TACHYKININ RECEPTORS MEDIATING RESPONSES TO SENSORY NERVE-STIMULATION AND EXOGENOUS TACHYKININS AND ANALOGS IN THE RABBIT ISOLATED IRIS SPHINCTER

1 We have used selective tachykinin receptor agonists and antagonists to investigate the nature of the receptors mediating responses to endogenous and exogenous tachykinins in the rabbit iris sphincter preparation in vitro. 2 The NK1-selective agonist, substance P methyl ester, induced contraction with a pD2 of 9.16 indicating the presence of NK1 receptors. In confirmation, the NK1-selective antagonist, GR82334, competitively antagonized responses to substance P methyl ester with high affinity (pK(B) 7.46). 3 NK3 receptors also mediate contraction since NK3-selective agonists exhibited high potency, e.g. the pD2 of [Me-Phe]-neurokinin B was 9.67, and their responses were not inhibited by GR82334 (10 muM). 4 NK2 receptor activation does not seem to contribute to contraction since the NK2-selective agonist [beta-Ala8]-neurokinin A(4-10) had relatively low potency (pD2 6.43), and the NK2-selective antagonists MEN10207 (1 muM) and L-659,877 (10 muM) were inactive or had low affinity, respectively. 5 GR82334 (1 muM) significantly inhibited responses to electrical field-stimulation of non-adrenergic non-cholinergic sensory nerves (3, 10 and 30 Hz), and caused a rightward shift of the log concentration-response curve to bradykinin (lateral shift ca. 1000 fold). Higher concentrations of GR82334 (10 muM) significantly attenuated responses to capsaicin (1-60 muM) whilst completely abolishing responses to field-stimulation (3, 10 and 30 Hz) and bradykinin (1 nm - 3 muM). 6 In conclusion, NK1 and NK3 receptor activation results in contraction of the rabbit iris sphincter. The contractile response following sensory nerve stimulation by bradykinin, capsaicin and electrical field stimulation results from NK1 receptor activation.