Neuropeptide Y‐induced potentiation of noradrenergic vasoconstriction in the human saphenous vein: involvement of endothelium generated thromboxane
Authors: Fabi Fulvia , Argiolas Livio , Ruvolo Giovanni , Del Basso Paola 
Published: January 2005

We investigated the potentiating effect of low concentrations of neuropeptide Y (NPY) on the vasoconstriction induced by transmural nerve stimulation (TNS) and noradrenaline (NA) in human saphenous veins. The effects of (i) endothelium removal; (ii) the addition of the NO pathway precursor L‐arginine; (iii) the ETA/ETB endothelin receptor antagonist Ro 47‐0203; (iv) the cyclo‐oxygenase inhibitor, indomethacin; (v) the selective thromboxane A2 (TxA2) receptor antagonists Bay u3405 and ifetroban, and (vi) the TxA2 synthase inhibitor, UK 38485, were studied in order to gain information about the mechanisms of NPY‐induced potentiation.
Contractile response curves for TNS (0.5–8 Hz) and for exogenously administered NA (0.1–3 μM) were obtained in superfused saphenous vein rings. The contractions induced by both TNS and NA at all tested frequencies and concentrations, respectively, were significantly potentiated by 50 nM NPY in endothelium intact veins. Conversely, in endothelium‐denuded vessel rings the contractile‐response curves to TNS and NA overlapped both in the absence and presence of NPY, thus suggesting that a release of vasoactive substances from endothelial cells could account for the noradrenergic NPY‐induced potentiation.
In vessels with intact endothelium, the potentiating action of NPY on TNS and NA was unaffected by the presence of high concentrations of the NO precursor L‐arginine (3–10 mM) or the non‐selective ETA/ETB endothelin receptor antagonist, Ro 47‐0203 (10 μM). These data indicate that the NPY‐induced effect does not involve either the endothelium‐derived vasodilator nitric oxide or the vasoconstrictor endothelin. Conversely, in the presence of the cyclo‐oxygenase inhibitor, indomethacin (30 μM), NPY failed to potentiate the vasoconstrictions produced by either nerve stimulation or by exogenous NA, thus providing evidence that arachidonic acid metabolites through the cyclo‐oxygenase pathway are mainly responsible for the potentiation evoked by NPY.
When the TxA2 receptor antagonists, Bay u 3405 (1 μM) and ifetroban (1 μM) were added to the superfusing medium, NPY did not alter either the frequency‐ or the concentration‐response curves for either TNS or NA. Accordingly, both TNS‐ and NA‐induced contractions were not potentiated by NPY in the presence of the TxA2 synthase inhibitor, UK 38485 (10 μM). This clearly demonstrates the pivotal role of TxA2 in NPY‐induced potentiation.
In superfused vein rings with endothelium, a subthreshold concentration (0.2 nM) of the TxA2 mimetic U 46619 potentiated both TNS‐ and NA‐induced vasoconstrictions. This potentiation was higher at low stimulation frequencies and low NA concentrations, and resembled that produced by NPY.
Our results indicate that in the human saphenous vein NPY potentiates the contractions produced by sympathetic nerve stimulation acting at the postjunctional level, primarily on endothelial cells. In particular, the NPY‐induced release of a cyclo‐oxygenase metabolite, namely TxA2, may have a synergistic effect on the vasoconstriction induced by the noradrenergic mediator. Thus, such a mechanism may play a key role in the maintenance of the sympathetic tone of large human capacitance vessels.