Spontaneously hypertensive
stroke-prone rats (SHRSP) develop
hypertension and systemic
inflammation, with subsequent brain and renal disorders and early death. We tested the hypothesis that
valsartan, an
angiotensin II type 1 (AT1) receptor antagonist, exerts protective effects in SHRSP through its anti-inflammatory properties, even in the absence of a blood pressure-lowering effect. SHRSP fed a high-
salt diet were treated with vehicle or
valsartan (1-10 mg/kg/day). The vehicle-treated rats developed
hypertension,
proteinuria, progressive
kidney disease, and, 40 +/- 5 days from the beginning of the treatment, brain damage as visualized by magnetic resonance imaging. Rats treated with 1 mg/kg/day
valsartan developed brain damage after 61 +/- 3 days (p <0.01 versus vehicle-treated rats). No damage showed after 100 days in 80% of the rats treated with 10 mg/kg/day.
Valsartan treatment preserved renal structure, by preventing the infiltration of inflammatory cells, and lowered renal expression of
monocyte chemoattractant protein-1,
transforming growth factor-beta1, and
interleukin-1beta, compared with vehicle-treated SHRSP. Urinary excretion of
acute-phase proteins increased in the latter but remained negligible in the
drug-treated animals. Furthermore,
valsartan exerted protective effects also when given after established
proteinuria. In SHRSP, blockade of AT1 receptor with
valsartan prevents the development of
proteinuria, delays the appearance of brain damage, preserves renal structure, and increases survival under stressful conditions.
Valsartan exerts its beneficial effects independently of any blood pressure fall and by means of broad anti-inflammatory actions both at local and at systemic levels. These observations indicate that the administration of AT1 receptor antagonists may be useful in pathological situations in which an anti-inflammatory effect is required.