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Characteristics and Regulation of ¹²³I-MIBG Transport in Cultured Pulmonary Endothelial Cells

¹ Department of Nuclear Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; and ² Center for Molecular Imaging, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Correspondence: For correspondence contact: Kyung-Han Lee, MD, Department of Nuclear Medicine, Samsung Medical Center, 50 Ilwondong, Kangnamgu, Seoul, Korea. E-mail: khleenm{at}yahoo.co.kr

¹²³I-Metaiodobenzylguanidine (¹²³I-MIBG) is used for lung scintigraphy to assess pulmonary endothelial cell integrity, but its processing at the cellular level has not been investigated to date. We thus characterized the mechanisms that mediate ¹²³I-MIBG transport in pulmonary endothelial cells and investigated the effects of stimuli associated with pulmonary dysfunction. Methods: Calf pulmonary artery endothelial (CPAE) cells were examined for ¹²³I-MIBG uptake and efflux rates and evaluated for the presence of norepinephrine (NE) transporters by Western blotting. The specificity of ¹²³I-MIBG uptake was investigated with inhibitors of the uptake 1 and uptake 2 transport systems. In addition, we tested the effects of hypoxia (1% O₂), phorbol 12-myristate 13-acetate (PMA, a protein kinase C [PKC] activator), and NG-nitro-L-arginine methyl ester (L-NAME) (a nitric oxide synthase inhibitor) treatments on CPAE cell ¹²³I-MIBG uptake. Results: CPAE cells demonstrated a time-dependent increase in ¹²³I-MIBG uptake that reached a relative plateau (mean ± SD) at 4 h of 375.6% ± 5.9% the 30-min level. When the culture medium was changed after 30 min of uptake, ¹²³I-MIBG gradually was eluted from the cells at an efflux rate of 43.8% over 2 h. Western blotting confirmed the presence of NE transporters in CPAE cells. The uptake 1 inhibitors desipramine, imipramine, and phenoxybenzamine at 50 µmol/L reduced ¹²³I-MIBG uptake to 55.3% ± 2.7%, 62.4% ± 3.5%, and 48.0% ± 2.2% control levels, respectively, whereas none of the uptake 2 inhibitors had an effect. Exposure to hypoxia resulted in a reduction in ¹²³I-MIBG uptake to 77.5% ± 0.2% and 50.0% ± 3.4% control levels at 0.5 and 4 h, respectively. PMA (10 ng/mL) and L-NAME (2 nmol/L) decreased ¹²³I-MIBG uptake to 76.7% ± 9.0% and 86.5% ± 5.6% control levels, respectively. Conclusion: Pulmonary endothelial cells express NE transporters and actively take up ¹²³I-MIBG through the specific uptake 1 system. Furthermore, ¹²³I-MIBG transport can be reduced by hypoxia, PKC activation, and nitric oxide deficiency, which may contribute partly to the lower levels of lung uptake observed in diseases that compromise pulmonary endothelial cell integrity.

Key Words: ¹²³I-MIBG • endothelial cells • norepinephrine transporters • pulmonary disease • hypoxia

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JNM 2006 47: 7a-8a. [Full Text]