Published Online
on December 5, 2002

A more recent version of this article appeared on January 1, 2003

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Submitted on July 18, 2002
Accepted on August 22, 2002

HMG-CoA Reductase Inhibitor Has Protective Effects Against Stroke Events in Stroke-Prone Spontaneously Hypertensive Rats

Seinosuke Kawashima MD^*; Tomoya Yamashita MD; Yoichi Miwa MD; Masanori Ozaki MD; Masayuki Namiki MD; Tetsuaki Hirase MD; Nobutaka Inoue MD; Ken-ichi Hirata MD; and Mitsuhiro Yokoyama MD

From the Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.

^* To whom correspondence should be addressed. E-mail: kawashim{at}med.kobe-u.ac.jp.

Background and Purpose—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.

Key words: mortality • rats, inbred SHR • statins • stroke • superoxides

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