Doxycycline ameliorates ischemic and border-zone remodeling and endothelial dysfunction after myocardial infarction in rats.
BACKGROUND
Although matrix metalloproteinase (MMP) activity increases, endothelial function decreases after myocardial infarction (MI). The antibiotic doxycycline inhibits MMP activity in vitro. The role of doxycycline-mediated MMP inhibition in endothelial function is unclear.


OBJECTIVE
Doxycycline ameliorates endothelial dysfunction, in part, by inhibiting MMP activity.


METHODS
We subjected Sprague-Dawley male rats to MI by ligating the left anterior descending arteries. We subjected another group of rats to sham surgery. We administered doxycycline in drinking water (0.67 mg/ml) to both groups 2 days before surgery: the sham group underwent sham surgery and received doxycycline therapy, and the MI group underwent MI and received doxycycline therapy (n = 6 in each group). After 4 weeks, we anesthetized rats and prepared left ventricular rings from infarcted-ischemic (I), non-infarcted near-infarcted (NI), and sham surgery hearts with and without doxycycline treatment.


RESULTS
The MMP-2 activity increased significantly in I and NI hearts, and we observed a selective increase in MMP-9 activity only in I hearts, when compared with other groups (p < 0.05), measured by zymography. Cardiac inhibitor of metalloproteinase decreased only in I hearts (p < 0.05 vs other groups), measured by Western analysis, and doxycycline treatment reversed this decrease. Contractile response of rings to acetylcholine was attenuated in the I group, suggesting nitric oxide-mediated dysfunction, and was reversed by doxycycline. The response to nitroprusside was attenuated in I hearts and ameliorated by doxycycline, suggesting cardiomyocyte dysfunction. Bradykinin induced relaxation in rings from sham surgery hearts and from NI hearts, but induced paradoxic contraction in rings from I hearts. Treatment with doxycycline reversed the paradoxic contraction.


CONCLUSIONS
Results suggest a protective action of doxycycline in the ischemic heart, possibly because of additional pharmacologic actions such as metalloproteinase inhibition.
Camp
Teresa M
TM
Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky 40202, USA.
Tyagi
Sam C
SC
Aru
Giorgio M
GM
Hayden
Melvin R
MR
Mehta
Jay L
JL
Tyagi
Suresh C
SC
D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004318:Doxycycline / Q000494:pharmacology*; D004699:Endocardium / Q000187:drug effects* / Q000503:physiopathology; D006909:Hydroxyproline / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000187:drug effects / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000187:drug effects / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D009203:Myocardial Infarction / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019714:Tissue Inhibitor of Metalloproteinases / Q000187:drug effects / Q000378:metabolism; D020257:Ventricular Remodeling / Q000187:drug effects*; D000097792:Tissue Inhibitor of Metalloproteinase-4
D002316:Cardiotonic Agents; D004318:Doxycycline; D006909:Hydroxyproline; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4