression of NAD(P)H Oxidase Subunits and Their Contribution to Cardiovascular Damage in Aldosterone/Salt-Induced Hypertensive Rat

NAD(P)H oxidase plays an important role in hypertension and its complication in aldosterone-salt rat. We questioned whether NAD(P)H oxidase subunit expression and activity are modulated by aldosterone and whether this is associated with target- organ damage. Rats were infused with aldosterone (0.75 microgram/hr/day) for 6 weeks and were given 0.9% NaCl+/-losartan (30 mg/kg/day), spironolactone (200 mg/kg/ day), and apocynin (1.5 mM/L). Aldosterone-salt hypertension was prevented completely by spironolactone and modestly by losartan and apocynin. Aldosterone increased aortic NAD(P)H oxidase activity by 34% and spironolactone and losartan inhibited the activity. Aortic expression of the subunits p47(phox), gp91(phox), and p22(phox) increased in aldosterone-infused rats by 5.5, 4.7, and 3.2-fold, respectively, which was decreased completely by spironolactone and partially by losartan and apocynin. Therefore, the increased expression of NAD(P)H oxidase may contribute to cardiovascular damage in aldosterone-salt hypertension through the increased expression of each subunit.

Síndrome de exceso aparente de mineralocorticoides por déficit de 11 ß hidroxiesteroide deshidrogenasa / A syndrome of apparent mineralocorticoid excess associated with a deficiency of 11 ß-hydroxysteroid dehydrogenase

An 11-year old girl was seen in 1981 with hypokalemia, low renin, low aldosterone, and severe hypertension. A medical adrenalectomy with dexamethasone and aminoglutethimide, and the blockade of mineralocorticoid receptors with spironolactone improved her condition, but the blockade of glucocorticoid receptors with RU-486 worsened it. An aldosterone infusion induced no changes. A sister was born in 1982 with similar findings. Both patients had an impaired ability to convert cortisol to cortisone after an oral load of 200 mg cortisol. In urine, an elevated ratio for metabolites of cortisol to metabolites of cortisone was found. These data suggested a defect in the activity of renal 11ß-hydroxysteroid dehydrogenase. Both parents were asymptomatic, phenotypically normal and non-consanguineous. Their urinary metabolites of cortisol and cortisone were normal before and after stimulation with ACTH. However, the mother reached a peak plasma cortisone concentration 3 SD below the mean reached by normal subjects after an oral 200-mg cortisol load, a fact that suggests that this test could be used to detect heterozygotes. The genetic studies revealed a homozygous mutation on exon 3 of the HSD11K gene, which by substituting TGC for CGC changes Arg 213 for Cys and induces a loss of 84 percent of the enzymatic activity in transfected cells. Both unrelated parents had the same heterozygous mutation. Both patients have been treated with dexamethasone but have also required spironolactone. The older sister has also required high doses of nifedipine to lower her blood pressure. After 19 years of follow-up, the older sister has become normotensive and normokalemic under therapy, and reached a final height of 140 cm at age 17. The younger sister has increased her mean blood pressure at a rate of 1 mm Hg per year, in spite of treatment. Her final height is 143.5 cm

Drogas dopaminergicas: aspectos farmacológicos y terapeúticos / Drug therapy dopamine effects pharmacology and therapeutic

Está ampliamente establecido que la dopamina y sus agonistas ejercen un papel importante en la regulación del sistema cardiovascular, renal y hormonal, actuando a través de los receptores-adrenérgicos y ß adrenérgicos. Existen varios agonistas DA-2 tales como bromocriptina, el pergolide, el lisuride pertenece a la familia de las ergolinas que actúan tanto a nivel central como a nivel periférico, inhibiendo la liberación de norepinefrina lo cual produce una disminución de la presión arterial y en algunos casos tales como la bromocriptina y el pergolide, causan una disminución de la frecuencia cardíaca. Desde el punto de vista terapéutico, los agonistas DA-2 antes mencionados se utilizan ampliamente en el tratamiento de la enfermedad de Parkinson, estos agonistas actúan a nivel de receptores DA2 situados en el sistema nigroestríado. La bromocriptina y los otros agonistas DA2 mencionados, se utilizan en el tratamiento de la hiperprolactinemia y en tumores hipofisarios, estos agonistas disminuyen la secreción de prolactina y reducen el tamaño del tumor actuando a través de receptores DA2 inhibidores situados en el sistema tuberoinfundibular. De manera similar también existen agonistas DA-1 como el fenoldopam (selectivo) y el piribedil (no selectivo) estos agonistas actúan los receptores periféricos causando una reducción de la resistencia periférica, de la resistencia vascular renal y un aumento del flujo sanguíneo renal. Todos estos efectos traen como consecuencia un descenso en la presión arterial y un aumento reflejo en la frecuencia cardíaca. El fenoldopam se utiliza en el tratamiento de la hipertensión arterial, insufiencia renal e insuficiencia cardíaca este agonista ejerce su acción a nivel de la de los receptores DA-1 localizados en las arterias periféricas y renales reduciendo la resistencia periférica, y la resistencia renal, esto trae como consecuencia un aumento del flujo sanguíneo renal y una disminución de la presión arterial. Dentro de los antagonsitas de los receptores DA-2 selectivos podemos mencionar la metoclopramida y la domperidona. ambos antagonistas causan disminución de la respuesta depresora de la dopamina. Se utiliza ampliamente en el tratamiento de desórdenes gastrointestinales. El antagonista específico de los receptores DA1 es la clozapina y el SCH23390. La clozapina se utiliza ampliamente en el tratamiento de la esquizofrenia, actúa activando los receptores DA1 y DA4 situados en el hipotálamo bulbo olfatorio y corteza frontal