Oral pre-treatment with rosuvastatin protects porcine myocardium from ischaemia/reperfusion injury via a mechanism related to nitric oxide but not to serum cholesterol level.
OBJECTIVE
The aim of this study was to test whether oral pre-treatment with rosuvastatin at a dosage giving clinically relevant plasma concentrations protects the myocardium against ischaemia/reperfusion injury and to investigate the involvement of nitric oxide (NO) and neutrophil infiltration.


METHODS
Pigs were given placebo (n = 7), rosuvastatin (80 mg day(-1), n =7), rosuvastatin (160 mg day(-1), n = 7) or pravastatin (160 mg day(-1), n = 7) orally for 5 days before being subjected to coronary artery ligation and reperfusion. An additional group was given rosuvastatin 160 mg day(-1) and a nitric oxide synthase (NOS) inhibitor.


RESULTS
Rosuvastatin 80 and 160 mg day(-1) resulted in plasma concentrations of 2.6 +/- 0.7 and 5.6 +/- 1.0 ng mL(-1), respectively. Serum cholesterol was not affected. Rosuvastatin 160 mg day(-1) and pravastatin limited the infarct size from 82 +/- 3% of the area at risk in the placebo group to 61 +/- 3% (P < 0.05), and to 61 +/- 2% (P < 0.05) respectively. Rosuvastatin 80 mg day(-1) limited the infarct size to 69 +/- 2%, however, this effect was not statistically significant. Rosuvastatin 160 mg day(-1) attenuated neutrophil infiltration in the ischaemic/reperfused myocardium. The protective effect of rosuvastatin 160 mg day(-1) was abolished by NOS inhibition. The expression of NOS2 and NOS3 in the myocardium did not differ between the groups.


CONCLUSIONS
Oral pre-treatment with rosuvastatin limited infarct size following ischaemia/reperfusion without affecting cholesterol levels. The cardioprotective effect is suggested to be dependent on maintained bioactivity of NO, without influencing NOS expression.
Bulhak
A A
AA
Division of Cardiology, Department of Medicine, Karolinska Institute, Stockholm, Sweden.
Gourine
A V
AV
Gonon
A T
AT
Sjöquist
P-O
PO
Valen
G
G
Pernow
J
J
D000284:Administration, Oral; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002784:Cholesterol / Q000097:blood*; D005260:Female; D005464:Fluorobenzenes / Q000008:administration & dosage* / Q000097:blood; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D008297:Male; D017202:Myocardial Ischemia / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology; D020556:Neutrophil Infiltration / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000032:analysis; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009195:Peroxidase / Q000378:metabolism; D017035:Pravastatin / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage* / Q000097:blood; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000008:administration & dosage* / Q000097:blood; D013552:Swine
D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D009569:Nitric Oxide; D000068718:Rosuvastatin Calcium; D002784:Cholesterol; D009195:Peroxidase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D017035:Pravastatin