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New Insights on Flow-Independent Mechanisms of ^99mTc-HMPAO Retention in Nervous Tissue: In Vitro Study

Department of Experimental and Clinical Medicine, Sections of Nuclear Medicine and Pharmacology, University of Ferrara, Ferrara, Italy

Correspondence: For correspondence or reprints contact: Simone Sbrenna, MD, Department of Experimental and Clinical Medicine, Section of Pharmacology, Via Fossato di Mortara 17, 44100 Ferrara, Italy.

ABSTRACT

SPECT using ^99mTc-hexamethyl propyleneamine oxime (HMPAO) mainly reflects regional cerebral blood flow, however metabolic abnormalities also affect the retention of ^99mTc-HMPAO. Methods: To rule out any flow factor, a test-tube model was used to evaluate the effects of metabolical alterations both on intracellular trapping of ^99mTc-HMPAO and on extracellular glutamate and lactate dehydrogenase (LDH) outflow from rat brain slices. Results: Under control conditions, slices took up 7.0% ± 1.4% of ^99mTc-HMPAO contained in the medium, whereas prelabeled slices released 10.8% ± 2.6% of their radioactive content; glutamate and LDH outflow were 49.1 ± 21.6 pmol/mg protein/ min and 4.8 ± 0.9 U/L/mg protein/min, respectively. The control medium was altered by adding a metabolic poison (5 mmol/L azide), removing glucose and replacing O₂ with N₂ to mimic ischemia (in vitro ischemia) and replacing Krebs solution with hypotonic medium to evoke cell lysis. Both azide and in vitro ischemia induced a significant increase in ^99mTc-HMPAO release (15.8% ± 3.3% and 18.3% ± 6.2%, respectively), without any modification in LDH efflux. However, only azide reduced the uptake of the tracer. Conversely, glutamate outflow was massive during in vitro ischemia and was far lower during azide treatment. Under hypotonic medium conditions, the release of ^99mTc-HMPAO, glutamate and LDH were dramatically increased. Surprisingly, a two-fold increase of ^99mTc-HMPAO uptake was also found. When 1 mmol/L glutathione was added to the medium, to convert native lipophilic ^99mTc-HMPAO into hydrophilic derivatives, tracer uptake was inhibited both under control and hypotonic medium conditions. Conclusion: This study provides evidence that not only poisoning of the tissue but also in vitro ischemia induced a reduction of ^99mTc-HMPAO retention. Moreover, we demonstrated that injuries causing cell membrane disruption led to hyperfixation of ^99mTc-HMPAO.

Key Words: cerebral cortex slices • ^99mTc-labeled hexamethyl propyleneamine oxime • brain metabolism • hyperfixation • in vitro ischemia • cell membrane damage

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