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.
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 micromol/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.
Tanaka
Noriko
N
Division of Neurology, Department of Internal Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan.
Katayama
Yasuo
Y
Katsumata
Toshiya
T
Otori
Tatsuo
T
Nishiyama
Yutaka
Y
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood; D000069059:Atorvastatin; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology; D002536:Cerebral Arteries / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006973:Hypertension / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000097:blood / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011918:Rats, Inbred SHR; D020521:Stroke / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D015996:Survival Rate; D013995:Time; D013997:Time Factors; D016896:Treatment Outcome
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018696:Neuroprotective Agents; D011758:Pyrroles; C487735:dimethylarginine; D009569:Nitric Oxide; D001120:Arginine; D000069059:Atorvastatin; D019001:Nitric Oxide Synthase