Uptake mechanisms of meta-[¹²³I]iodobenzylguanidine in isolated rat heart

In order to clarify the uptake and retention mechanisms of radioiodinated meta-iodobenzylguanidine (MIBG) in heart, the kinetics of no-carrier-added [¹²³I]MIBG were studied in the isolated working rat heart in interaction with pharmacologic agents. The tracer was administered in the perfusate as a 10-min pulse, followed by a 90-min washout period. Kinetic analysis of the externally monitored time-activity curves of control hearts showed avid uptake (K_i = 4.4 ± 0.7 mL/min/g), and monoexponential clearance (k_o = 0.0056 ± 0.0017 l/min), indicating a distribution volume (V_d = K_i k_o) of 834 ± 214 mL/g. Blocking experiments (n = 41) were performed with neuronal uptake (uptake-1) inhibitor desipramine (DMI; 50-100 nM) and the extraneuronal uptake (uptake-2) inhibitor N-(9-fluorenyl)-N-methyl-β-chloroethylamine (SKF550; 0.4-0.8 μM). Uptake rate was 27% reduced (P < 0.05) by 50 nM DMI but not significantly affected by 0.4 μM SKF550. Distribution volume was 88% reduced (P < 0.0005) by 50 nM DMI and 28% reduced (P < 0.05) by 0.4 μM SKF550. In DMI-blocked hearts, uptake rate was dramatically decreased (-80%, P < 0.0005) by SKF550 (0.4 μM), indicating uptake-2 transport contributed predominantly to the extraneuronal uptake of the tracer. The slow uptake rate seen with concomitant inhibition of uptake-1 and uptake-2 was further decreased by addition of unlabeled MIBG (1-10 μM) in a concentration-dependent manner, yet unaffected by addition of the vesicular uptake inhibitor Ro 4-1284 (1 μM). Thus, the uptake rate of [¹²³I]MIBG is primarily dependent on uptake-1 and uptake-2 activity. Other possible mechanisms of uptake such as passive diffusion in association with intracellular binding are significant only in conditions where uptake-1 and uptake-2 mechanisms are largely inhibited.