J. Haynes, S. Hill, L. Selbie
Dec 1, 1997
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Journal
British Journal of Pharmacology
Abstract
1 The effects of peptide YY (PYY), neuropeptide Y (NPY) and structurally related peptides upon field stimulation‐induced and phenylephrine‐mediated contractile responses in the cauda epididymis of the guinea‐pig were investigated. 2 Preparations of cauda epididymis responded to field stimulation with contractions which were completely attenuated by both the neurotoxin, tetrodotoxin (500 nM), and also by the α‐adrenoceptor antagonist, phentolamine (3 μM). PYY (n=7) and the truncated peptide analogue PYY(3–36) (n=5) inhibited field stimulation‐induced contractions (pIC50+s.e.mean: 8.9±0.2 and 9.4±0.2, respectively). Pancreatic polypeptide (PP, up to 1 μM, n=6), NPY (up to 100 nM, n=6) and the NPY analogues [Leu31,Pro34]NPY (n=6) and NPY (13–36) (both up to 1 μM, n=5) had no significant effect. 3 The NPY Y1 receptor antagonist BIBP3226 ((R)‐N2‐(diphenylacetyl)‐N[(4‐hydroxyphenyl)‐methyl]‐argininamide) at 750 nM (n=6) and 7.5 μM (n=6) did not affect the PYY‐mediated inhibition of field stimulation‐induced contractions (pIC50 8.9±0.3 and 9.0±0.3, respectively). In the presence of BIBP3226 (7.5 μM), NPY (n=6) inhibited field stimulation‐induced contractions (pIC50 8.0±0.2). 4 NPY, PYY and PYY(3–36) inhibited [3H]‐noradrenaline release from preparations of epididymis (pIC50 values 7.9±0.7, 9.6±0.8 and 10.0±0.9, respectively, all n=6). The agonists PP and [Leu31,Pro34]PYY (both up to 100 nM) were without significant effect (both n=6). 5 In preparations of cauda epididymis, stimulated with threshold concentrations of the α1‐adrenoceptor agonist, phenylephrine (1 μM), both NPY (n=6) and PYY (n=7) elicited concentration‐dependent increases in contractile force (with pEC50 values of 8.9±0.2 and 8.6±0.1, respectively). The effects of both NPY (n=6) and PYY (n=6) were antagonized by preincubation with BIBP3226 (75 nM; apparent pKB±s.e. values 8.3±1.0 and 8.2±0.6, respectively). The peptide analogues NPY(13–36) (n=5), PYY (3–36) (n=7) and [Leu31,Pro34]NPY (n=5) did not significantly augment responses to threshold concentrations of phenylephrine. 6 These results are consistent with the proposal that distinct NPY receptors mediate the (prejunctional) inhibition of field stimulation‐induced contractions and the (postjunctional) potentiation of responses to phenylephrine in the cauda epididymis of the guinea‐pig. The rank order of agonist potency (NPYPYY≫NPY(13–36), [Leu31,Pro34]NPY and PYY(3–36) and the high potency of BIBP3226 indicate that the postjunctional receptor may be Y1‐like. The rank orders of agonist potency in inhibiting field stimulation‐induced contractile responses and [3H]‐noradrenaline release (PYY(3–36)PYY> NPY≫PP, NPY(13–36), [Leu31,Pro34]NPY and PYY(3–36)PYY>NPY≫;PP,[Leu31,Pro34]PYY, respectively) are consistent with the action of these peptides at a PYY‐preferring receptor subtype, which may be distinct from the presently characterized NPY receptor subtypes.