Aim of the present study was to investigate the influence of the
angiotensin II (ANG II) subtype 1 (AT(1)) receptor blockers
fonsartan and
losartan on blood pressure, cardiac -dynamics and -metabolism as well as functional and morphological changes in the kidney of rats after long-term inhibition of the
nitric oxide (
NO) synthase by
N(G)-nitro-L-arginine methyl ester (
L-NAME). Oral chronic treatment with
L-NAME in a dose of 25 mg/kg/d over 6 weeks caused a significant increase in systolic blood pressure (198+/-13 mmHg) when compared to untreated rats (144+/-4 mmHg). Animals receiving simultaneously
L-NAME and
fonsartan (10 mg/kg/d) or
losartan (30 mg/kg/d) were protected against blood pressure increase.
L-NAME treatment caused a significant decrease in glomerular filtration rate (GFR) from 4.52+/-0.81 to 1.34+/-0.26 ml/kg(-1)/min(-1) and renal plasma flow (RPF) from 10.52+/-1.29 ml/kg(-1)/min(-1) to 5.66+/-1.06 ml/kg(-1)/min(-1). Co-treatment with
fonsartan and
losartan prevented
L-NAME-induced reduction in GFR and RPF. There was no difference in urine,
sodium and
potassium excretion in groups under investigation. Plasma
renin activity (PRA) was further stimulated by
fonsartan and
losartan treatment.
L-NAME produced a significant elevation in urinary
protein excretion which was antagonised by both AT(1) blockers. Isolated hearts from animals treated with
L-NAME showed a significant prolongation in the duration of
ventricular fibrillation and a significant decrease in coronary flow as compared to control hearts. Treatment with
fonsartan and
losartan significantly decreased the duration of
ventricular fibrillation as compared to
L-NAME group. In addition, both AT(1) blockers given alone significantly reduced the duration of
ventricular fibrillation as compared to hearts from untreated controls. During
ischemia the cytosolic
enzymes lactate dehydrogenase and
creatine kinase as well as
lactate in the coronary effluent were significantly increased in the
L-NAME group. Myocardial tissue values of
glycogen,
ATP, and
creatine phosphate were decreased, whereas
lactate was increased.
Fonsartan and
losartan treatment totally abolished these effects. Histological examination of kidneys revealed that simultaneous administration of
fonsartan and
losartan with
L-NAME abolished
L-NAME-induced arteriolar
hyalinosis, segmental sclerosis of glomerular capillaries and focal tubular
atrophies. In conclusion, long-term blockade of ANG II subtype AT(1) receptors by
fonsartan and
losartan prevented
L-NAME-induced
hypertension, renal insufficiency, as well as cardio-dynamic, cardio-metabolic, and morphological deteriorations.