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Sympathomimetic Effects of MIBG: Comparison with Tyramine

Departments of Pharmacology and Nuclear Medicine, University of Würzburg, Würzburg
Department of Nuclear Medicine, University of Essen, Essen
Department of Pharmacology, University of Bonn, Bonn, Germany

Correspondence: For correspondence or reprints contact: Karl-Heinz Graefe, MD, Department of Pharmacology, University of Würzburg, Versbacher Strasse 9, D-97078 Würzburg, Germany.

ABSTRACT

Because nothing is known about whether metaiodobenzylguanidine (MIBG) has tyramine-like actions, the sympathomimetic effects of MIBG were determined in the isolated rabbit heart and compared with those of tyramine. Methods: Spontaneously beating rabbit hearts were perfused with Tyrode's solution (Langendorff technique; 37°C; 26 mL/min), and the heart rate as well as the norepinephrine and dopamine overflow into the perfusate was measured before and after doses of MIBG or tyramine (0.03–10 µmol) given as bolus injections (100 µL) into the aortic cannula. K_m and V_max values for the neuronal uptake (uptake₁) of ¹²⁵I-MIBG and ¹⁴C-tyramine were obtained in human neuroblastoma (SK-N-SH) cells. The K_i of MIBG for inhibition of the ³H-catecholamine uptake mediated by the vesicular monoamine transporter was determined in membrane vesicles obtained from bovine chromaffin granules and compared with the previously reported K_i value for tyramine determined under identical experimental conditions. Results: By producing increases in heart rate and norepinephrine overflow, both compounds had dose-dependent sympathomimetic effects in the rabbit heart. MIBG was much less effective than tyramine in increasing heart rate (maximum effect 59 versus 156 beats/min) and norepinephrine overflow (maximum effect 35 versus 218 pmol/g). Tyramine also caused increases in dopamine overflow, whereas MIBG was a poor dopamine releaser. At a dose of 10 µmol, the increase in heart rate lasted more than 60 min after MIBG and about 20 min after tyramine injection. Accordingly, the norepinephrine overflow caused by 10 µmol MIBG and tyramine declined with half-lives of 57.8 and 2.2 min, respectively. The effects of both drugs were drastically reduced in hearts exposed to 2 µmol/L desipramine. The kinetic parameters characterizing the saturation of neuronal uptake by ¹²⁵I-MIBG and ¹⁴C-tyramine were similar for the two compounds: K_m values of MIBG and tyramine were 1.6 and 1.7 µmol/L, respectively, and V_max values of MIBG and tyramine were 43 and 37 pmol/mg protein/min, respectively. However, in inhibiting the vesicular ³H-catecholamine uptake, MIBG was eight times less potent than tyramine. Conclusion: MIBG is much less effective than tyramine as an indirect sympathomimetic agent. This is probably a result of its relatively low affinity for the vesicular monoamine transport and explains the relatively poor ability of the drug to mobilize norepinephrine stored in synaptic vesicles. The long duration of MIBG action results primarily from the drug not being metabolized by monoamine oxidase. The sympathomimetic effects of MIBG described here are not likely to come into play in patients given diagnostic or common therapeutic doses of radioiodinated MIBG.

Key Words: metaiodobenzylguanidine • tyramine • indirect sympathomimetic action • neuronal uptake • vesicular monoamine transporter

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