Use of Selective Agonists and Antagonists to Characterize Tachykinin Receptors Mediating Airway Responsiveness in Anaesthetized Guinea-pigs

Summary: Tachykinins are potent bronchoconstrictors. Here we have used novel highly selective agonists and antagonists to characterize tachykinin receptors mediating bronchoconstriction and hypotension in anaesthetized, paralysed guinea-pigs. Total lung resistance ( R L ) and dynamic lung compliance ( C dyn ) were measured using an online, breath-by-breath method to analyse lung mechanics. The effects of iv injections of neuropeptide γ (NPγ), [Sar 9 ,Met(O 2 ) 11 ]-SP (Sar-SP) (NK-1 agonist), [Lys 5 ,MeLeu 9 ,Nle 10 ]-NKA(4-10) (Lys-NKA) (NK-2 agonist) and senktide (NK-3 agonist) were compared, before and after iv injection of the NK-1 antagonist CP 96345 or the NK-2 antagonists MDL 29913 and SR 48968. NPγ, Sar-SP and Lys-NKA, but not senktide, increased R L and decreased C dyn , accompanied by a fall in blood pressure (BP). The potency for increase of R L was Lys-NKA>NPγ≃Sar-SP, for reduction of C dyn was Lys-NKA=Sar-SP>NPγ, and for fall in BP was Sar-SP>NPγ>>Lys-NKA. CP 96345 (50 nmol/kg & 200 nmol/kg) significantly antagonized the changes in R L , C dyn and BP induced by Sar-SP, and the fall in BP (but not changes in lung mechanics) in response to NPγ, but did not alter any responses to Lys-NKA. In contrast, MDL 29913 (200 nmol/kg & 10 μmol/kg) weakly and SR 48968 (100 nmol/kg) potently inhibited the effects on R L and C dyn induced by Lys-NKA and NPγ. Our results show that both NK-1 and NK-2 receptors are represented in guinea-pig airways. MDL 29913 is a weak NK-2 antagonist in guinea-pig airways compared to SR 48968. In addition, NK-1 but not NK-2 receptors appear to be important in mediating the hypotensive response to these tachykinins. In spite of its ability to cause a fall in BP via NK-1 receptors, NPγ exerted its effects on R L and C dyn solely via NK-2 receptors.