MYOCARDIAL KINETICS OF A PUTATIVE HYPOXIC TISSUE MARKER, TC-99M-LABELED NITROIMIDAZOLE (BMS-181321), AFTER REGIONAL ISCHEMIA AND REPERFUSION

Background A new nitroimidazole complex, Tc-99m-propylene amine oxime- 1,2-nitroimidazole (BMS-181321), has been developed to allow the posit ive imaging of hypoxic myocardium by standard gamma camera techniques. Methods and Results To determine the myocardial kinetics of BMS-18132 1 during myocardial ischemia and reperfusion, seven open-chest swine w ere prepared according to a model of extracorporeal coronary perfusion in which left ventricular wall thickening (percent end-diastolic thic kness) and substrate use in the left anterior descending (LAD) region ([C-14]palmitate and [H-3]glucose infusions) were determined. Measurem ents were obtained at baseline, during 40 minutes of ischemia produced by reducing flow in the LAD distribution by 60%, and during 70 minute s of reperfusion. Three aerobic control hearts were also studied in wh ich LAD blood flow was not reduced. Regional coronary circulation was further assessed in all hearts by use of radiolabeled microspheres inj ected during ischemia. BMS-181321 (20 to 30 mCi) was injected after 30 minutes of ischemia, and its myocardial uptake was assessed by dynami c planar gamma imaging. Ischemia was associated with declines in fatty acid metabolism (15+/-11 mu mol . h(-1). g dry wt(-1), mean+/-SEM), s ystolic wall thickening (20+/-6%), and myocardial oxygen consumption ( 3+/-1 mL . min(-1). 100 g(-1)) and an increase in exogenous glucose ut ilization (75+/-13 mu mol . h(-1). g dry wt(-1)). Systolic wall thicke ning recovered by only 8+/-3% with reperfusion. Initial distribution o f BMS-181321 in the aerobic hearts appeared homogeneous. Washout from the ischemic and reperfused LAD bed was slower than the aerobically pe rfused LAD bed in the control group (t(1/2)=136+/-1 versus 80+/-1 minu tes, P<.05), allowing visualization of the LAD region during reperfusi on. Tissue activity of BMS-181321 was inversely related to LAD blood f low during ischemia (r=-.68+/-.05), and the ratio of BMS-181321 in the LAD region versus normal myocardium was 1.7+/-0.2. Control swine lack ed regional deposition of the tracer in the normally perfused LAD dist ribution. Conclusions Thus, acute regional ischemia in these studies w as visualized as an increase in retention of BMS-181321, suggesting it s applicability in the imaging of clinical conditions of myocardial hy poperfusion.