Inducible nitric oxide synthase activation after ischemia/reperfusion contributes to myocardial dysfunction and extent of infarct size in rabbits: evidence for a late phase of nitric oxide-mediated reperfusion injury
Background: Ischemia/reperfusion (I/R) leads to the induction of inducible nitric oxide synthase. The present study investigated the effects of selective and continuous inhibition of iNOS on myocardial performance, infarct size and histomorphological changes after I/R in rabbits. Methods and Results: Ischemia/reperfusion (I/R) was induced by occlusion of the circumflex coronary artery for 30 min followed by 48 h of reperfusion. Sham animals (group A) served as control. Three groups were subjected to I/R: (B) placebo; (C) aminoguanidine (AMG; 10 mg/kg bolus) given prior to and 48 h after I/R to test its acute effects; (D) AMG (300 mg/kg/day sc) to test effects of continuous treatment. Hemodynamics, myocardial blood flow, infarct size, iNOS activity, cGMP levels, immunohistochemical analysis of iNOS expression and AMG tissue levels were determined. Continuous AMG treatment improved myocardial performance (hemodynamics and blood flow) compared to placebo group. iNOS was highest in placebo-treated animals. AMG tissue levels were highest in tissues affected by I/R. Infarct size (% of the circumflex region) was significantly smaller in group B when compared to group B. Conclusions: This is the first study showing that activation of myocardial iNOS isozyme during 48 h of reperfusion contributes to a late phase of I/R-induced injury in rabbits. Selective and continuous modulation of iNOS by AMG over this time period exerts protective effects with respect to myocardial performance, coronary blood flow, cellular infiltration and reduction of infarct size; this may be a novel therapeutic approach in the clinical situation to limit irreversible myocardial injury associated with ischemia and reperfusion. (C) 1999 Elsevier Science B.V. All rights reserved.
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Virginia Commonwealth Univ, Med Coll Virginia, Div Cardiol, Richmond, VA 23298 USAVirginia Commonwealth Univ, Med Coll Virginia, Div Cardiol, Richmond, VA 23298 USA
Xi, L
Jarrett, NC
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Virginia Commonwealth Univ, Med Coll Virginia, Div Cardiol, Richmond, VA 23298 USAVirginia Commonwealth Univ, Med Coll Virginia, Div Cardiol, Richmond, VA 23298 USA
Jarrett, NC
Hess, ML
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Virginia Commonwealth Univ, Med Coll Virginia, Div Cardiol, Richmond, VA 23298 USAVirginia Commonwealth Univ, Med Coll Virginia, Div Cardiol, Richmond, VA 23298 USA
Hess, ML
Kukreja, RC
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Virginia Commonwealth Univ, Med Coll Virginia, Div Cardiol, Richmond, VA 23298 USAVirginia Commonwealth Univ, Med Coll Virginia, Div Cardiol, Richmond, VA 23298 USA
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Sapporo Med Univ, Sch Med, Dept Surg 1, Chuo Ku, Sapporo, Hokkaido 0608543, JapanSapporo Med Univ, Sch Med, Dept Surg 1, Chuo Ku, Sapporo, Hokkaido 0608543, Japan
Isobe, M
Katsuramaki, T
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Sapporo Med Univ, Sch Med, Dept Surg 1, Chuo Ku, Sapporo, Hokkaido 0608543, JapanSapporo Med Univ, Sch Med, Dept Surg 1, Chuo Ku, Sapporo, Hokkaido 0608543, Japan
Katsuramaki, T
Kimura, H
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Sapporo Med Univ, Sch Med, Dept Surg 1, Chuo Ku, Sapporo, Hokkaido 0608543, JapanSapporo Med Univ, Sch Med, Dept Surg 1, Chuo Ku, Sapporo, Hokkaido 0608543, Japan
Kimura, H
Nagayama, M
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Sapporo Med Univ, Sch Med, Dept Surg 1, Chuo Ku, Sapporo, Hokkaido 0608543, JapanSapporo Med Univ, Sch Med, Dept Surg 1, Chuo Ku, Sapporo, Hokkaido 0608543, Japan
Nagayama, M
Matsuno, T
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Sapporo Med Univ, Sch Med, Dept Surg 1, Chuo Ku, Sapporo, Hokkaido 0608543, JapanSapporo Med Univ, Sch Med, Dept Surg 1, Chuo Ku, Sapporo, Hokkaido 0608543, Japan
Matsuno, T
Yagihashi, A
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Sapporo Med Univ, Sch Med, Dept Surg 1, Chuo Ku, Sapporo, Hokkaido 0608543, JapanSapporo Med Univ, Sch Med, Dept Surg 1, Chuo Ku, Sapporo, Hokkaido 0608543, Japan
Yagihashi, A
Hirata, K
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Sapporo Med Univ, Sch Med, Dept Surg 1, Chuo Ku, Sapporo, Hokkaido 0608543, JapanSapporo Med Univ, Sch Med, Dept Surg 1, Chuo Ku, Sapporo, Hokkaido 0608543, Japan