Resumen de Left Ventricular Hypertrophy Inhibition, Normalization of the Contractile Response and Oxidative Stress in Experimental Hypertension

Hernán Jorge Gómez Llambí, Bruno Buchholz, Gabriel Cao, Graciela Ottaviano, Angélica Müller, Ricardo Jorge Gelpi, Matilde E. Otero Losada, José Milei

• español

  Objetivo. Evaluar si el tratamiento antihipertensivo crónico inhibe el desarrollo de HVI y revierte el deterioro de la respuesta beta-adrenérgica cardíaca y su posible relación con cambios en el metabolismo oxidativo del miocardio. Métodos: Se distribuyeron ratas macho espontáneamente hipertensas (SHR, 2 meses de edad) en grupos (ngrupo=18) según (mg/kg, v.o.): losartán 30 (L), hidralazina 11 (H), rosuvastatina 10 (R), carvedilol 20 (C, n =16), agua (control tratamiento). Control hipertensión: 18 ratas normotensas (Wistar-Kyoto, WKY). Periódicamente se midieron presión arterial sistólica (PAS) (pletismografía, en animales despiertos) y peso corporal (PC). Luego de 16 meses se practicó eutanasia. El 50% de los corazones se montó en preparación Langendhorff para medir contractilidad pre y post estímulo beta adrenérgico (isoproterenol, Iso: 10-9M, 10-7M, 10-5M). En los corazones restantes se midió el peso ventricular izquierdo (PVI) que se normalizo por el PC .Se cuantificó la expresión inmunohistoquímica de Trx-1, Prx-2 y Grx-3 (indicadores antioxidantes). Resultados. Peso corporal: similar en todos los grupos. PAS (mm Hg): 154±3 (L), 137±1 (H), 190±3 (R)**, 206±3 (SHR)*, 183±1 (C)**, 141±1 (WKY) (*p<0.05 vs. L, H, WKY; **p<0.05 vs L, H, WKY, SHR). El PVI/PC de SHR y R fue mayor (p<0,05)  respecto a  L, H, C y WKY. En C no se observó correlación entre hipertensión e HVI. Grupos SHR, R y C: mostraron depresión de contractilidad basal vs L, H y WKY. Respuesta a Iso 10-5 M: similar en WKY y L; disminuída en C, H, R y SHR. Expresión de Trx-1, Prx-2 y Grx-3: aumentó en C, H, R y L (1.5-2 veces promedio, p<0.01 vs SHR y WKY). Conclusiones. El tratamiento con L, H y C previno el desarrollo de HVI. Losartán normalizó la respuesta a isoproterenol en SHR. Factores adicionales participarían en el desarrollo de HVI con deterioro de la respuesta inotrópica a la estimulación beta-adrenérgica en hipertensión. El aumento en la expresión de tiorredoxinas por tratamientos antihipertensivos sugiere un beneficio asociado, aumentando la respuesta antioxidante frente al estrés oxidativo en hipertensión.

• English

  Introduction and objectives: Left ventricular hypertrophy secondary to hypertension has been perceived as a protective mechanism toreduce wall stress and prevent heart failure. However, its presence is paradoxically associated with increased cardiovascular morbidity andmortality. The aim of this study was to evaluate whether chronic antihypertensive treatment inhibits the development of left ventricularhypertrophy and normalize the impaired cardiac beta-adrenergic response, and its possible association with changes in myocardial oxidativemetabolism.Methods: Spontaneously hypertensive male rats (SHR, 2 months old) were divided into groups (ngroup = 18) according to (mg/kg, p.o):losartan 30 (L), hydralazine-11 (H), rosuvastatin 10 (R), carvedilol 20 (C), and water (control treatment). The control hypertension groupconsisted of 18 normotensive rats (Wistar-Kyoto, WKY). Systolic blood pressure (SBP) (plethysmography in awake animals) and bodyweight (BW) were measured periodically. The animals were sacrificed at 16 months and 50% of the hearts were mounted in a Langendorffsystem to measure contractility before and after beta-adrenergic stimulation [isoproterenol (Iso): 10-9 M, 10-7 M, and 10-5 M]. In theremaining hearts left ventricular weight (LVW) was measured and normalized by BW. Immunohistochemical expression of thioredoxin 1(Trx-1), peroxyredoxin 2 (Prx-2) and glutaredoxin 3 (Grx-3) (antioxidant indicators) was quantified.Results: Body weight was similar in all groups. Systolic blood pressure (mm Hg) was 154 ± 3 (L), 137 ± 1 (H), 190 ± 3 (R)**, 206 ± 3(SHR)*, 183 ± 1 (C)**, and 141 ± 1 (WKY) (* p < 0.05 vs. L, H, WKY, ** p < 0.05 vs. L, H, WKY, SHR). LVW/BW was higher in SHR andR (p < 0.05) compared with L, H, C and WKY. In C, there was no correlation between hypertension and left ventricular hypertrophy. SHR,R and C evidenced baseline contractile depression vs. L, H and WKY. The response to 10-5 M Iso was similar in WKY and L, and reducedin C, H, R and SHR. The expression of Trx-1, Prx-2 and Grx-3 increased in C, H, R and L (average increase: 1.5-2 times; p < 0.01 vs. SHRand WKY).Conclusions: Treatment with losartan, hydralazine, and carvedilol prevented the development of left ventricular hypertrophy. Losartannormalized the response to isoproterenol in SHR. Additional factors might participate in the development of left ventricular hypertrophywith impaired inotropic response to beta-adrenergic stimulation in hypertension. The increased expression of thioredoxins as a result ofantihypertensive treatment suggests an additional benefit, increasing the antioxidant response against oxidative stress in hypertensi