Modulation by 5-HT_1A receptors of the 5-HT₂ receptor-mediated tachykinin-induced contraction of the rat trachea in vitro

Abstract

1. In the Fisher 344 rat, tachykinins have been shown to cause the release of 5-hydroxytryptamine (5-HT) from airway mast cells, which then causes direct smooth muscle activation as well as the release of acetylcholine from cholinergic nerves. The aim of the present study was to examine the modulatory effects of 5-HT receptors on the neurokinin A (NKA)-induced release of endogenous 5-HT and airway smooth muscle contraction in the isolated Fisher 344 rat trachea.

2. The selective 5-HT₂ receptor antagonist ketanserin (0.1 μM) produced an almost complete inhibition of the contractions caused by NKA (n=4, P<0.0001, two-way ANOVA), and a significant rightward shift of the concentration-response curve to 5-HT (n=8, P<0.001, two-way ANOVA).

3. The partial agonist for 5-HT_1A receptors, 8-OH-DPAT (1 μM), and the full agonist for 5-HT₁ receptors, 5-CT (0.3 μM), potentiated the submaximal contractions induced by the 5-HT₂ receptor agonist α-methyl-5-HT (0.1 μM) (n=4; P<0.005 and P<0.05, respectively). 8-OH-DPAT (1 μM), as well as the 5-HT_1A receptor antagonists pMPPI, SDZ 216525 and NAN-190 (0.1 μM each), caused significant inhibition of the tracheal contractions induced both by NKA (10  nM–3  μM) and 5-HT (10 nM–10 μM) (n=4–10). This suggests that activation of 5-HT_1A receptors potentiates the 5-HT₂ receptor-mediated contractions.

4. SDZ 216525 (0.1 μM) significantly reduced the maximal contraction produced by 1 μM NKA (n=10, P<0.001), without affecting the release of endogenous 5-HT. These data rule out the involvement of a 5-HT_1A receptor-mediated positive feedback mechanism of the 5-HT release from mast cells.

5. Even in the presence of atropine (1 μM), 8-OH-DPAT (1 μM) further reduced the maximal NKA-induced contraction (n=4, P<0.0001), while the contractions of the rat isolated trachea induced by electrical field stimulation and the concentration-response curve to carbachol were unaffected by pMPPI (0.1 μM), SDZ 216525 (0.1 μM), NAN-190 (0.1 μM) and 8-OH-DPAT (1 μM) (n=4–6). These data demonstrate that the 5-HT_1A receptor-mediated potentiation of contractile responses is not due to non-specific inhibition of airway smooth muscle contraction or to modulation of postganglionic nerve activation.

6. The selective 5-HT_1B/1D receptor antagonist GR 127935, the selective 5-HT₃ receptor antagonist tropisetron and the selective 5-HT₄ receptor antagonists SB 204070 and GR 113808 (0.1 μM each) had no effect on the concentration-response curve for NKA (n=6–10), ruling out the involvement of 5-HT_1B/1D, 5-HT₃ and 5-HT₄ receptors.

7. The α-adrenoreceptor antagonist phentolamine (1 μM) had no effect on the 5-HT-induced contractions (n=4), ruling out the involvement of α-adrenoreceptors.

8. In conclusion, the tachykinin-induced contraction of the F334 rat isolated trachea is mediated by the stimulation of 5-HT₂ receptors. Activation of 5-HT_1A receptors located on airway smooth muscle potentiates the direct contractile effects of 5-HT₂ receptor activation. The 5-HT_1B/1D, 5-HT₃ and 5-HT₄ receptors are not involved in the NKA-induced contraction of rat airways.

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