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

Abstract

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), [Nle¹⁰]-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 NK₁ agonist, the NK₂ 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 [Nle¹⁰]-neurokinin A(4–10) and capsaicin (depolarization by 10⁻⁶ M: 11, 17 and 10 mV for substance P, [Nle¹⁰]neurokinin A(4–10) and capsaicin, respectively).

5. In the presence or absence of tetraethylammonium, [MePhe⁷]-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 [Nle¹⁰]-neurokinin A(4–10) (10⁻⁶ M) were blocked only by the specific antagonists for NK₁ and NK₂ 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), [Nle¹⁰]-neurokinin A(4–10) (10⁻¹⁰ to 10⁻⁵ M), [MePhe⁷]-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 [Nle¹⁰]-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 [Nle¹⁰]-neurokinin A(4–10).

9. Neither SR 140333 (10⁻⁷ M) nor SR 48968 (10⁻⁷ M) alone influenced the contractions to [MePhe⁷]-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 NK₁ and NK₂ 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 NK₃ receptors in the contractile and electrical activity of the guinea-pig isolated trachea.

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