ABSTRACT
Previamente hemos demostrado que la eficacia de enalapril, candesartán y de fasudil -inhibidor de la vía RhoA/ROCK,- en el tratamiento del remodelado cardíaco en la hipertensión (HTA) e infarto al miocardio está mediada por aumento en los niveles circulantes del péptido vasoactivo angiotensina [Ang]-(1-9). Sin embargo, no hay información disponible si el antagonista del receptor de mineralocorticoide, espironolactona (espiro) disminuye el remodelado cardíaco aumentando los niveles circulantes de Ang-(1-9). El objetivo de este trabajo fue determinar si espironolac-tona disminuye el remodelado cardíaco aumentando los niveles circulantes de Ang-(1-9) en la hipertensión arterial experimental. Métodos. Estudio comparativo de 3 grupos experimentales. Se utilizaron ratas Sprague Dawley macho (150 ± 10 grs) unifrectomizadas tratadas con desoxi-corticosterona (DOCA, 60mg/Kg 2 veces sem, im) por 6 semanas. Como controles (Sham) se usaron ratas unifrectomizadas. A partir de la 3° semana las ratas DOCA con HTA> 140 mmHg fueron randomizadas a recibir vehículo o espiro (100 mg/kg día, gavage) por 3 sem. Al finalizar el tratamiento se determinó la presión arterial sistólica (PAS), masa corporal, peso del corazón (PC) y masa cardíaca relativa al largo de la tibia (MCR, mg ventrículos/LT*100). El grado de hipertrofia car-diomiocitaria se determinó midiendo el área y perímetro de los cardiomiocitos y la fibrosis por el contenido de colágeno en cortes teñidos con rojo picrosirio. Resultados (promedio ± ES): Conclusión: Espironolactona disminuye la PAS y aumenta los niveles circulantes de Ang-(1-9). Este aumento en los niveles circulantes de Ang-(1-9) se asocia con una disminución significativa de la hipertrofia y la fibrosis cardiaca hipertensiva. Este nuevo efecto de espironolactona en los niveles circulantes de Ang-(1-9), - péptido vasoactivo de la vía paralela del sistema renina-angiotensina-aldosterona,- podría contribuir al efecto antihipertensivo y disminución del daño cardiaco en la hipertensión y remodelamiento cardiovascular y renal patológico. Estos hallazgos pueden tener relevancia terapéutica en términos que Ang-(1-9) podría disminuir el daño cardiovascular patológico.
We have previously demonstrated that the efficacy of enalapril, candesartan and fasudil,- RhoA / ROCK inhibitor-, in the treatment of cardiac remodeling in hypertension (HT) and myocardial infarction is mediated by an increase in circulating levels of the vasoactive peptide angiotensin (Ang) -(1-9). However, it is not known whether the mineralocorticoid receptor antagonist, spironolactone (spiro) decreases cardiac remodeling by increasing the circulating levels of Ang- (1-9). The aim of this study was to determine whether spironolactone decreases cardiac remodeling by increasing circulating levels of Ang-(1-9) in experimental hypertension. Methods. Comparative study of 3 experimental groups. Unifirectomized male Sprague Dawley rats (150 ± 10 grams) were treated with deoxycorticos-terone (DOCA, 60 mg / kg 2 times a week, im) for 6 weeks. Unifirectomized rats were used as controls (Sham). At 3rd week after surgery, DOCA rats with HTA> 140 mmHg were randomized to receive vehicle or spironolactone (Spiro, 100 mg / kg day, gavage) for 3 weeks. At the end of treatment, systolic blood pressure (SBP), body mass (BM), heart weight (HW) and relative cardiac mass to the tibia length (MCR, mg ventricles / LT * 100) were determined. The degree of cardiomyocyte hypertrophy was determined by measuring the area and perimeter of cardiomyocytes and fibrosis by collagen content in sections stained with picrosirius red. Results (mean ± ES): Conclusion: Spironolactone decreases systolic blood pressure and increases circulating levels of Ang-(1-9). This increase in circulating levels of Ang- (1-9) was associated with a significant decrease in hypertrophy and hypertensive cardiac fibrosis. This new effect of spironolactone on the circulating levels of Ang- (1-9) - vasoactive peptide of the parallel pathway of the re-nin-angiotensin-aldosterone system - could contribute to the antihypertensive effect and decrease of cardiac damage in HT and cardiovascular remodeling and renal disease. These findings may have therapeutic relevance supporting that Ang-(1-9) may decreases pathologic cardiovascular damage.
Subject(s)
Animals , Male , Rats , Spironolactone/pharmacology , Angiotensins/drug effects , Ventricular Remodeling/drug effects , Hypertension/drug therapy , Rats, Sprague-Dawley , Disease Models, Animal , Mineralocorticoid Receptor Antagonists/pharmacologyABSTRACT
Estrogen stimulates the renin-angiotensin system by augmenting both tissue and circulating levels of angiotensinogen and renin. We show, however, that angiotensin converting enzyme (ACE) activity in the circulation and in tissues is reduced in two animal models of postmenopausal chronic hormone replacement. We observed a reduction of ACE activity in association with a significant increase in plasma angiotensin I (Ang I) and hyperreninemia in ovariectomized monkeys treated with Premarin (conjugated equine estrogen) replacement for 30 months. Plasma angiotensin II (Ang II) levels were not increased in monkeys treated with estrogen, suggesting that the decrease in ACE curtailed the formation of the peptide. The Ang II/Ang I ratio, an in vivo index of ACE activity, was significantly reduced by estrogen treatment, further supporting the biochemical significance of estrogen's inhibition of ACE. In ovariectomized transgenic hypertensive (mRen2)27 rats submitted to estrogen replacement treatment for 3 weeks, ACE activity in plasma and tissue (aorta and kidney) and circulating Ang II levels were reduced, whereas circulating levels of angiotensin-(1-7) (Ang-(1-7) were increased. Ang-(1-7), the N-terminal fragment of Ang II, is a novel vasodilator and antihypertensive peptide. Thus, the net balance of these effects of estrogen on the renin-angiotensin vasoconstrictor/vasodilator system is to promote the antihypertensive effect.