Sympathomimetic effects of MIBG: Comparison with tyramine

Because nothing is known about whether metaiodobenzylguanidine (MIBG) has t yramine-like actions, the sympathomimetic effects of MIBG were determined i n the isolated rabbit heart and compared with those of tyramine. Methods: S pontaneously beating rabbit hearts were perfused with Tyrode's solution (La ngendorff technique; 37 degrees C; 26 mL/min), and the heart rate as well a s the norepinephrine and dopamine overflow into the perfusate was measured before and after doses of MIBG or tyramine (0.03-10 mu mol) given as bolus injections (100 mu L) into the aortic cannula. K-m and V-max values for the neuronal uptake (uptake(1)) of I-125-MIBG and C-14-tyramine were obtained in human neuroblastoma (SK-N-SH) cells. The K-i of MIBG for inhibition of t he H-3-catecholamine uptake mediated by the vesicular monoamine transporter was determined in membrane vesicles obtained from bovine chromaffin granul es and compared with the previously reported K-i value for tyramine determi ned under identical experimental conditions. Results: By producing increase s in heart rate and norepinephrine overflow, both compounds had dose-depend ent sympathomimetic effects in the rabbit heart. MIBG was much less effecti ve than tyramine in increasing heart rate (maximum effect 59 versus 156 bea ts/min) and norepinephrine overflow (maximum effect 35 versus 218 pmol/g). Tyramine also caused increases in dopamine overflow, whereas MIBG was a poo r dopamine releaser. At a dose of 10 mu mol, the increase in heart rate las ted more than 60 min after MIBG and about 20 min after tyramine injection. Accordingly, the norepinephrine overflow caused by 10 mu mol MIBG and tyram ine 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 mu mol/L des ipramine. The kinetic parameters characterizing the saturation of neuronal uptake by I-125-MIBG and C-14-tyramine were similar for the two compounds: K-m values of MIBG and tyramine were 1.6 and 1.7 mu mol/L, respectively, an d V-max values of MIBG and tyramine were 43 and 37 pmol/mg protein/min, res pectively. However, in inhibiting the vesicular H-3-catecholamine uptake, M IBG was eight times less potent than tyramine. Conclusion: MIBG is much les s effective than tyramine as an indirect sympathomimetic agent. This is pro bably a result of its relatively low affinity for the vesicular monoamine t ransporter and explains the relatively poor ability of the drug to mobilize norepinephrine stored in synaptic vesicles. The long duration of MIBG acti on results primarily from the drug not being metabolized by monoamine oxida se. The sympathomimetic effects of MIBG described here are not likely to co me into play in patients given diagnostic or common therapeutic doses of ra dioiodinated MIBG.