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 delta-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-gamma-lactam-Leu9]-NKA(3-10) (GR64349) was active only at the highest concentrations tested (> 10-mu-M), and the NK3 selective agonist, succ-[Asp6,N-MePhe8]-SP(6-11) (senktide) was essentially inactive (10 nM-32-mu-M). 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 pK(B)s 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 pK(B)s less-than-or-equal-to 5.0-5.0). 4 In contrast, the recently developed NK1-selective receptor antagonist [D-Pro9[Spiro-gamma- lactam]Leu10, Trp11]-SP(1-11) (GR71251) did not produce agonist-dependent pK(B) estimates. Schild plot analysis indicated a competitive interaction with a single receptor population where the antagonist had an estimated overall pK(B) of 7.58 +/- 0.13 for the four antagonists of differeing 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 (pK(B) = 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 alpha-2-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.
