Article

Cardiac uptake of minocycline and mechanisms for in vivo cardioprotection.

Department of Medicine, University of California, San Diego, San Diego, California 92093, USA.
Journal of the American College of Cardiology (impact factor: 14.16). 10/2008; 52(13):1086-94. DOI:10.1016/j.jacc.2008.06.028 pp.1086-94
Source: PubMed

ABSTRACT The ability of minocycline to be transported into cardiac cells, concentrate in normal and ischemic myocardium, and act as a cardioprotector in vivo was examined. We also determined minocycline's capacity to act as a reducer of myocardial oxidative stress and matrix metalloproteinase (MMP) activity.
The identification of compounds with the potential to reduce myocardial ischemic injury is of great interest. Tetracyclines are antibiotics with pleiotropic cytoprotective properties that accumulate in normal and diseased tissues. Minocycline is highly lipophilic and has shown promise as a possible cardioprotector. However, minocycline's potential as an in vivo cardioprotector as well as the means by which this action is attained are not well understood.
Rats were subjected to 45 min of ischemia and 48 h of reperfusion. Animals were treated 48 h before and 48 h after thoracotomy with either vehicle or 50 mg/kg/day minocycline. Tissue samples were used for biochemical assays and cultured cardiac cells for minocycline uptake experiments.
Minocycline significantly reduced infarct size (approximately 33%), tissue MMP-9 activity, and oxidative stress. Minocycline was concentrated approximately 24-fold in normal (0.5 mmol/l) and approximately 50-fold in ischemic regions (1.1 mmol/l) versus blood. Neonatal rat cardiac fibroblasts, myocytes, and adult fibroblasts demonstrated a time- and temperature-dependent uptake of minocycline to levels that approximate those of normal myocardium.
Given the high intracellular levels observed and results from the assessment of in vitro antioxidant and MMP inhibitor capacities, it is likely that minocycline acts to limit myocardial ischemic injury via mass action effects.

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Keywords

50 mg/kg/day minocycline
 
biochemical assays
 
cultured cardiac cells
 
intracellular levels
 
ischemic myocardium
 
ischemic regions
 
limit myocardial ischemic injury
 
mass action effects
 
minocycline acts
 
minocycline uptake experiments
 
minocycline's capacity
 
minocycline's potential
 
MMP inhibitor capacities
 
myocardial ischemic injury
 
myocardial oxidative stress
 
Neonatal rat cardiac fibroblasts
 
normal myocardium
 
pleiotropic cytoprotective properties
 
tissue MMP-9 activity
 
vitro antioxidant