IN-VIVO CHARACTERIZATION OF THE TACHYKININ RECEPTORS INVOLVED IN THE DIRECT AND INDIRECT BRONCHOCONSTRICTOR EFFECT OF TACHYKININS IN 2 INBRED RAT STRAINS

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, [Sar(9), Met(O-2)(11)]SP and Ac[Arg(6),Sar(9),Met(O-2)(11)]SP(6-11), caused a dose-dependent bronchoconstriction and increase in BAL 5HT comparable to those of NKA and SP. 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. The NK2 receptor antagonist SR 48968 largely reduced the bronchoconstrictor effect of NKA in the BDE rat, but it had only a small inhibitory effect on the increase in RL caused by NKA in the F344 rat. In conclusion, tachykinins caused bronchoconstriction in F344 rats mainly by an indirect mechanism that involves stimulation of NK1 receptors and mast cell activation. In BDE rats they cause bronchoconstriction by a direct effect on airway smooth muscle via activation of NK2 receptors. Thus, different tachykinin receptors are involved in the direct and indirect bronchoconstrictor effect of tachykinins in the rat.