Cardiac uptake of minocycline and mechanisms for in vivo cardioprotection.
OBJECTIVE
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.


BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Department of Medicine, University of California, San Diego, San Diego, California 92093, USA.
Diego
D
Romero-Perez
Eduardo
E
Fricovsky
Katrina Go
KG
Yamasaki
Michael
M
Griffin
Maraliz
M
Barraza-Hidalgo
Wolfgang
W
Dillmann
Francisco
F
Villarreal
D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use; D002316:Cardiotonic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D008911:Minocycline / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009203:Myocardial Infarction / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
D000975:Antioxidants; D002316:Cardiotonic Agents; D061965:Matrix Metalloproteinase Inhibitors; D008911:Minocycline