PRE-CLINICAL RESEARCH
Cardiac Uptake of Minocycline and Mechanisms for In Vivo Cardioprotection
Diego Romero-Perez, BS,
Eduardo Fricovsky, PharmD,
Katrina Go Yamasaki, BS,
Michael Griffin, PhD,
Maraliz Barraza-Hidalgo, BS,
Wolfgang Dillmann, MD and
Francisco Villarreal, MD, PhD*
Department of Medicine, University of California, San Diego, San Diego, California
Manuscript received May 6, 2008;
revised manuscript received June 19, 2008,
accepted June 20, 2008.
* Reprint requests and correspondence: Dr. Francisco Villarreal, UCSD Cardiology, 9500 Gilman Drive, 0613J, BSB 4028, La Jolla, California 92093 (Email: fvillarr{at}ucsd.edu).
Objectives: 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 ( 33%), tissue MMP-9 activity, and oxidative stress. Minocycline was concentrated 24-fold in normal (0.5 mmol/l) and 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.
Key Words: myocardial infarction • cardioprotection • pleiotropic action
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Abbreviations and Acronyms
| | ARVF = adult rat ventricular fibroblast | | GSH = glutathione | | GSSG = glutathione disulfide | | HBSS = Hank's balanced salt solution | | I/R = ischemia/ reperfusion | | LV = left ventricular | | MMP = matrix metalloproteinase | | NRVF = neonatal rat ventricular fibroblasts | | NRVM = neonatal rat ventricular myocyte | | ROS = reactive oxygen species | | TTC = tetracycline |
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