Pharmacological characterization of presynaptic alpha-adrenoceptors in the modulation of the 5-hydroxytryptamine release from vascular adrenergic nerves in the rat.

The role of presynaptic alpha-adrenoceptors in modulation of the 5-hydroxytryptamine (5-HT) release from vascular adrenergic nerves was investigated in the perfused mesenteric vascular bed of the rat. After treatment with 5-HT (10 microM) for 15 min, the vasoconstrictor response to periarterial nerve stimulation (PNS, 4 to 16 Hz, 2 msec in duration for 30 sec) was greatly potentiated without significantly affecting the pressor response to exogenously administered noradrenaline (0.5 nmol). The potentiating effect was more pronounced at low frequencies of PNS (4 and 8 Hz). The potentiation of the pressor response to PNS after 5-HT treatment did not occur in the presence of LY53857 (0.01 microM), a selective 5-HT2 receptor antagonist. The enhanced pressor response to PNS seen after 5-HT treatment was further exaggerated in the presence of clonidine (0.1 and 1 microM), a preferential alpha 2-adrenoceptor agonist, while methoxamine (1 and 10 microM), a selective alpha 1-adrenoceptor agonist, did not affect the enhanced PNS response. This effect of clonidine was more pronounced in low frequencies of PNS (4 and 8 Hz) and was abolished by LY53857 (0.01 microM). In the perfused mesenteric vascular bed labelled with [3H]-5-HT, PNS (8 Hz) evoked an increase of tritium efflux in the perfusate. The PNS-evoked tritium efflux was facilitated by yohimbine (0.1 to 1 microM), an alpha 2-adrenoceptor antagonist, and prazosin, a selective alpha 1-adrenoceptor antagonist, at a high concentration (1 microM), while LY53857 (0.01 to 0.1 microM) and a low concentration of prazosin (0.1 microM) had no effect on the tritium efflux. Clonidine (0.01 to 1 microM) produced a dose-dependent increase of PNS-evoked tritium efflux, while methoxamine (0.1 to 10 microM) was without effect. The monoamine uptake inhibitor, cocaine (10 microM) produced a significant inhibition of the PNS-evoked tritium efflux. The effects of clonidine and cocaine on the PNS-evoked tritium efflux were antagonized by yohimbine (1 microM). These results suggest that the release of 5-HT from adrenergic nerve endings by PNS is modulated by presynaptic alpha 2-adrenoceptors.