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Ann Thorac Surg 2000;70:895-900
© 2000 The Society of Thoracic Surgeons
a Department of Surgery, University of Connecticut School of Medicine, Farmington, Connecticut, USA
b RIBI ImmunoChem Research, Inc, Hamilton, Montana, USA
c Department of Surgery, Baystate Medical Center, Springfield, Massachusetts, USA
Address reprint requests to Dr Richard Engelman, Division of Cardiac Surgery, Baystate Medical Center, 759 Chestnut St, Suite 4628, Springfield, MA 01199
Background. Ischemic preconditioning has been proven to be a powerful tool for myocardial protection in the setting of ischemia and reperfusion. A new drug to provide pharmacologic preconditioning, monophosphoryl lipid A (MLA), was administered 24 hours before an acute coronary occlusion in pigs to determine the effect on pharmacologic preconditioning.
Methods. Two studies were completed. In the first, swine were distributed into five groups: group I, control; group II,. aminoguanidine (AMG) (30 mg/kg), a selective inducible nitric oxide synthase (iNOS) blocker; group III, MLA (10 µg/kg); group IV, MLA (35 µg/kg); and group V, MLA and AMG (35 µg/kg and 30 mg/kg, respectively). Twenty-four hours after administration of the MLA, AMG, or both, regional left anterior descending coronary artery ischemia was induced for 15 minutes followed by one hour of global normothermic cardioplegic arrest and three hour reperfusion. Left ventricular function, tissue injury, and percentage of myocardial infarction were measured. Left ventricular myocardium in the left anterior descending coronary artery region was sampled for iNOS messenger RNA (mRNA) during ischemia and reperfusion. In the second study, pigs were sacrificed 0, 4, 6, 8, and 24 hrs after MLA/AMG administration for iNOS mRNA determination in nonischemic myocardium.
Results. Use of MLA significantly improved postischemic ventricular function, and reduced creatinine kinase release and percentage of infarction. Monophosphoryl lipid A induced expression of iNOS mRNA in nonischemic myocardium within four hours of administration which returned to base line by 24 hours. Normothermic regional ischemia then induced expression of iNOS mRNA, which returned to base line during reperfusion. Aminoguanidine completely abolished both MLA-induced and ischemia-induced iNOS mRNA and blocked the beneficial effects of MLA.
Conclusions. Use of MLA can provide myocardial preservation through enhanced expression of iNOS mRNA.
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