Postischemic administration of angiotensin II type 1 receptor blocker reduces cerebral infarction size in hypertensive rats.
Lowering the blood pressure (BP) during the acute period following ischemic stroke is still a controversial treatment. In this study, we investigated the effect of postischemic treatment using the angiotensin II type 1 receptor blocker, candesartan, on brain damage in focal cerebral ischemia. Spontaneously hypertensive rats underwent transient occlusion of the middle cerebral artery for 1 h. Candesartan (0.1, 1 and 10 mg kg(-1)) or vehicle was administered orally 3 and 24 h after ischemia. Blood pressure and neurological function were monitored, and infarct volume was evaluated 48 h after occlusion. Cerebral blood flow was measured using laser Doppler flowmetry before and after treatment with candesartan. Activation of Rho-kinase in cerebral microvessels was evaluated by immunohistochemistry. Systolic blood pressure was markedly lowered with both moderate and high doses, but it did not fall with a low dose of candesartan. The infarct volume was reduced in rats treated with the low dose of candesartan but not in those treated with the moderate or high doses. Cerebral blood flow decreased in parallel with the reduction in BP 3 h after treatment using the moderate dose, but it did not change after treatment with the low dose of candesartan, compared with vehicle. Rho-kinase was activated in the brain vessels of the ischemic cortex, but treatment with candesartan suppressed it. Our results show that oral administration of candesartan after transient focal ischemia reduced infarct volume at doses that showed little effect on BP. The neurovascular protective effects of candesartan may be caused by the inhibition of Rho-kinase in brain microvessels.
Stroke Division, Department of Neurology, Osaka University Graduate School of Medicine, Suita-city, Osaka, Japan.
Emi
E
Omura-Matsuoka
Yoshiki
Y
Yagita
Tsutomu
T
Sasaki
Yasukazu
Y
Terasaki
Naoki
N
Oyama
Yukio
Y
Sugiyama
Shuhei
S
Okazaki
Saburo
S
Sakoda
Kazuo
K
Kitagawa
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D001562:Benzimidazoles / Q000627:therapeutic use; D001713:Biphenyl Compounds; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature; D002545:Brain Ischemia / Q000188:drug therapy*; D002196:Capillaries / Q000201:enzymology / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D006973:Hypertension / Q000150:complications* / Q000188:drug therapy*; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D009422:Nervous System Diseases / Q000517:prevention & control / Q000523:psychology; D051381:Rats; D011918:Rats, Inbred SHR; D015427:Reperfusion Injury / Q000517:prevention & control; D013777:Tetrazoles / Q000627:therapeutic use; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; D054460:rho-Associated Kinases; C081643:candesartan