USE OF SELECTIVE AGONISTS AND ANTAGONISTS TO CHARACTERIZE TACHYKININ RECEPTORS MEDIATING AIRWAY RESPONSIVENESS IN ANESTHETIZED GUINEA-PIGS

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 gamma (NP gamma), [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. NP gamma, Sar-SP and Lys-M(A, 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>NP gamma similar or equal to Sar-SP, for reduction of C-dyn was Lys-NKA=Sar-SP>NP gamma, and for fall in BP was Sar-SP>NP gamma>>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 NP gamma, but did not alter any responses to Lys-NKA. In contrast, MDL 29913 (200 nmol/kg and 10 mu mol/kg) weakly and SR 48968 (100 nmol/kg) potently inhibited the effects on R(L) and C-dyn induced by Lys-NKA and NP gamma. 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, NP gamma exerted its effects on R(L) and C-dyn solely via NK-2 receptors.