Comparison between early and delayed systemic treatment with candesartan of rats after ischaemic stroke.
OBJECTIVE
The effects of candesartan treatment starting early (3 h) and delayed (24 h) after middle cerebral artery occlusion (MCAO) with reperfusion was investigated in normotensive rats.


METHODS
Subcutaneous treatment with candesartan (0.3 and 3 mg/kg) or vehicle was initiated 3 or 24 h after the onset of MCAO and continued for seven consecutive days (n=20 per group and timepoint). Neurological outcome was evaluated daily using two different scoring systems. Infarct and oedema volumes were determined in rats 2 or 7 days after MCAO. Mean arterial, systolic and diastolic blood pressures were recorded before and after the application of candesartan.


RESULTS
Mean arterial, systolic and diastolic blood pressures were markedly decreased with the high dose, but only moderately decreased with the low dose of candesartan. Vehicle-treated rats showed marked neurological deficits 24 h after MCAO, which gradually improved with time. Candesartan improved neurological outcomes at all timepoints only when treatment was started 3, but not 24 h after MCAO. The infarct volume was reduced on days 2 and 7 after MCAO in rats treated with the low but not the high dose of candesartan.


CONCLUSIONS
The present study demonstrates that only an early but not a delayed onset of treatment with candesartan exerts neuroprotection after focal ischaemia. The degree of neurological impairments did not correlate with the infarct volume, which was reduced only after the low dose of candesartan. The high dose of candesartan failed to reduce the infarct volume, probably because of an excessive blood pressure decrease.
Brdon
Jan
J
Institute of Pharmacology, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany.
Kaiser
Sabine
S
Hagemann
Friederike
F
Zhao
Yi
Y
Culman
Juraj
J
Gohlke
Peter
P
D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D001929:Brain Edema / Q000517:prevention & control; D002545:Brain Ischemia / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006339:Heart Rate / Q000187:drug effects; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012018:Reflex / Q000187:drug effects; D015427:Reperfusion Injury / Q000503:physiopathology* / Q000517:prevention & control*; D020521:Stroke / Q000150:complications / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D018696:Neuroprotective Agents; D013777:Tetrazoles; C081643:candesartan