Effects of tachykinins and capsaicin on the mechanical and electrical activity of the guinea‐pig isolated trachea

1 The effects of tachykinins and capsaicin were studied by means of intracellular membrane potential and isometric tension recordings in the isolated trachea of the guinea‐pig. 2 The basal membrane potential averaged −51 mV, and most preparations demonstrated spontaneous slow waves. Tetraethylammonium (TEA), a potassium channel blocker (8×10 −3   M ), depolarized the membrane potential to −44 mV and induced a rhythmic activity. 3 In control solution, substance P (10 −8 –10 −6   M ), [Nle 10 ]‐neurokinin A(4–10) (10 −8 –10 −6   M ) and capsaicin (10 −7 –10 −6   M ) induced concentration‐dependent depolarizations which were statistically significant at the highest concentration tested (depolarization by 10 −6   M : 8, 11 and 16 mV for the NK 1 agonist, the NK 2 agonist and capsaicin, respectively). 4 In the presence of TEA (8×10 −3   M ), the three substances induced depolarizations which were statistically significant at the highest concentration tested for substance P (10 −6   M ) and at 10 −7 and 10 −6   M for both [Nle 10 ]‐neurokinin A(4–10) and capsaicin (depolarization by 10 −6   M : 11, 17 and 10 mV for substance P, [Nle 10 ]neurokinin A(4–10) and capsaicin, respectively). 5 In the presence or absence of tetraethylammonium, [MePhe 7 ]‐neurokinin B (10 −8 –10 −6   M ) did not induce any significant changes in membrane potential. 6 The depolarizing effects of substance P (10 −6   M ) and [Nle 10 ]‐neurokinin A(4–10) (10 −6   M ) were blocked only by the specific antagonists for NK 1 and NK 2 receptors, SR 140333 (10 −7   M ) and SR 48968 (10 −7   M ), respectively. The effects of capsaicin (10 −6   M ) were partially inhibited by each antagonist and fully blocked by their combination. 7 Substance P (10 −9 to 10 −4   M ), [Nle 10 ]‐neurokinin A(4–10) (10 −10 to 10 −5   M ), [MePhe 7 ]‐neurokinin B and capsaicin (10 −7 to 10 −5   M ) evoked concentration‐dependent contractions. 8 The contractions to substance P were significantly inhibited by SR 140333 (10 −8 to 10 −6   M ) but unaffected by SR 48968 (10 −8 to 10 −6   M ). Furthermore, the response to [Nle 10 ]‐neurokinin A(4–10) was significantly inhibited by SR 48968 and unaffected by SR 140333 at the same concentrations. Although SR 48968 (10 −7   M ) alone did not influence the effects of substance P, it potentiated the inhibitory effect of SR 140333 (10 −7   M ). A similar synergetic effect of these two compounds was observed in the inhibition of the contractile response to [Nle 10 ]‐neurokinin A(4–10). 9 Neither SR 140333 (10 −7   M ) nor SR 48968 (10 −7   M ) alone influenced the contractions to [MePhe 7 ]‐neurokinin B and capsaicin. However, the combination of the two antagonists abolished the contractions to either peptide. 10 These results demonstrate that the stimulation of both NK 1 and NK 2 tachykinin‐receptors induced contraction and depolarization of the guinea‐pig tracheal smooth muscle and that both receptors were stimulated during the endogenous release of tachykinins by capsaicin. There was no evidence for a major role of NK 3 receptors in the contractile and electrical activity of the guinea‐pig isolated trachea.British Journal of Pharmacology (1997) 122 , 841–848; doi: 10.1038/sj.bjp.0701459