5-Hydroxytryptamine(1A) receptor activation enhances norepinephrine release from nerves in the rabbit saphenous vein

Although serotonergic receptor agonists are known to modulate release of ce ntral serotonin, less is known about the ability of serotonin to alter neur otransmission in peripheral adrenergic nerves. The present study used field stimulation (40V, 0.7 ms duration, 1-16 Hz) to contract the rabbit sapheno us vein, an effect that was abolished in the presence of tetrodotoxin and p razosin (10(-6) M), consistent with stimulation of neuronal norepinephrine release. Furthermore, the field-stimulated contraction was not altered by t he 5-hydroxytryptamine (5-HT)(1B/1D) receptor antagonist GR127935 (10(-6) M ), but was markedly inhibited by the 5-HT1A receptor antagonist WAY 100635 (10(-6) M). GR127935 (10(-8) M) inhibited contraction to sumatriptan, docum enting that the concentration used was sufficient to block 5-HT1B/1D-like v ascular receptors in this tissue. Likewise, WAY 100635 (10-6 M) inhibited c ontraction to the 5-HT1A receptor agonists (+/-)-8-hydroxydipropylaminotetr alin hydrobromide (8-OH-DPAT) and LY238729, without altering contraction to norepinephrine or sumatriptan. Furthermore, both 8-OH-DPAT and LY228729 en hanced the contractile response to field stimulation (1.0-8.0 Hz) and activ ated norepinephrine release in the absence of field stimulation. Contractil e responses of the rabbit saphenous vein to both 5-HT1A receptor agonists w ere markedly inhibited by prazosin and dextrally shifted by WAY 100635, sup porting the idea that the 5-HT1A receptor agonists were activating presynap tic 5-HT1A receptors to enhance norepinephrine release even in the absence of field stimulation. Thus, in the rabbit saphenous vein, 5-HT1A but not 5- HT1B/1D receptors enhanced neurotransmitter release from adrenergic nerves. These observations suggested that serotonergic nerves or other cell types in the saphenous vein are activated by field stimulation to release seroton in, which in turn activates presynaptic 5HT(1A) receptors on adrenergic neu rons to effect norepinephrine release. To support this hypothesis, serotoni n levels were measured in the saphenous vein and were increased after pargy line pretreatment (30 mg/kg s.c.), decreased after dl-p-chlorophenylalanine methyl ester pretreatment (300 mg/kg s.c.), and unaltered after pretreatme nt with 6-hydroxydopamine hydrobromide (100 mg/kg s.c.). Thus, we provide s trong evidence for the 1) presence of serotonin and its direct synthesis in dependent of adrenergic nerves and 2) a novel excitatory effect of presynap tic 5-HT1A receptor activation on adrenergic nerves in a peripheral blood v essel.