Losartan's protective effects in stroke-prone spontaneously hypertensive rats persist durably after treatment withdrawal.
The effects of long-term oral administration of losartan on the occurrence of stroke and on mortality were investigated in young salt-loaded stroke-prone spontaneously hypertensive rats (SHR-SPs) during the treatment period (5-20 weeks of age) and up to 8 weeks thereafter. Two doses of losartan, 1 and 10 mg/kg/day, were investigated, which afforded no and only moderate antihypertensive effects, respectively. During the treatment period, losartan at both doses completely suppressed stroke and mortality and strongly opposed (low dose) or abolished (high dose) the increases in saline intake, diuresis, and proteinuria observed in controls. It markedly limited (low dose) or abolished (high dose) vascular fibrinoid necrosis formation in the brain, kidneys, and heart. Finally, losartan, especially at the high dose, reduced arterial thickening and glomerular and tubulo-interstitial lesions in the kidneys, as well as arterial thickening, infarction, and fibrosis in the heart. Eight weeks after treatment discontinuation, all animals but one (low dose) were still alive. Vascular fibrinoid necrosis development remained strongly prevented (low dose) or fully suppressed (high dose) in all investigated organs. Finally, cardiac and renal lesions tended to worsen, and proteinuria was noted only in the low-dose group. We conclude that in SHR-SPs, angiotensin II, through AT1 receptor stimulation, most likely plays a major role in fibrinoid necrosis formation, vascular proliferative changes, and stroke occurrence and that losartan, most likely independently of its effect on blood pressure, affords a full and long-lasting protection against stroke and mortality both during and after the treatment period.
Fornes
P
P
Département de Pharmacologie, Faculté de Médecine Paris-Sud, France.
Richer
C
C
Vacher
E
E
Bruneval
P
P
Giudicelli
J F
JF
D000375:Aging / Q000502:physiology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000473:pathology; D002561:Cerebrovascular Disorders / Q000235:genetics*; D004231:Diuresis / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000473:pathology; D007093:Imidazoles / Q000627:therapeutic use*; D007668:Kidney / Q000473:pathology; D019808:Losartan; D008297:Male; D009206:Myocardium / Q000473:pathology; D011507:Proteinuria / Q000517:prevention & control; D051381:Rats; D011918:Rats, Inbred SHR; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control*; D015996:Survival Rate; D013777:Tetrazoles / Q000627:therapeutic use*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D007093:Imidazoles; D013777:Tetrazoles; D019808:Losartan