Effects of S-11701 on accumulation, release and metabolism of norepinephrine in isolated canine saphenous veins

Abstract

1. The effects S-11701 ([morpholinyl-2)-methoxy]-8-tetrahydro-1,2,3,4-quinoleine) on accumulation, overflow and metabolism of [ 3H]norepinephrine were investigated in isolated canine saphenous veins. 2. Saphenous veins were incubated with [ 3H]norepinephrine in the absence or the presence of S-11701; the drug caused a concentration-dependent inhibition of the tissue content of [ 3H]norepinephrine and its metabolites, except for 3-methoxy-4-hydroxymandelic acid (VMA). 3. In helical strips of canine saphenous veins previously incubated with [ 3H]norepinephrine and then suspended for isometric tension recording and measurement of the overflow of labelled transmitter and its metabolites, S-11701 (30 μM) significantly increased the spontaneous efflux of total 3H; this effect was almost exclusively due to an augmentation of the efflux of [ 3H]DOPEG. 4. During electrical stimulation (9 V, 1 Hz), S-11701 at 1 μM slightly increased the overflow of extraneuronal norepinephrine metabolites without affecting the contractile response. At the higher concentration (30μM) the compound increased the contractive response and the overflow of 3H; the latter was due mainly to an increase in [ 3H]DOPEG and, to a lesser extent, in [ 3H]norepinephrine. 5. DMI (1 μM) did not interfere with the effects of S-11701 on DOPEG efflux. 6. These experiments indicate that in the canine saphenous vein, S-11701 causes a concentration-dependent inhibition of neuronal accumulation of [ 3H]norepinephrine. At higher concentrations, S-11701 enters the adrenergic nerve terminals independently of the neuronal amine carrier and displaces [ 3H]norepinephrine from its storage sites.