Prevention of ischemia-reperfusion injury by the allergy drug lodoxamide tromethamine.
Lodoxamide tromethamine, an orphan antiallergy drug, inhibits degranulation of mast cells that reside in the myocardium and inhibits xanthine oxidase located in myocytes and predominantly in the vascular endothelium. The hypothesis evaluated was that lodoxamide tromethamine would attenuate oxygen free radical damage. Isolated working rat hearts were perfused with Krebs-Henseleit buffer containing 0, 1, 10, 100, or 1,000 mumol/L lodoxamide tromethamine at 37 degrees and 24 degrees C with ischemic times of 22 and 93 minutes, respectively. These ischemic intervals yielded 50% survival and 50% return of function in untreated hearts. Lodoxamide treatment alone at the onset of reperfusion was also studied. Performance end points were aortic flow, pressure, and coronary flow. Biochemical analyses included serotonin collected from coronary effluent as a marker of mast cell degranulation, uric acid for xanthine oxidase inhibition, myocardial adenosine triphosphate, and carbonyl group concentrations. Performance data demonstrated that lodoxamide was beneficial in a log-linear dose response when given continuously at both temperatures. Percent of preischemic values for untreated and maximal responses at 1,000 mumol/L of lodoxamide were as follows: a mortality of 50% in nontreated hearts versus 0%; aortic flow, 47% to 94% (37 degrees C), 46% to 86% (24 degrees C); cardiac output, 60% to 98% (37 degrees C), 58% to 97% (24 degrees C); adenosine triphosphate, 59% to 90% (37 degrees C), 48% to 65% (24 degrees C). Serotonin was undetectable from any hearts. Uric acid concentrations and carbonyl group content did not change with increasing dose. Lodoxamide demonstrated no benefit when given only during reperfusion, suggesting injury occurred at times other than reperfusion.
Surgery Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892.
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Parenteau
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Clark
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000627:therapeutic use; D006439:Hemodynamics / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D009570:Nitriles; D010072:Oxamic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051381:Rats; D011919:Rats, Inbred Strains; D013997:Time Factors; D014022:Tissue Survival; D014325:Tromethamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use
D000975:Antioxidants; D009570:Nitriles; D014325:Tromethamine; C022028:lodoxamide tromethamine; D000255:Adenosine Triphosphate; D010072:Oxamic Acid