In vivo characterization of the tachykinin receptors involved in the direct and indirect bronchoconstrictor effect of tachykinins in two inbred rat strains.

Abstract

Three receptors for the tachykinins, NK1, NK2, and NK3, have been defined pharmacologically and have been cloned. We previously demonstrated that in Fisher 344 (F344) rats neurokinin A (NKA) and substance P (SP) cause bronchoconstriction mainly by indirect mechanisms that involve both cholinergic nerves and mast cells. Preliminary results suggested that in a less responsive strain, the BDE strain, tachykinins did not activate airway mast cells. We have now compared in F344 and BDE rats the airway effects of the tachykinins SP and NKA with those of specific NK1 and NK2 receptor agonists and have studied the effect of potent and specific nonpeptide NK1 and NK2 receptor antagonists on NKA-induced airway effects. Lung resistance (RL) and serotonin in bronchoalveolar lavage fluid (BAL 5HT) were measured in anaesthetized, mechanically ventilated, rats. In contrast to F344 rats, BDE rats were less sensitive to SP and NKA challenge, and no subsequent increase in BAL 5HT was observed. In F344 rats, the specific NK1 receptor agonists, [Sar9, Met(O2)11]SP and Ac[Arg6,Sar9,Met(O2)11]SP(6-11), caused a dose-dependent bronchoconstriction and increase in BAL 5HT comparable to those of NKA and SP. The NK1 receptor agonists had no effect in BDE rats. The NK2 receptor agonist [beta Ala8]NKA(4-10) caused a small, dose-dependent increase in RL in the F344 as well as in the BDE rat, but it had no effect on BAL 5HT. The NK1 receptor antagonists RP 67580 and CP 96,345 significantly reduced the increase in RL and BAL 5HT caused by NKA in the F344 rat, but they had no effect on the NKA-induced bronchoconstriction in the BDE rat.(ABSTRACT TRUNCATED AT 250 WORDS)