DISCRIMINATION BY BENEXTRAMINE BETWEEN THE NPY-Y-1 RECEPTOR SUBTYPES PRESENT IN RABBIT ISOLATED VAS-DEFERENS AND SAPHENOUS-VEIN

1 In order to characterize the neuropeptide Y (NPY) Y-1 receptors know n to be present in rabbit isolated vas deferens and saphenous vein, th e pharmacological activity of the selective NPY Y-1 receptor agonists, [Leu(31),Pro(34)] NPY and various other peptide agonists, together wi th the putative NPY antagonist, benextramine, were compared in the two tissues. 2 In rabbit isolated saphenous vein, cumulative dose-respons e curves to various NPY agonists were obtained. All the peptides teste d caused contractions which developed quite slowly. The rank order of potency obtained was: PYY > NPY > [Leu(31),Pro(34)] NPY = NPY2-36 > hP P >> NPY13-36 = NPY18-36. Incubation with benextramine (BXT) at 100 mu M for 30 min irreversibly abolished the contractile response to [Leu( 31),Pro(34)] NPY but was ineffective against NPY18-36-induced contract ions. 3 Cumulative dose-response curves to [Leu(31),Pro(34)] NPY were performed in the same preparation before and after incubation with 100 mu M BXT for 20 min in order to inactivate NPY Y-1 receptors. The pK( A) (-logK(A)) estimation for [Leu(31),Pro(34)] Npy was 7.60 +/- 0.30 u sing the operational model and 7.20 +/- 0.33 using the null method; th e difference between the two methods was not statistically significant (P = 0.36). 4 Prostatic segments of rabbit vas deferens were electric ally stimulated with single pulses. Immediately after stabilization of the contractile response, a cumulative dose-response curve to various NPY agonists was obtained in each tissue. The rank order of potency f or twitch inhibition was: PYY > [Leu(31),Pro(34)] NPY greater than or equal to NPY greater than or equal to hPP > NPY2-36 >> NPY13-36 >> NPY 18-36 which indicates the presence of a prejunctional NPY Y-1 receptor . BXT at 100 mu M incubated for 10 or 60 min did not antagonize the re sponse to [Leu(31),Pro(34)] NPY. 5 We conclude that rabbit isolated sa phenous vein contains a population of post-junctional NPY Y-1 receptor s irreversibly blocked by BXT, as well as a population of post-junctio nal NPY Y, receptors, which are insensitive to BXT. In contrast, the r abbit isolated vas deferens express a pre-junctional NPY Y-1 receptor subtype which is not blocked by BXT. Tetramine disulphides such as BXT could be useful tools in classifying NPY receptors.