Pravastatin reduces myocardial infarct size via increasing protein kinase C-dependent nitric oxide, decreasing oxyradicals and opening the mitochondrial adenosine triphosphate-sensitive potassium channels in rabbits.
BACKGROUND
Statins reportedly protect against myocardial infarction, but the precise mechanism is unclear.


RESULTS
Rabbits underwent 30 min of coronary occlusion followed by 48 h of reperfusion. Pravastatin (1 or 5 mg/kg) or saline was intravenously administered 10 min before ischemia. Pravastatin (5 mg/kg) was also administered 10 min before reperfusion. N(omega)-nitro-L-arginine methylester (L-NAME, 10 mg/kg), chelerythrine (5 mg/kg) or 5-hydroxydecanoic acid sodium salt (5-HD, 5 mg/kg) was intravenously administered 10 min before pravastatin injection. The infarct size was determined. The myocardial interstitial levels of 2,5-dihydroxybenzoic acid (DHBA) and nitrogen oxide (NOx), and the intensity of myocardial dihydroethidium staining were measured. Pre-ischemic treatment with pravastatin reduced the infarct size (34+/-5% and 24+/-4%, 1 and 5 mg/kg, respectively), but not pre-reperfusion treatment (42.1+/-3.7%), compared with the control (45+/-3%). This effect was blocked by L-NAME (42.6+/-4%), chelerythrine (50.9+/-3%) and 5-HD (52.7+/-2%). Pre-ischemic treatment with pravastatin increased myocardial NOx levels, and attenuated both the 2,5-DHBA level and the intensity of dihydroethidium staining during reperfusion. Chelerythrine abolished the increase in NOx levels by pravastatin.


CONCLUSIONS
Pre-ischemic treatment with pravastatin reduces the myocardial infarct size via protein kinase C-dependent nitric oxide production, decreasing hydroxyl radicals and superoxide, and opening the mitochondrial adenosine triphosphate-sensitive potassium channels.
Bao
Narentuoya
N
Second Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan.
Minatoguchi
Shinya
S
Kobayashi
Hiroyuki
H
Yasuda
Shinji
S
Kawamura
Itta
I
Iwasa
Masamitsu
M
Yamaki
Takahiko
T
Sumi
Syohei
S
Misao
Yu
Y
Arai
Masazumi
M
Nishigaki
Kazuhiko
K
Takemura
Genzou
G
Fujiwara
Takako
T
Fujiwara
Hisayoshi
H
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods; D054086:KATP Channels / Q000378:metabolism*; D008297:Male; D008929:Mitochondria, Heart / Q000378:metabolism*; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control*; D009569:Nitric Oxide / Q000378:metabolism*; D017035:Pravastatin / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism*; D011817:Rabbits; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D054086:KATP Channels; D017382:Reactive Oxygen Species; D013481:Superoxides; D009569:Nitric Oxide; D011493:Protein Kinase C; D017035:Pravastatin