Synergism between neuropeptide Y and norepinephrine highlights sympatheticcotransmission: Studies in rat arterial mesenteric bed with neuropeptide Y, analogs, and BIBP 3226
V. Cortes et al., Synergism between neuropeptide Y and norepinephrine highlights sympatheticcotransmission: Studies in rat arterial mesenteric bed with neuropeptide Y, analogs, and BIBP 3226, J PHARM EXP, 289(3), 1999, pp. 1313-1322
Citations number
49
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
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.