Elsevier

Brain Research

Volume 1169, 12 September 2007, Pages 125-132
Brain Research

Research Report
Effects of long-term administration of HMG-CoA reductase inhibitor, atorvastatin, on stroke events and local cerebral blood flow in stroke-prone spontaneously hypertensive rats

https://doi.org/10.1016/j.brainres.2007.07.012Get rights and content

Abstract

The objective of this study was to determine whether the long-term administration of an HMG-CoA reductase inhibitor, atorvastatin, confers protective effects against stroke events in stroke-prone spontaneously hypertensive rats (SHRSPs). Atorvastatin (2 mg/kg, 20 mg/kg) or vehicle was orally administered to 8-week-old SHRSPs for 11 weeks. The survival ratio and stroke incidence were calculated, and plasma lipids and plasma levels of asymmetric dimethylarginine (ADMA), a circulating endogenous competitive inhibitor of NO synthase, were measured after sacrifice. The effect of atorvastatin on local cerebral blood flow (l-CBF) was also determined in 13-week-old SHRSPs after treatment with 20 mg/kg atorvastatin daily for 5 weeks. The survival ratios at 19 weeks of age were 15, 30, and 50% in the vehicle, low-dose (2 mg/kg), and high-dose groups (20 mg/kg), respectively. The survival ratio was significantly higher in the high-dose group than in the vehicle group. The incidence of stroke was significantly lower in the high-dose group than in the vehicle group. The levels of ADMA were 0.81 ± 0.18 (mean ± S.D.), 0.62 ± 0.09, and 0.61 ± 0.06 μmol/l in the vehicle, low-dose, and high-dose groups, respectively. Atorvastatin administration significantly reduced the ADMA levels without affecting the levels of plasma lipids. The level of l-CBF tended to be higher in the treated group, but not to a significant extent. Thus, atorvastatin was determined to confer a protective effect against hypertension-based stroke. The data suggest that the efficacy of the statin for stroke protection may be partially involved in the improvement of endothelial function via NO production and reduction of ADMA. Statins may confer useful protection against not only atherosclerosis-based stroke, but also hypertension-based stroke.

Introduction

A well-established action of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) is to reduce the biosynthesis of cholesterol by blocking mevalonate synthesis. Statins are widely prescribed agents for cholesterol reduction in individuals with hypercholesterolemia, a condition associated with a high incidence of cardiovascular disease.

Statins reduce the incidence of cardiovascular and cerebrovascular events in clinical trials (Sacks et al., 1996, Scandinavian Simvastatin Survival Study Group, 1994, Shephered et al., 1995). In fact, they even reduce the risk of myocardial infarction and stroke in patients with normal or average cholesterol levels (Sacks et al., 1996, West of Scotland Coronary Prevention Study Group, 1998). Atorvastatin also prevents coronary and stroke events in hypertensive patients with average or lower-than-average cholesterol concentrations (Sever et al., 2003).

Growing clinical and experimental evidence suggests that statins provide additional beneficial actions beyond cholesterol reduction (Tsunekawa et al., 2001, Vaughan et al., 2000), including the enhancement of CBF (Amin-Hanjani et al., 2001, Endres et al., 1998).

Hypertension is one of the major risk factors for stroke. Long-lasting hypertension leads to dysfunction and injury of the cerebral arteries and induces both cerebral infarctions and cerebral hemorrhages.

Multiple lacunar infarctions are commonly recognized in hypertensive patients.

Stroke-prone spontaneously hypertensive rats (SHRSPs) developed from normotensive Wistar Kyoto rats (WKY) (Okamoto et al., 1974, Yamori et al., 1976) have proven to be useful for the study of pathogenesis of stroke and the testing of prophylactic anti-stroke compounds (Biagini et al., 1997, Katayama et al., 1997, Ogiku et al., 1993, Tagami et al., 1987). SHRSPs develop severe hypertension with age and > 80% of the animals die from stroke due to infarction and hemorrhage. Another study has confirmed a reduction of cerebral blood flow during the development of hypertension in spontaneously hypertensive rats (Katayama et al., 1997, Yamori and Horie, 1977).

Thus, the etiology of stroke in these rats is very similar to that in humans (Akiguchi et al., 1997, Okamoto et al., 1974, Yamori et al., 1976).

For the foregoing reasons, we speculated that statins might provide a favorable effect even for the prevention of strokes with a pathogenesis linked to hypertension.

The objectives of this study were to study whether atorvastatin reduced the incidence of stroke in SHRSPs. We chronically treated SHRSPs with atorvastatin and evaluated the effects of the agent on stroke incidence, survival ratio, and l-CBF.

Section snippets

Physiological parameters

The absolute values of the physiological parameters are listed in Table 1, Table 2. According to the measurements in the 8-week-old animals at the beginning of the experiment, there were no significant differences in body weight (g) or heart rate among the vehicle-treated animals, the animals treated at the low dose (2 mg/kg), and the animals treated at the high dose (20 mg/kg). There were significant differences in the systolic, diastolic, and mean blood pressure between the high-dose and

Discussion

In this study we explored whether atorvastatin gave beneficial effects on incidental stroke based on hypertension using SHRSPs.

The doses of atorvastatin used in this study were 2 mg/kg and 20 mg/kg. These doses were decided on the basis of the previous studies (Hayashi et al., 2004, Hayashi et al., 2005, Nagotani et al., 2005).

Our results indicated that the 20 mg/kg atorvastatin administration lowered the incidence of stroke and reduced mortality in the SHRSPs.

In a similar study, Nagotani et

Protocol

The experiments were carried out on 8-week-old male SHRSPs of the Izumo strain (Japan SLC Inc. Shizuoka, Japan). The SHRSPs were separated into three groups of 20 animals each. The first and second groups were administered a suspension of atorvastatin (Pfizer Co. Ltd.) by gavage at dosages of 2 mg/kg body weight and 20 mg/kg body weight, respectively, for 11 weeks. The third group was administered the same amount of vehicle (0.5% sodium methylcellulose in saline) over the same period. The

Acknowledgment

We thank Mrs. Kyoko Yamada for her secretarial help.

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