Neuropeptide Y (NPY) and peptide YY (PYY) effects in the epididymis of the guinea-pig: evidence of a pre-junctional PYY-selective receptor

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 pK_B±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 (NPY⩾PYY≫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.

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