Captopril pre-treatment produces additive cardioprotective effects to isoflurane preconditioning in attenuating myocardial ischemia reperfusion injury in rabbits and in humans

Abstract

INTRODUCTION: Pre-treatment with the angiotensin-converting inhibitor captopril or volatile anesthetic isoflurane has, respectively, been shown to attenuate myocardial ischemia reperfusion (MI/R) injury in rodents1 or in patients2 undergoing coronary artery bypass graft (CABG) surgery using cardiopulmonary bypass (CPB). It is unknown whether or not captopril pre-treatment and isoflurane preconditioning may additively or synergistically attenuate MI/R injury. METHODS: Patients (n=100) selected for CABG surgery were randomly assigned to five groups (n=20 per group): untreated control (Control), captopril pre-treatment for 3 days group (group Cap3d, captopril 12.5 mg, p.o., 3 times a day) before surgery or single dose captopril group (group Cap1hr, captopril 12.5 mg, p.o., 1 h before surgery) in the absence or presence of inhalational isoflurane at 1.1% end tidal concentration administrated for 30 min before CPB (in group Cap3d+Iso and Caplhr+Iso). Rabbit in vivo MI/R injury model was induced by occluding the left descending coronary artery for 30 min followed by 2 hours reperfusion. Rabbits (8 per groups) were randomized to receive sham operation (group Sham), MI/R (group I/R), captopril (group Cap, 25 mg/kg given intravenously 24 h prior to inducing MI/R), isoflurane preconditioning (group Iso, 15 min 1.1% end tidal isoflurane followed by a 15 min washout period before inducing MI/R), or the combination of captopril and isoflurane (group Iso+Cap). RESULTS: In patients, 3 days captopril treatment combined with isoflurane (Cap3d+Iso), but not 1 hour captopril treatment combined with isoflurane, additively reduced myocardial injury [reduced plasma cardiac troponin I and creatine kinase MB, P<0.05 vs. all other groups], and attenuated myocardial inflammation (reduced plasma TNFα, IL-6, and ICAM-1), which were associated with reduced the usage of vasoactive drugs after surgery. In rabbits, post-ischemic myocardial infarct size in group Cap or group Iso was significantly lower than that in group I/R (P<0.05). Captopril and isoflurane (Iso+Cap) additively reduced IS (P<0.05 vs. Cap or Iso) and cellular injury that were associated with improved postischemic myocardial functional recovery and reduced myocardial apoptosis and attenuated oxidative stress (all P<0.05 vs. Cap or Iso). CONCLUSIONS: A joint use of 3-day captopril treatment and isoflurane preconditioning additively attenuated MI/R by reducing oxidative stress and inflammation.