title: Matrix metalloproteinase inhibition attenuates right ventricular dysfunction and improves responses to dobutamine during acute pulmonary thromboembolism.
abstract: Activated matrix metalloproteinases (MMPs) cause cardiomyocyte injury during acute pulmonary thromboembolism (APT). However, the functional consequences of this alteration are not known. We examined whether doxycycline (a MMP inhibitor) improves right ventricle function and the cardiac responses to dobutamine during APT. APT was induced with autologous blood clots (350 mg/kg) in anaesthetized male lambs pre-treated with doxycycline (Doxy, 10 mg/kg/day, intravenously) or saline. Non-embolized control lambs received doxycycline pre-treatment or saline. The responses to intravenous dobutamine (Dob, 1, 5, 10 μg/kg/min.) or saline infusions at 30 and 120 min. after APT induction were evaluated by echocardiography. APT increased mean pulmonary artery pressure and pulmonary vascular resistance index by ~185%. Doxycycline partially prevented APT-induced pulmonary hypertension (P < 0.05). RV diameter increased in the APT group (from 10.7 ± 0.8 to 18.3 ± 1.6 mm, P < 0.05), but not in the Doxy+APT group (from 13.3 ± 0.9 to 14.4 ± 1.0 mm, P > 0.05). RV dysfunction on stress echocardiography was observed in embolized lambs (APT+Dob group) but not in embolized animals pre-treated with doxycycline (Doxy+APT+Dob). APT increased MMP-9 activity, oxidative stress and gelatinolytic activity in the RV. Although doxycycline had no effects on RV MMP-9 activity, it prevented the increases in RV oxidative stress and gelatinolytic activity (P < 0.05). APT increased serum cardiac troponin I concentrations (P < 0.05), doxycycline partially prevented this alteration (P < 0.05). We found evidence to support that doxycycline prevents RV dysfunction and improves the cardiac responses to dobutamine during APT.
authors.affiliation: Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: Evandro M
authors.initials: EM
authors.lastname: Neto-Neves
authors.forename: Ozelia
authors.initials: O
authors.lastname: Sousa-Santos
authors.forename: Karina C
authors.initials: KC
authors.lastname: Ferraz
authors.forename: Elen
authors.initials: E
authors.lastname: Rizzi
authors.forename: Carla S
authors.initials: CS
authors.lastname: Ceron
authors.forename: Minna M D
authors.initials: MM
authors.lastname: Romano
authors.forename: Luis G
authors.initials: LG
authors.lastname: Gali
authors.forename: Benedito C
authors.initials: BC
authors.lastname: Maciel
authors.forename: Richard
authors.initials: R
authors.lastname: Schulz
authors.forename: Raquel F
authors.initials: RF
authors.lastname: Gerlach
authors.forename: Jose E
authors.initials: JE
authors.lastname: Tanus-Santos
mesh_terms: D000208:Acute Disease; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D004280:Dobutamine / Q000494:pharmacology / Q000627:therapeutic use*; D004318:Doxycycline / Q000494:pharmacology / Q000627:therapeutic use; D004591:Electrophoresis, Polyacrylamide Gel; D006352:Heart Ventricles / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors / Q000627:therapeutic use*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D011655:Pulmonary Embolism / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D012756:Sheep; D019210:Troponin I / Q000097:blood; D014655:Vascular Resistance / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D018497:Ventricular Dysfunction, Right / Q000150:complications* / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D019210:Troponin I; D004280:Dobutamine; D004318:Doxycycline
keywords: cardiomyocyte injury; doxycycline; matrix metalloproteinases; pulmonary hypertension; pulmonary thromboembolism; right ventricular dysfunction