Synergism between neuropeptide Y and norepinephrine highlights sympatheticcotransmission: Studies in rat arterial mesenteric bed with neuropeptide Y, analogs, and BIBP 3226

Although abundant literature supports the notion that neuropeptide Y (NPY) synergizes in vivo and in vitro, the vasomotor activity elicited by norepin ephrine (NE), the converse interaction (i.e,, the adrenergic modulation of the NPY vasomotor response) has been less characterized. To assess whether NE synergizes the vasomotor effect of NPY, the rat arterial mesenteric bed was chosen as a model experimental system. Mesenteries were precontracted w ith NE and few minutes later were pelf used with exogenous NPY. Under these conditions, NPY contracted the arterial mesenteric bed with an EC50 value of 0.72 +/- 0.06 nM. NPY was unable to contract this vascular territory wit hout an agonist-induced precontraction, Other agonists, such as endothelin- 1, a synthetic analog of prostaglandin F-2 alpha, or 5-hydroxytryptamine, a lso were effective primers because in their presence, NPY was a potent vaso constrictor. In contrast, mesenteries precontracted with KCI failed to evid ence the NPY-induced rise in perfusion pressure. Two structural analogs of NPY, PW and [Leu(31),Pro(34)]NPY, mimicked the activity of NPY. The NPY fra gment 13-36 did not elicit such a response. All NPY analogs exhibited less efficacy and potency relative to NPY. The NPY- and related structural analo g-induced vasoconstriction was competitively and reversibly antagonized by BIBP 3226; the pA(2) of the NPY interaction was 7.0. The application of 0.1 to 1 mu M BIBP 3226 or 0.1 to 10 nM prazosin at the peak of the NPY vasomo tor response elicited a gradual blockade of the vasoconstriction. Although BIBP 3226 blocked the increase in perfusion pressure elicited by NPY, leavi ng unaffected the NE-induced tone, 10 nM prazosin blocked the full response , including the NE-induced component. Tissue preincubation with 200 nM nife dipine abolished the NPY-induced vasoconstriction; likewise, the acute appl ication of 10 to 100 nM nifedipine blocked gradually the maximal NPY-induce d contraction. Removal of the mesenteric endothelial layer increased the po tency of NPY by 2-fold; it also slightly potentiated the antagonist activit y of BIBP 3226, The synergism between NPY and NE backs the principle of sym pathetic cotransmission.