EXPERIMENTAL STUDY
Improved post-myocardial infarction survival with probucol in rats: Effects on left ventricular function, morphology, cardiac oxidative stress and cytokine expression
Ying Tung Sia, MD, MSc*,
Thomas G. Parker, MD ,
Peter Liu, MD,
James N. Tsoporis, PhD,
Albert Adam, PhD and
Jean L. Rouleau, MD ,*
* Department of Medicine, Montreal Heart Institute, Montreal, Canada
Division of Cardiology and Department of Medicine, Toronto General Hospital, Toronto, Canada
University Health Network, Toronto, Canada
Department of Pharmacy, University of Montreal, Montreal, Canada
Manuscript received December 12, 2000;
revised manuscript received September 17, 2001,
accepted September 20, 2001.
* Reprint requests and correspondence: Dr. Jean L. Rouleau, Toronto General Hospital, Eaton North 13-212, 200 Elizabeth Street, Toronto, Ontario, M5G 2C4, Canada.
jean.rouleau{at}uhn.on.ca
OBJECTIVES: The goal of this study was to evaluate whether reducing the potentially deleterious effects of oxidative stress with the potent anti-oxidant probucol improves prognosis after myocardial infarction (MI) in rats.
BACKGROUND: Oxidative stress has been documented in patients early and late after MI, particularly when it is associated with congestive heart failure.
METHODS: Rats surviving acute MIs for 24 h (n = 247) were assigned to vehicle or probucol (61 mg/kg, daily) for four weeks, at which time cardiac hemodynamic, morphologic and molecular measurements were done.
RESULTS: In rats with large MIs, probucol improved survival (87.9%) when compared with vehicle (50.6%) (p < 0.001). Probucol also partially preserved left ventricular (LV) systolic but not diastolic function. Probucol increased scar thickness and decreased cardiac fibrosis but did not modify LV hypertrophy or dilation. Finally, probucol decreased cardiac oxidative stress, as assessed by measuring cardiac malondialdehydes, and decreased the cardiac expression of the pro-inflammatory cytokines interleukin (IL)-1ß and IL-6 but did not modify fetal gene re-expression in rats with large MIs.
CONCLUSIONS: This study indicates that the anti-oxidant probucol markedly improves post-MI survival in rats despite few demonstrable effects on cardiac remodeling or hemodynamics. Its beneficial effects may, however, be associated with reduced cardiac fibrosis, oxidative stress and expression of pro-inflammatory cytokines.
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Abbreviations and Acronyms
| | ANF | | atrial natriuretic factor | | BW | | body weight | | cDNA | | complementary DNA | | DMTU | | dimethylthiourea | | GAPDH | | glyceraldehyde 3-phosphate dehydrogenase | | HR | | heart rate | | IL | | interleukin | | LV | | left ventricle or left ventricular | | LVEDP | | left ventricular end-diastolic pressure | | LVSP | | left ventricular systolic pressure | | LVW | | left ventricle weight | | MHC | | myosin heavy chain | | MI | | myocardial infarction | | mRNA | | messenger RNA | | NE | | norepinephrine | | RV | | right ventricle or right ventricular | | RVSP | | right ventricular systolic pressure | | RVW | | right ventricle weight | | SkACT | | skeletal actin | | TNF | | tumor necrosis factor | | +dP/dt | | maximum rate of pressure rise | | –dP/dt | | maximum rate of pressure decline |
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