title: Angiotensin II subtype AT1 receptor blockade prevents hypertension and renal insufficiency induced by chronic NO-synthase inhibition in rats.
abstract: 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.
authors.affiliation: Cardiovascular Diseases, Aventis Pharma Deutschland GmbH, H 821, 65926 Frankfurt am Main, Germany. max.hropot@aventis.com
authors.forename: M
authors.initials: M
authors.lastname: Hropot
authors.forename: K H
authors.initials: KH
authors.lastname: Langer
authors.forename: Gabriele
authors.initials: G
authors.lastname: Wiemer
authors.forename: H
authors.initials: H
authors.lastname: Grötsch
authors.forename: W
authors.initials: W
authors.lastname: Linz
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D005919:Glomerular Filtration Rate; D006321:Heart / Q000187:drug effects; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D051437:Renal Insufficiency / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D014693:Ventricular Fibrillation / Q000517:prevention & control
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; C094626:fonsartan; D019001:Nitric Oxide Synthase; D019808:Losartan; D019331:NG-Nitroarginine Methyl Ester