EFFECT OF 6-HYDROXYDOPAMINE AND SOME OTHER COMPOUNDS ON THE CONCENTRATION OF NOREPINEPHRINE IN THE HEARTS OF MICE

Abstract

Some compounds were examined for potency in depleting mouse heart norepinephrine, which was measured 16 hours (or 1 hour for tyramine) after intraperitoneal drug administration. These compounds, in order of increasing ED50's (dose, in mg/kg, required to half deplete heart norepinephrine) were: reserpine, metaraminol, 6-hydroxydopamine (2,4,5-trihydroxyphenethylamine), guanethidine and tyramine. After administration of equipotent doses of the compounds, heart norepinephrine returned to normal with widely varying rates. Most rapid repletion occurred after tyramine, followed in order by guanethidine, metaraminol, reserpine and 6-hydroxydopamine. Tyramine, administered 1 hour previously, blocked the longer-lasting depletion of heart norepinephrine by 6-hydroxydopamine, but not by metaraminol, guanethidine and reserpine. Under similar conditions, guanethidine blocked 6-hydroxydopamine and reserpine, but not metaraminol; and metaraminol blocked 6-hydroxydopamine. A second suboptimal dose of reserpine, guanethidine or metaraminol, administered 1 day after a first dose, produced additional depletion of heart norepinephrine. However, a second dose of 6-hydroxydopamine produced no additional effect unless it was larger than the first dose. Consecutive dosing, at a 1-day interval, with reserpine, guanethidine and 6-hydroxydopamine, in any combination of two in either sequence, produced additive depletion of heart norepinephrine. The data can be interpreted, within the framework of the two-pool concept of norepinephrine storage, as follows: 1. Reserpine releases norepinephrine by acting upon pool 1; guanethidine, like bretylium, blocks the action of reserpine on this pool, but does not itself release norepinephrine from pool 1. 2. Tyramine, guanethidine and metaraminol, in order of increasing affinity for norepinephrine binding sites, release the amine through pool 2. 3. 6-Hydroxydopamine, although possessing less affinity for binding sites of pool 2 than tyramine, metaraminol and guanethidine, destroys or alters the binding sites in such a way that they must be replaced.