title: Effect of graded hypoxia on retention of technetium-99m-nitroheterocycle in perfused rat heart.
abstract: The purpose of this investigation was to determine the effects of graded hypoxia on the retention of a 99mTc-labeled nitroimidazole.
  
  
  METHODS
  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 were perfused with media equilibrated with gas mixtures containing 5% CO2 and various levels of O2, 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 perfusate PO2 brought about an increase in the retention of BMS-181321, resulting in a good correlation between its retention and perfusate PO2 (r = 0.97). Myocardial oxygen consumption was independent of oxygen delivery when the perfusate oxygen pressure was greater than 350 Torr. Below 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 was 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 increased by about 25% as compared to hearts perfused in the presence of this substrate.
  
  
  CONCLUSIONS
  These results indicate that myocardial retention of BMS-181321 is coupled to the level of tissue oxygenation and that hypoxic retention may be affected by substrate input.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey, USA.
authors.forename: W L
authors.initials: WL
authors.lastname: Rumsey
authors.forename: B
authors.initials: B
authors.lastname: Patel
authors.forename: K E
authors.initials: KE
authors.lastname: Linder
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D006321:Heart / Q000000981:diagnostic imaging*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009593:Nitroimidazoles / Q000493:pharmacokinetics; D015609:Organotechnetium Compounds / Q000493:pharmacokinetics; D010101:Oxygen Consumption; D010477:Perfusion; D011877:Radionuclide Imaging; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D009593:Nitroimidazoles; D015609:Organotechnetium Compounds; C082027:BMS 181321