Novel selective agonists and antagonists confirm neurokinin NK1 receptors in guinea-pig vas deferens

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Abstract
1 This study investigated the recognition characteristics of neurokinin receptors mediating potentiation of the contractile response to field stimulation in the guinea-pig vas deferens. 2 A predominant NK1 receptor population is strongly suggested by the relative activities of the common naturally-occurring tachykinin agonists, which fall within less than one order of magnitude. This conclusion is supported by the relative activities of the synthetic NK1 selective agonists substance P methyl ester, [Glp6,l-Pro9]-SP(6–11) and δ-aminovaleryl-[l-Pro9,N-MeLeu10]-SP(7–11) (GR73632) which were 0.78, 9.3 and 120 as active as substance P, respectively. Furthermore, the NK2 selective agonist [Lys3, Gly8,-R-γ-lactam-Leu9]-NKA(3–10) (GR64349) was active only at the highest concentrations tested (> 10 μm), and the NK3 selective agonist, succ-[Asp6,N-MePhe8]-SP(6–11) (senktide) was essentially inactive (10 nm-32 μm). 3 [d-Arg1,d-Pro2,d-Trp7,9, Leu11]-SP(1–11) antagonized responses to neurokinin A, neurokinin B, physalaemin, eledoisin, [Glp6,d-Pro9]-SP(6–11), GR73632 and GR64349 (apparent pKBs 5.6–6.2), but was less potent in antagonizing responses to substance P, substance P methyl ester and [Glp6,l-Pro9]-SP(6–11) (apparent pKBs ≤ 5.0–5.0). 4 In contrast, the recently developed NK1-selective receptor antagonist [d-Pro9[Spiro-γ- lactam]Leu10, Trp11]-SP(1–11) (GR71251) did not produce agonist-dependent pKB estimates. Schild plot analysis indicated a competitive interaction with a single receptor population where the antagonist had an estimated overall pKB of 7.58 ± 0.13 for the four agonists of differing subtype selectivity tested (GR73632, GR64349, substance P methyl ester and neurokinin B). This estimate is similar to that we obtained for NK1-mediated (substance P methyl ester) contraction in the guinea-pig ileum preparation (pKB = 7.86 ± 0.05). 5 Tachykinin action appears not to depend on release of a number of intermediary mediators including acetylcholine, histamine or cyclo-oxygenase products, nor to involve interaction with neuronal mechanisms including α2-adrenoceptor feedback, noradrenergic Uptake-1 or opioid-release, since antagonism or inhibition of these mechanisms did not modify responses to tachykinins. 6 We conclude that tachykinin action in the field-stimulated guinea-pig vas deferens preparation is mediated through interaction with a predominant neurokinin NK1 receptor population and this preparation can therefore be used to study NK1 modulation of sympathetic neurotransmission.