PREJUNCTIONAL ACTIONS OF TACRINE ON AUTONOMIC NEUROEFFECTOR TRANSMISSION IN RABBIT ISOLATED PULMONARY ARTERY AND RAT ISOLATED ATRIA
Authors: Fabiani Maurizio E. , Kabo Peter , Story David F. 
Published: June 2007

SUMMARY1. This study investigated the effects of tacrine (l,2,3,4‐tetrahydro‐9‐aminoacridine) on the resting and stimulation‐induced (SI) release of radioactive substances from isolated preparations of rat atria and rabbit pulmonary artery in which the noradrenergic transmitter stores had been labelled with [3H]‐noradrenaline, and from rat atrial preparations in which cholinergic transmitter stores had been labelled with [3H]‐acetylcholine. In addition, the effect of tacrine on the uptake of [3H]‐noradrenaline by noradrenergic nerves in rat atria was determined.2. Tacrine produced concentration‐dependent increases in the resting efflux of radioactivity from both the [3H]‐noradrenaline‐loaded artery and atrial preparations. Blockade of neuronal amine transport with desipramine reduced the release of radioactivity evoked by tacrine from atria but not that evoked from artery preparations. Inhibition of monoamine oxidase by pargyline pretreatment markedly reduced the tacrine‐evoked release of radioactivity in both atrial and artery preparations.3. The radioactivity released from [3H]‐noradrenaline‐labelled rat atrial preparations by 30 μmol/L tacrine consisted entirely of the deaminated metabolite [3H]‐DOPEG. The evoked release of [3H]‐DOPEG from atria was reduced by approximately 50% by desipramine (1 μmol/L). When atrial monoamine oxidase had been inhibited by pargyline treatment in vivo and in vitro, 30 μmol/L tacrine evoked the release of [3H]‐noradrenaline instead of [3H]‐DOPEG. However, the amounts of [3H]‐noradrenaline released by tacrine when monoamine oxidase was inhibited were only about 25% of the amounts of [3H]‐DOPEG released in untreated atria.4. Tacrine, in concentrations of 1 and 10 μmol/L, enhanced the release of radioactivity evoked by field stimulation of [3H]‐noradrenaline‐loaded rabbit pulmonary artery preparations. This effect was unaltered by desipramine or pretreatment with pargyline. However, in artery preparations pretreated with pargyline, a high concentration of tacrine (100 μmol/L) markedly reduced SI efflux. In contrast to the findings with artery preparations, tacrine (1–30 μmol/L) did not alter SI efflux in rat atrial preparations.5. It is concluded that tacrine displaces noradrenaline from intraneuronal transmitter stores of sympathetically‐innervated tissues, and that the displaced amine is totally metabolized by monoamine oxidase before leaving the nerve terminals. When deamination of neuronal cytoplasmic noradrenaline is prevented, only a portion of the noradrenaline displaced from storage vesicles passes to the extracellular space. It is likely that the transfer of cytoplasmic noradrenaline out of the terminals is limited by the activity of the amine transport mechanism.6. Tacrine, in concentrations of 30 and 100 μmol/L, reduced the uptake radioactivity by rat atria incubated for 5 min periods in [3H]‐noradrenaline to approximately 83 and 26%, respectively, of control uptake. Desipramine was much more potent than tacrine in inhibiting [3H]‐noradrenaline uptake: 1 μmol/L desipramine reduced the uptake radioactivity to approximately 18% of the control.7. Tacrine (30 μmol/L) did not alter the resting efflux of radioactivity from [3H]‐acetylcholine‐labelled rat atrial preparations, but it reduced the efflux of radioactivity evoked by stimulation of intramural cholinergic nerves. The inhibition of SI efflux in the [3H]‐acetylcholine‐labelled atria may have been mediated by acetylcholine that had accumulated as a consequence of the anticholinesterase activity of tacrine at cholinergic nerve terminals.