EFFECT OF GRADED HYPOXIA ON RETENTION OF TECHNETIUM-99M-NITROHETEROCYCLE IN PERFUSED RAT-HEART

The purpose of this investigation was to determine the effects of grad ed hypoxia on the retention of a (99)mTc-labeled nitroimidazole. Metho ds: Rat hearts were perfused retrogradely with Krebs-Henseleit buffer at 37 degrees C and paced at 5 Hz. After a 20-min stabilization period , coronary flow was maintained at 8 ml/min/g wet wt and the hearts wer e perfused with media equilibrated with gas mixtures containing 5% CO2 and various levels of O-2, from 544 to 29 Torr. Technetium-99m-O(PnAO -1-(2-nitroimidazole)), BMS-181321, was infused for 20 min into a side port of the aortic cannula. Perfusion continued for an additional 40 min to allow for compound clearance. Results: Each decrease of perfusa te PO2 brought about an increase in the retention of BMS-181321, resul ting in a good correlation between its retention and perfusate PO2 (r = 0.97). Myocardial oxygen consumption was independent of oxygen deliv ery when the perfusate oxygen pressure was greater than 350 Torr. Belo w this value, oxygen consumption declined markedly as influent PO2 was decreased. By contrast, the tissue lactate/pyruvate ratio and lactate efflux rose with each decrease of influent PO2. A good correlation wa s obtained between retention of the nitroheterocycle and the cytosolic lactate/pyruvate ratio (r = 0.98). When glucose was omitted from the perfusate (PO2 = 27 Torr), retention of the nitroheterocycle was incre ased by about 25% as compared to hearts perfused in the presence of th is substrate. Conclusion: These results indicate that myocardial reten tion of BMS-181321 is coupled to the level of tissue oxygenation and t hat hypoxic retention may be affected by substrate input.