Sympathomimetic effects of MIBG: comparison with tyramine.

UNLABELLED: 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 degrees 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 micromol) given as bolus injections (100 microL) into the aortic cannula. Km and Vmax values for the neuronal uptake (uptake1) of 125I-MIBG and 14C-tyramine were obtained in human neuroblastoma (SK-N-SH) cells. The Ki 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 Ki 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 micromol, 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 micromol 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 micromol/L desipramine. The kinetic parameters characterizing the saturation of neuronal uptake by 125I-MIBG and 14C-tyramine were similar for the two compounds: Km values of MIBG and tyramine were 1.6 and 1.7 micromol/L, respectively, and Vmax 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 transporter 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.

1,1'-Diisopropyl-2,4'-cyanine (disprocynium24), a potent uptake2 blocker, inhibits the renal excretion of catecholamines.

1,1'-Diisopropyl-2,4'-cyanine (disprocynium24), a potent inhibitor of the extraneuronal monoamine transport system (uptake2), was previously shown to reduce the clearance of catecholamines from plasma not only by blocking uptake2 but presumably also by blocking organic cation transport. To provide more direct evidence for the latter conclusion, the present study was carried out in anaesthetized rabbits. It aimed at determining the effect of disprocynium24 on the renal excretion of catecholamines which is known to be, at least in part, a consequence of organic cation transport in the kidney. To this end, the plasma clearance due to renal excretion (Cl(u)) of endogenous as well as infused 3H-labelled adrenaline, noradrenaline and dopamine was determined for 60-min periods of urine collection in rabbits treated either with disprocynium24 (270 nmol kg(-1) i.v. followed by i.v. infusion of 80 nmol kg(-1) min(-1)) or vehicle. Two groups of animals were studied: group I (monoamine oxidase and catechol-O-methyltransferase intact) and group II (monoamine oxidase and catechol-O-methyltransferase inhibited). A third group of animals with intact monoamine oxidase and catechol-O-methyltransferase was used to study the effect of disprocynium24 on the glomerular filtration rate (as determined by measuring the plasma clearance of inulin). In vehicle controls, Cl(u) of endogenous adrenaline, noradrenaline and dopamine was 7.2, 5.2 and 153.6 ml kg(-1) min(-1), respectively, in group I and 10.4, 7.0 and 134.3 ml kg(-1) min(-1), respectively, in group II. Similar control values of Cl(u) were obtained for infused 3H-adrenaline and 3H-noradrenaline, but not for infused 3H-dopamine; Cl(u) of 3H-dopamine (4.9 ml kg(-1) min(-1) in group I and 15.4 ml kg(-1) min(-1) in group II) was considerably smaller than Cl(u) of endogenous dopamine, indicating that most of the dopamine in urine (i.e., 98% in group I and 92% in group II) was derived from the kidneys rather than from the circulation. By contrast, only about one quarter of the noradrenaline in urine (32% in group I and 24% in group II) and none of the urinary adrenaline were of renal origin. In both groups, disprocynium24 markedly reduced the Cl(u) of endogenous catecholamines (by 72-90%) and of infused 3H-catecholamines (by 49-69%). Moreover, it preferentially inhibited the renal excretion of those components of urinary dopamine and noradrenaline which were derived from the kidney. Therefore, disprocynium24 inhibits the tubular secretion of catecholamines and, hence, organic cation transport in the kidney. This conclusion was substantiated by the observation that disprocynium24 did not alter the glomerular filtration rate.