The mechanism of the 3H-noradrenaline releasing effect of various substrates of uptake1: multifactorial induction of outward transport.

摘要: The mechanism of action indirectly acting sympathomimetic amines was studied in the rat vas deferens, after inhibition vesicular uptake (by reserpine), MAO pargyline) and COMT U-0521). 1. K m-values for neuronal 12 substrates were determined as IC50 unlabelled substrate inhibiting initial rate 0.2 μmol/l 3H-(−)-noradrenaline. ranged from 0.35 (for (+)-amphetamine) to 44.3 5-HT). V max (determined 8 substrates) substrate-dependent. 2. Tissues loaded with 3H-(−)-noradrenaline then washed out amine-free solution. All uptake1, induced an outward transport 3H-noradrenaline, equieffective concentrations positively correlated K m. Moreover, EC50 release greatly exceeded It is proposed that this discrepancy between K m indicative fact at least four factors (each one strict dependence on K m) contribute initiation 3H-noradrenaline: a) appearance carrier inside axonal membrane (facilitated exchange diffusion), b) co-transport Na+, c) Cl− (both lowering 3H-noradrenaline carrier), d) re-uptake released (through competition outside carrier). 3. At amezinium, V max. appears limit maximum transport. 4. For some (especially highly lipophilic ones) bell-shaped concentration-release curves obtained. Apparently, inward diffusion can lead partial saturation carrier. if expressed a FRL (fractional loss), loading 37 decreased releasing effect various substrates. In case be partially saturated by high axoplasmic concentration 3H-noradrenaline. 5. Very able induce additional intraneuronal mechanism, presumably increasing pH storage vesicles.