PT  - JOURNAL ARTICLE
AU  - Marlene L. Cohen
AU  - Kathryn W. Schenck
AU  - Susan H. Hemrick-Luecke
TI  - 5-Hydroxytryptamine<sub>1A</sub> Receptor Activation Enhances Norepinephrine Release from Nerves in the Rabbit Saphenous Vein
DP  - 1999 Sep 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1195--1201
VI  - 290
IP  - 3
4099  - http://jpet.aspetjournals.org/content/290/3/1195.short
4100  - http://jpet.aspetjournals.org/content/290/3/1195.full
SO  - J Pharmacol Exp Ther1999 Sep 01; 290
AB  - Although serotonergic receptor agonists are known to modulate release of central serotonin, less is known about the ability of serotonin to alter neurotransmission in peripheral adrenergic nerves. The present study used field stimulation (40V, 0.7 ms duration, 1–16 Hz) to contract the rabbit saphenous vein, an effect that was abolished in the presence of tetrodotoxin and prazosin (10−6 M), consistent with stimulation of neuronal norepinephrine release. Furthermore, the field-stimulated contraction was not altered by the 5-hydroxytryptamine (5-HT)1B/1D receptor antagonist GR127935 (10−6 M), but was markedly inhibited by the 5-HT1A receptor antagonist WAY 100635 (10−6M). GR127935 (10−8 M) inhibited contraction to sumatriptan, documenting that the concentration used was sufficient to block 5­HT1B/1D­like vascular receptors in this tissue. Likewise, WAY 100635 (10−6 M) inhibited contraction to the 5-HT1A receptor agonists (±)-8-hydroxydipropylaminotetralin hydrobromide (8-OH-DPAT) and LY238729, without altering contraction to norepinephrine or sumatriptan. Furthermore, both 8-OH-DPAT and LY228729 enhanced the contractile response to field stimulation (1.0–8.0 Hz) and activated norepinephrine release in the absence of field stimulation. Contractile responses of the rabbit saphenous vein to both 5-HT1Areceptor agonists were markedly inhibited by prazosin and dextrally shifted by WAY 100635, supporting the idea that the 5-HT1Areceptor agonists were activating presynaptic 5-HT1Areceptors 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 serotonin, which in turn activates presynaptic 5-HT1A receptors on adrenergic neurons to effect norepinephrine release. To support this hypothesis, serotonin levels were measured in the saphenous vein and were increased after pargyline pretreatment (30 mg/kg s.c.), decreased afterdl-p-chlorophenylalanine methyl ester pretreatment (300 mg/kg s.c.), and unaltered after pretreatment with 6-hydroxydopamine hydrobromide (100 mg/kg s.c.). Thus, we provide strong evidence for the 1) presence of serotonin and its direct synthesis independent of adrenergic nerves and 2) a novel excitatory effect of presynaptic 5-HT1A receptor activation on adrenergic nerves in a peripheral blood vessel. The American Society for Pharmacology and Experimental Therapeutics