Enalapril prevents imminent and reduces manifest cerebral edema in stroke-prone hypertensive rats.
OBJECTIVE
Stroke-prone spontaneously hypertensive rats (SHRSP), subjected to high NaCl intake, show severe hypertension, organ damage, and early death. Preventive treatment with an angiotensin-converting enzyme (ACE) inhibitor is known to reduce mortality. Previously we found that proteinuria always precedes cerebral edema in SHRSP. Hence, in this study ACE inhibition was started later, ie, directly after manifestation of either proteinuria or cerebral edema.


METHODS
SHRSP were subjected to 1% NaCl intake. Group 1 served as a control. In group 2 early-onset treatment with the ACE inhibitor enalapril was initiated after proteinuria was >40 mg/d. In group 3 late-onset ACE inhibition was started after the first observation of cerebral edema with T2-weighted MRI. Cerebral edema was expressed as the percentage of pixels with an intensity above a defined threshold.


RESULTS
In controls median survival was 54 days (range, 32 to 80 days) after start of salt loading. The terminal level of cerebral edema was 19.0+/-3.0%. Under early-onset enalapril, median survival increased to 320 days (range, 134 to 368 days; P<0.01 versus group 1). Cerebral edema was prevented in all but 1 rat. Systolic blood pressure was slightly and transiently reduced at day 14. Proteinuria was markedly reduced (52+/-7 versus 190+/-46 mg/d in group 1 at day 7; P<0.05). Under late-onset enalapril, median survival was 264 days (range, 154 to 319 days; P<0.01 versus group 1). Cerebral edema decreased to baseline levels (9.6+/-2.9 at day 0 to 3.4+/-0.5% at day 3; (P<0.05). Ultimately cerebral edema reoccurred in 6 of the 8 rats. SBP decreased slightly at day 7 only. Proteinuria decreased from 283+/-27 at day 0 to 116+/-22 mg/d at day 7 (P<0.05). Complete remission of the original locus of cerebral edema was confirmed histologically.


CONCLUSIONS
In SHRSP with proteinuria, treatment with an ACE inhibitor both prevented the development of cerebral edema and reduced manifest cerebral edema and proteinuria. Survival was markedly prolonged. These findings support the use of ACE inhibition for treatment in hypertensive encephalopathy.
Department of Nephrology, University Hospital Utrecht, Netherlands.
E L
EL
Blezer
K
K
Nicolay
D
D
Bär
R
R
Goldschmeding
G H
GH
Jansen
H A
HA
Koomans
J A
JA
Joles
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001835:Body Weight; D001929:Brain Edema / Q000175:diagnosis / Q000188:drug therapy* / Q000517:prevention & control*; D002561:Cerebrovascular Disorders / Q000175:diagnosis / Q000401:mortality / Q000517:prevention & control*; D004326:Drinking; D004435:Eating; D004656:Enalapril / Q000494:pharmacology*; D008279:Magnetic Resonance Imaging; D008297:Male; D011507:Proteinuria / Q000188:drug therapy; D051381:Rats; D011918:Rats, Inbred SHR; D012982:Sodium, Dietary / Q000494:pharmacology; D016019:Survival Analysis
D000806:Angiotensin-Converting Enzyme Inhibitors; D012982:Sodium, Dietary; D004656:Enalapril