HMG-CoA reductase inhibitor has protective effects against stroke events in stroke-prone spontaneously hypertensive rats.
OBJECTIVE
Recent clinical studies suggest that 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert protective effects against nonhemorrhagic stroke. In a murine cerebral ischemia model produced by occlusion of the middle cerebral artery, statins were shown to reduce infarct size. However, the effect of statins on hypertension-based stroke is unknown. The purpose of this study is to clarify the effect of a statin on stroke in stroke-prone spontaneously hypertensive rats (SHR-SP), in which both cerebral hemorrhage and infarction occur.


METHODS
We treated SHR-SP chronically from 4 weeks of age with cerivastatin (2 mg/kg per day by gavage) or vehicle. The physiological parameters, the incidence of stroke-associated symptoms, and mortality were assessed.


RESULTS
At 14 weeks of age, the incidence (13+/-3% versus 37+/-8%; P<0.01) and the size of stroke (1.6+/-0.2 versus 2.2+/-0.1 arbitrary units; P<0.01) were significantly decreased by cerivastatin, although blood pressure and plasma cholesterol levels were not different. Moreover, stroke-associated symptoms and early mortality of SHR-SP were markedly reduced in the statin-treated group (mortality at the age of 15 weeks: 15% versus 50%; P<0.05). Statin treatment significantly reduced superoxide production from nonstroke parenchyma of brain and infiltration of inflammatory cells to the stroke lesions.


CONCLUSIONS
Our data show that a high dose of statin exerts protection against hypertension-based stroke and ameliorates the disease severity via inhibition of superoxide production and modulation of inflammation in brain.
Kawashima
Seinosuke
S
Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan. kawashim@med.kobe-u.ac.jp
Yamashita
Tomoya
T
Miwa
Yoichi
Y
Ozaki
Masanori
M
Namiki
Masayuki
M
Hirase
Tetsuaki
T
Inoue
Nobutaka
N
Hirata
Ken-ichi
K
Yokoyama
Mitsuhiro
M
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000201:enzymology; D001921:Brain / Q000473:pathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006973:Hypertension / Q000150:complications* / Q000503:physiopathology; D007249:Inflammation / Q000473:pathology; D007700:Kinetics; D008055:Lipids / Q000097:blood; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D020521:Stroke / Q000175:diagnosis / Q000378:metabolism / Q000517:prevention & control*; D013481:Superoxides / Q000378:metabolism; D016019:Survival Analysis
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D011725:Pyridines; D013481:Superoxides; C086276:cerivastatin; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat