Beneficial effects of angiotensin II AT1 blocker on cardiovascular adverse remodeling due to nitric oxide synthesis blockade / Efectos beneficiosos del bloqueador AT1 de la angiotensina II en la remodelacion cardiovascular adversa causada por el bloqueo de la sintesis de oxido nitrico.

FERNANDES-SANTOS, C.; MENDONCA, L. D. & MANDARIM-DE-LACERDA, C. A. Beneficial effects of angiotensin II AT1 blocker on cardiovascular adverse remodeling due to nitric oxide synthesis blockade. Int. J. Morphol., 24(3):309-318, 2006.

SUMMARY: We studied with morphological tools the effects of different doses of Losartan upon the cardiovascular remodeling in nitric oxide deficient rats. At 15 weeks of age, thirty Wistar rats were separated in six groups: control (C), L-NAME (LN), and four groups were LN was given plus Losartan at different doses (1, 5, 20 and 40 mg/kg/day). The L-NAME was given for 9 weeks, the Losartan administration starting on the 2nd week of experiment. We studied the heart, thoracic aorta and superior mesenteric artery with light microscopy and stereology. The blood pressure (BP) increased since the first week of L-NAME administration, the Losartan treatment at doses of 20 and 40 mg/kg/day was efficient to reduce BP after the 7th week of treatment. The cardiac adverse remodeling in the LN group was characterized by intense interstitial fibrosis, impairment of the myocardial microvascularization, cardiomyocyte hypertrophy and consequent loss of cardiomyocytes. The aortic wall structure (density per area of smooth muscle cell nuclei and surface density of lamellae), and the superior mesenteric artery media/lumen ratio were also strongly affected by L-NAME administration. Only in the dose equal or higher than 20 mg/kg/day Losartan showed beneficial effects treating these alterations. In conclusion, both the heart and the arterial wall of NO deficient rats suffer a marked adverse remodeling process that is efficiently treated by a dose-dependent Losartan administration. The efficiency of Losartan treatment in this model of NO synthesis blockade correlates with the hypotensor effect of the drug mainly in the high dose treatment.

KEY WORDS: Losartan; Angiotensin II; L-NAME; Hypertension; Renin-angiotensin system; Stereology.

FERNANDES-SANTOS, C.; MENDONCA, L. D. & MANDARIM-DE-LACERDA, C. A. Efectos beneficiosos del bloqueador AT1 de la angiotensina II en la remodelacion cardiovascular adversa causada por el bloqueo de la sintesis de oxido nitrico. Int. J. Morphol., 24(3):309-318, 2006.

RESUMEN: Se estudiaron con herramientas morfologicas, los efectos de diferentes dosis de Losartan sobre el remodelamiento cardiovascular, en ratas deficientes en oxido nitrico. 30 ratas Wistar, con 15 semanas de edad, fueron separadas en 6 grupos. control (C), L-NAME (LN), y 4 grupos en que administro LN junto con Losartan, en diferentes dosis (1, 5, 20 y 40 mg/kg/dia). El L-NAME fue administrado durante 9 semanas y la administracion de Losartan se inicio en la segunda semana de experimentacion. Se estudiaron el corazon, la parte toracica de la aorta y la arteria mesenterica craneal, con microscopia de luz y estereologia. La presion arterial (PA) aumento desde la primera semana de administracion de L-NAME. El tratamiento con Losartan, en las dosis de 20 y 40 mg/kg/dia, fue eficiente para reducir la PA despues de la septima semana de tratamiento. El remodelamiento cardiaco adverso en el grupo LN se caracterizo por intensa fibrosis intersticial, disminucion de la microvascularizacion miocardica e hipertrofia y consecuente perdida de cardiomiocitos. La estructura de la pared de la aorta (densidad por area de nucleos de celulas musculares lisas y densidad de superficie de lamelas), y la relacion media/luz de la arteria mesenterica craneal, tambien fueron muy alteradas por la administracion de L-NAME. Solo en una dosis igual o mayor que 20 mg/kg/dia, el Losartan tuvo efecto benefico tratando estas alteraciones. En conclusion, tanto el corazon como la pared arterial de ratas deficientes en oxido nitrico, presentan un proceso de remodelamiento acentuado, y este es eficientemente tratado con Losartan en diferentes dosis. La eficiencia del tratamiento con Losartan en el modelo de bloqueo de la sintesis de oxido nitrico se correlaciona con el efecto hipotensor de la droga, principalmente en las dosis mas elevadas.

PALABRAS CLAVE: Losartan; Angiotensina II; L-NAME; Hipertension; Sistema renina-angiotensina, Estereologia.

INTRODUCTION

The nitric oxide (NO), a paracrine vasodilator, plays an important role in the regulation of vascular tone, the inhibition of platelet aggregation, and the suppression of smooth muscle cell proliferation, and therefore may be critical in the developing of arterial hypertension and atherosclerosis (Furchgott & Zawadzki, 1980; Ignarro et al., 1987; Rees et al., 1989). The blood pressure (BP) shows a sustained elevation after a long-lasting inhibition of NO synthase by administering L-NAME in drinking water to rats and the NO-deficient hypertension is now considered an experimental model of hypertension besides Goldblatt renal hypertension, Okamoto spontaneous hypertension, and DOCA-salt hypertension (Baylis et al., 1992; Ribeiro et al., 1992). Chronic inhibition of NO biosynthesis causes cardiac ischemia associated with a mechanical dysfunction which is similar to those seen in some patients suffering from chronic arterial hypertension (Moreno et al., 1996) and we know that changes in the arterial and heart structure in hypertension are a risk factor for cardiovascular morbidity and …