EXPERIMENTAL STUDIES
Pravastatin restored the infarct size-limiting effect of ischemic preconditioning blunted by hypercholesterolemia in the rabbit model of myocardial infarction
Yasunori Ueda, MD, PhD ,
Masafumi Kitakaze, MD, PhD, FACC*  ,
Kazuo Komamura, MD, PhD,
Tetsuo Minamino, MD, PhD* ,
Hiroshi Asanuma, MD* ,
Hideyuki Sato, MD, PhD* ,
Tsunehiko Kuzuya, MD, PhD* ,
Hiroshi Takeda, MD, PhD* and
Masatsugu Hori, MD, PhD, FACC*
* Division of Cardiology, Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan
Cardiovascular Division, Osaka Police Hospital, Osaka, Japan
Division of Cardiology, National Cardiovascular Center, Suita, Japan
Manuscript received February 28, 1999;
revised manuscript received June 18, 1999,
accepted August 23, 1999.
Reprint requests and correspondence: Masafumi Kitakaze, Division of Cardiology, Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City, Osaka, 565-0871, Japan
OBJECTIVES
We tested to find out whether pravastatin restores the infarct size (IS)-limiting effect of ischemic preconditioning (IP) and if it has any effect on the IP-induced activation of adenosine producing enzyme ecto-5'-nucleotidase which plays a key role in the IP-induced cardioprotection.
BACKGROUND
The IS-limiting effect of IP is blunted by hypercholesterolemia. Recently, HMG-CoA reductase inhibitors are shown to have direct cytoprotective effects.
METHODS
Rabbits were fed with a normal or cholesterol (1%) added diet with or without pravastatin (5 mg/kg/day) treatment. Infarct size was measured after 30 min occlusion and 3 h reperfusion of circumflex coronary artery with or without the IP procedure (5 min occlusion and 10 min reperfusion). Additionally, ecto-5'-nucleotidase activities of ischemic and nonischemic myocardium were measured immediately after IP procedure.
RESULTS
This dose of pravastatin did not normalize the increased level of serum cholesterol. The IS-limiting effect of preceding IP (IS reduced from 36.7% to 9.6%, p < 0.001) was abolished by hypercholesterolemia (from 46.1% to 31.3%, p = NS) and restored by pravastatin treatment (from 35.2% to 9.4%, p < 0.001). Pravastatin treatment did not affect IS or the effect of IP under normocholesterolemia. The activation of ecto-5'-nucleotidase presented as the activity ratio of ischemic to nonischemic myocardium (3.1-fold in normocholesterolemia) was blunted by hypercholesterolemia (1.8-fold, p < 0.05) and restored by pravastatin treatment (2.9-fold).
CONCLUSIONS
Pravastatin, at the dose serum cholesterol was not normalized, restored the IS-limiting effect of IP and IP-induced ecto-5'-nucleotidase activation, which were both blunted by hypercholesterolemia. The activation of ecto-5'-nucleotidase may be worth further investigation as a possible mechanism for the hypercholesterolemia-induced retardation and pravastatin-mediated restoration of the cardioprotective effect of IP.
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Abbreviations and Acronyms
| | ANCOVA | = analysis of covariance | | ANOVA | = analysis of variance | | HC | = hypercholesterolemia | | HCP | = hypercholesterolemia with pravastatin treatment | | HDL | = high density lipoprotein | | IP | = ischemic preconditioning | | IS | = infarct size | | MI | = myocardial infarction | | NC | = normocholesterolemia | | NCP | = normocholesterolemia treated with pravastatin | | PLSD | = protected least significant difference |
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