Losartan versus enalapril on cerebral edema and proteinuria in stroke-prone hypertensive rats.
Stroke-prone spontaneously hypertensive rats (SHRSP), subjected to high NaCl, show severe hypertension, organ damage, and early death. Preventive treatment with angiotensin II type 1 (AT1) receptor antagonists is known to be effective. Previously, we found that angiotensin converting enzyme (ACE) inhibition could reduce cerebral edema when treatment was started after manifestation of either proteinuria or cerebral edema. In this study AT1 receptor blockade was started at the same time points to evaluate whether this had an effect superior to ACE inhibition. SHRSP drank 1% NaCl. Group 1 served as controls. Group 2 and 3 rats were started on losartan and enalapril after proteinuria exceeded 40 mg/day. Group 4 and 5 rats were started on losartan and enalapril after the first observation of cerebral edema with T2-weighted magnetic resonance imaging scans. In controls, median survival was 54 days (range, 35 to 80 days) after the start of salt loading. With early-onset losartan and enalapril, survival increased to 305 days (range, 184 to 422 days) and 320 days (range, 134 to 368 days) (both P < .01 v group 1). Cerebral edema formation was prevented in all but two rats, one from each treatment modality. Development of proteinuria was markedly reduced. With late-onset treatment with losartan and enalapril, survival was 290 days (range, 120 to 367 days) and 264 days (range, 154 to 319 days) (both P < .01). Both losartan and enalapril decreased cerebral edema to baseline levels. Ultimately cerebral edema reoccurred, despite continued treatment, in 75% of the rats. Systolic blood pressure did not decrease after losartan treatment, but, similarly to early-onset treatment, decreased transiently after enalapril treatment. Cerebral edema and proteinuria were prevented and reduced in SHRSP treated with either an AT1 receptor antagonist or an ACE inhibitor. Survival was markedly and similarly prolonged by both treatments, whether initiated directly before or after development of cerebral edema. In rats where treatment was initiated after manifestation of cerebral edema, both cerebral edema and proteinuria reappeared despite continued treatment. Apparently, when hypertension is sustained, reappearance of target organ damage may not be entirely dependent on angiotensin.
Blezer
E L
EL
Department of Nephrology and Hypertension, University Medical Centre, Utrecht, The Netherlands.
Nicolay
K
K
Koomans
H A
HA
Joles
J A
JA
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001929:Brain Edema / Q000188:drug therapy* / Q000517:prevention & control*; D004334:Drug Administration Schedule; D004656:Enalapril / Q000008:administration & dosage / Q000627:therapeutic use*; D020022:Genetic Predisposition to Disease; D006973:Hypertension / Q000150:complications*; D019808:Losartan / Q000008:administration & dosage / Q000627:therapeutic use*; D008297:Male; D011507:Proteinuria / Q000188:drug therapy* / Q000517:prevention & control*; D051381:Rats; D011918:Rats, Inbred SHR / Q000235:genetics; D020521:Stroke / Q000235:genetics; D016019:Survival Analysis
D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D004656:Enalapril; D019808:Losartan