Original papers: Stroke

Therapeutic effects of postischemic treatment with hypotensive doses of an angiotensin II receptor blocker on transient focal cerebral ischemia

Fu, Huaa; Hosomi, Naohisaa,b; Pelisch, Nicolasa; Nakano, Daisukec; Liu, Gangc; Ueno, Masakid; Miki, Takanorie; Masugata, Hisashif; Sueda, Yoshimasab; Itano, Toshifumig; Matsumoto, Masayasub; Nishiyama, Akirac; Kohno, Masakazua

Author Information

aDepartment of Cardiorenal and Cerebrovascular Medicine, Kagawa University School of Medicine

bDepartment of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima

cDepartment of Pharmacology, Kagawa University School of Medicine

dDepartment of Pathology and Host Defense, Kagawa University School of Medicine

eDepartment of Anatomy and Neurobiology, Kagawa University School of Medicine

fDepartment of Integrated Medicine, Kagawa University School of Medicine

gDepartment of Neurobiology, Kagawa University School of Medicine, Kagawa, Japan

Correspondence to Naohisa Hosomi, MD, PhD, FAHA, Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical Sciences, 1-2-3 Kasumi, Minami-Ku, Hiroshima 734-8551, Japan Tel: +81 82 257 5201; fax: +81 82 505 0490; e-mail: [email protected]

Abbreviations: ACE, angiotensin-converting enzyme; ANOVA, analysis of variance; ARB, angiotensin II receptor blocker; AT1 receptors , angiotensin type 1 receptors; BP, blood pressure; DW, dry weight; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; MCAO, middle cerebral artery occlusion; RAS, renin-angiotensin system; RT-PCR, reverse-transcriptase polymerase chain reaction; SCAST, Scandinavian Candesartan Acute Stroke Trial; SD rat, SpragueDawley rat; TTC, 2,3,5-triphenyltetrazolium chloride; WW, wet weight

Received 11 January, 2011

Revised 14 June, 2011

Accepted 8 August, 2011

Journal of Hypertension 29(11):p 2210-2219, November 2011. | DOI: 10.1097/HJH.0b013e32834bbb30

Abstract

Background 

Neurovascular protection against cerebral ischemia is not consistently observed with a postischemia hypotensive dose of candesartan. The aim of this study was to determine the levels of brain angiotensin II after reperfusion and the efficacy and therapeutic time window of postischemic treatments with hypotensive doses of candesartan for the treatment of cerebral ischemia.

Method 

Occlusions of the right middle cerebral artery (60 min) followed by reperfusion were performed using the thread method under halothane anesthesia in Sprague–Dawley (SD) rats. Protein levels of brain angiotensin II and mRNA levels of renin–angiotensin system components were evaluated following reperfusion (n=184 in total). Low-dose or high-dose treatments with candesartan cilexetil (1 or 10 mg/kg per day, respectively) were administered orally immediately following reperfusion once daily for 4 or 7 days (n = 119 in total). An additional group was treated with low-dose candesartan cilexetil after a 12-h delay based on the brain angiotensin II levels (n = 14).

Results 

Levels of brain angiotensin II transiently increased 4–12 h after reperfusion, which followed an increase in angiotensinogen mRNA. Candesartan cilexetil treatments significantly reduced blood pressure (BP) in rats administered the high dose and moderately in rats receiving the low dose. A low dose of candesartan cilexetil reduced the infarct size, cerebral edema, and neurological deficits, whereas the high-dose treatments showed limited reductions. Furthermore, oxidative stress following reperfusion was reduced with the low-dose treatments. The therapeutic time window was open for at least 12 h after reperfusion when brain angiotensin II levels had peaked.

Conclusion 

Postischemic treatments using low hypotensive doses of candesartan cilexetil provided protection against cerebral ischemic injury and may have a clinically relevant therapeutic time window.

© 2011 Lippincott Williams & Wilkins, Inc.

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