title: Doxycycline ameliorates ischemic and border-zone remodeling and endothelial dysfunction after myocardial infarction in rats.
abstract: 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.
authors.affiliation: Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky 40202, USA.
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Camp
authors.forename: Sam C
authors.initials: SC
authors.lastname: Tyagi
authors.forename: Giorgio M
authors.initials: GM
authors.lastname: Aru
authors.forename: Melvin R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Jay L
authors.initials: JL
authors.lastname: Mehta
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Tyagi
mesh_terms: 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
chemical_list: 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