Inhibition of in vivo myocardial ischemic and reperfusion injury by a synthetic manganese-based superoxide dismutase mimetic.
We determined whether an organic superoxide dismutase mimetic could reduce myocardial injury resulting from a 90-min occlusion of the left circumflex coronary artery, followed by 18 hr of reperfusion in an anesthetized canine. The superoxide dismutase-mimetic studied (SC-52608) was a synthetic Mn-based macrocyclic compound. SC-52608 or the inactive analog SC-54385 was administered as four doses of 4 mg/kg i.v. Drug, inactive analog or vehicle was administered 30 and 15 min before ischemia and 15 min and immediately before reperfusion. To ensure parity of left circumflex coronary artery occlusion-induced ischemia, only animals with ischemic zone blood flow of less than 0.15 ml/min/g were included in the final analysis. Ischemic zone blood flow was 0.069 +/- 0.016 ml/min/g in control animals (n = 10), 0.072 +/- 0.010 ml/min/g in SC-52608-treated animals (n = 11) and 0.053 +/- 0.011 ml/min/g in SC-54385-treated (n = 9) animals. A transient hypotensive effect was observed upon SC-52608 administration. Hemodynamic parameters were otherwise unaffected by SC-52608 or SC-54385. The areas at risk of infarct were 39.6 +/- 1.9%, 38.7 +/- 1.1% and 39.4 +/- 1.1% in control, SC-52608-treated and SC-54385-treated animals, respectively. Myocardial infarct sizes (% of area at risk of infarct) were 44.2 +/- 5.6%, 25.7 +/- 4.3% and 35.1 +/- 4.9% in control, SC-52608-treated and SC-54385-treated animals, respectively (P < .05 control vs. SC-52608-treated). Therefore, the synthetic superoxide dismutase mimetic protected the regionally ischemic and reperfused myocardium from injury, implicating oxygen-derived radicals in the tissue-injury process.
Black
S C
SC
Department of Pharmacology, University of Michigan Medical School, Ann Arbor.
Schasteen
C S
CS
Weiss
R H
RH
Riley
D P
DP
Driscoll
E M
EM
Lucchesi
B R
BR
D000818:Animals; D002317:Cardiovascular Agents / Q000737:chemistry / Q000627:therapeutic use*; D003326:Coronary Circulation; D003331:Coronary Vessels / Q000503:physiopathology; D004285:Dogs; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D008345:Manganese / Q000737:chemistry; D018716:Molecular Mimicry; D009203:Myocardial Infarction / Q000188:drug therapy / Q000473:pathology; D017202:Myocardial Ischemia / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009942:Organometallic Compounds / Q000737:chemistry / Q000627:therapeutic use*; D013482:Superoxide Dismutase / Q000737:chemistry*; D016019:Survival Analysis
D002317:Cardiovascular Agents; D009942:Organometallic Compounds; C089774:SC 52608; D008345:Manganese; D013482:Superoxide Dismutase