Control of blood pressure and end-organ damage in maturing salt-loaded stroke-prone spontaneously hypertensive rats by oral angiotensin II receptor blockade.
OBJECTIVE
To study the effects of renin-angiotensin system blockade by a novel non-peptide angiotensin II receptor antagonist, losartan, on development of hypertension and acceleration of end-organ damage in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP).


METHODS
One hundred and eighty-one male SHRSP were fed a 4% sodium diet from 6 to 18 weeks of age. Seventy-eight SHRSP were treated orally with losartan, 30 mg/kg per day. One hundred and three rats constituted untreated controls. Blood pressure, plasma renin activity (PRA), renal function and end-organ damage were monitored during the transition to malignant hypertension.


RESULTS
Losartan prevented a blood pressure rise during the first 4 weeks of salt loading. Thereafter, blood pressure rose slowly in losartan-treated rats; however, at each time-point studied blood pressure was significantly lower in losartan-treated rats than in control rats. Losartan treatment increased PRA during the first 4 weeks, but this effect was not sustained. Thereafter, PRA decreased to control (week 0) levels. In contrast, 2 weeks after high-sodium feeding started, untreated SHRSP failed to suppress PRA appropriately; thereafter, PRA rose significantly. Losartan affected renal pathophysiology by blunting the decline in glomerular filtration rate, controlling proteinuria and preventing or delaying the appearance of malignant nephrosclerosis. Losartan treatment significantly increased survival and completely prevented cerebrovascular infarcts.


CONCLUSIONS
The results indicate that angiotensin II blockade markedly reduces both hypertension and end-organ damage in chronically salt-loaded SHRSP and that the renin-angiotensin system may play an important role in the development of hypertensive cardiovascular disease in SHRSP.
Camargo
M J
MJ
Department of Medicine, Cornell University Medical College, New York, NY 10021.
von Lutterotti
N
N
Campbell
W G
WG
Pecker
M S
MS
James
G D
GD
Timmermans
P B
PB
Laragh
J H
JH
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000473:pathology; D002712:Chlorides / Q000097:blood / Q000652:urine; D003404:Creatinine / Q000097:blood; D004231:Diuresis / Q000187:drug effects; D006973:Hypertension / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D007668:Kidney / Q000473:pathology; D019808:Losartan; D008297:Male; D009206:Myocardium / Q000473:pathology; D009929:Organ Size; D009994:Osmolar Concentration; D011188:Potassium / Q000097:blood / Q000652:urine; D011507:Proteinuria / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects; D012964:Sodium / Q000097:blood / Q000652:urine; D013777:Tetrazoles / Q000494:pharmacology*
D001713:Biphenyl Compounds; D001798:Blood Proteins; D002712:Chlorides; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D012964:Sodium; D003404:Creatinine; D012083:Renin; D019808:Losartan; D011188:Potassium