Effects of timed administration of doxycycline or methylprednisolone on post-myocardial infarction inflammation and left ventricular remodeling in the rat heart.
The development of strategies to ameliorate post-myocardial infarction (MI) remodeling and improve function continues to be an area of clinical importance. Use of steroids for this purpose is controversial since the effects of timed treatment on relevant inflammatory, biochemical and structure/function endpoints are unclear. In a previous report, we demonstrated that use of doxycycline pre-treatment improves post-MI remodeling and passive left ventricular (LV) function. However, the effects of timed doxycycline post-MI treatment are unknown. To examine these issues, we performed a study using a rat MI model. Animals were administered one of the following: doxycycline (DOX), the corticosteroid methylprednisolone (MP), or aqueous vehicle. Treatment was given early, short-term (at time of MI to 24 h post-MI) or late, long term (2-7 days post-MI). Animals were sacrificed at 3, 7 or 42 days post-surgery. We assessed LV hemodynamics, pressure-volume, and pressure-scar strains, histomorphometry, inflammation via measurements of myeloperoxidase activity, and matrix metalloproteinase (MMP) activity. Late MP treatment yielded a robust right-shifted pressure-volume curve, which was accompanied by increased scar strains. Late DOX treatment yielded reduced average heart weight and size and preserved scar thickness. DOX treatment did not suppress inflammation, which contrasts with the suppressive effects of MP. Use of early or late MP yielded increased MMP activity in infarcted and non-infarcted regions. Early and late treatment with DOX yielded infarct-associated MMP activity levels comparable to those of vehicle-treated animals. In conclusion, results indicate that late use of MP yields adverse post-MI structure/function outcomes that correlate with suppression of inflammation and increased MMP activity. These observations contrast with those of DOX, in particular, late treatment where improved outcomes were observed in LV structure and were accompanied by the lack of suppression of inflammation.
Garcia
Ricardo A
RA
Department of Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA.
Go
Katrina V
KV
Villarreal
Francisco J
FJ
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000494:pharmacology; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003971:Diastole / Q000187:drug effects; D004318:Doxycycline / Q000008:administration & dosage* / Q000494:pharmacology*; D004334:Drug Administration Schedule; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D007249:Inflammation; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008775:Methylprednisolone / Q000008:administration & dosage* / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000503:physiopathology*; D009195:Peroxidase / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013599:Systole / Q000187:drug effects; D013997:Time Factors; D020257:Ventricular Remodeling / Q000187:drug effects*
D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D009195:Peroxidase; D020782:Matrix Metalloproteinases; D004318:Doxycycline; D008775:Methylprednisolone