MODULATION BY 5-HT1A RECEPTORS OF THE 5-HT2 RECEPTOR-MEDIATED TACHYKININ-INDUCED CONTRACTION OF THE RAT TRACHEA IN-VITRO

1 In the Fisher 344 rat, tachykinins have been shown to cause the rele ase of 5-hydroxytryptamine (5-HT) from airway mast cells, which then c auses direct smooth muscle activation as well as the release of acetyl choline from cholinergic nerves. The aim of the present study was to e xamine the modulatory effects of 5-HT receptors on the neurokinin A (N KA)-induced release of endogenous 5-HT and airway smooth muscle contra ction in the isolated Fisher 344 rat trachea. 2 The selective 5-HT2 re ceptor antagonist ketanserin (0.1 mu M) produced an almost complete in hibition of the contractions caused by NKA (n=4, P<0.0001, two-way ANO VA), and a significant rightward shift of the concentration-response c urve to 5-HT (n=8, P<0.001, two-way ANOVA). 3 The partial agonist for 5-HT1A receptors, 8-OH-DPAT (1 mu M), and the full agonist for 5-HT1 r eceptors, 5-CT (0.3 mu M), potentiated the submaximal contractions ind uced by the 5-HT2 receptor agonist alpha-methyl-5-HT (0.1 mu M) (n=4; P<0.005 and P<0.05, respectively). 8-OH-DPAT (1 mu M), as well as the 5-HT1A receptor antagonists pMPPI, SDZ 216525 and NAN-190 (0.1 mu M ea ch), caused significant inhibition of the tracheal contractions induce d both by NKA (10 nM-3 mu M) and 5-HT (10 nM-10 mu M) (n=4-10). This s uggests that activation of 5-HT1A receptors potentiates the 5-HT2 rece ptor-mediated contractions. 4 SDZ 216525 (0.1 mu M) significantly redu ced the maximal contraction produced by 1 mu M NKA (n=10, P<0.001), wi thout affecting the release of endogenous 5-HT. These data rule out th e involvement of a 5-HT1A receptor-mediated positive feedback mechanis m of the 5-HT release from mast cells. 5 Even in the presence of atrop ine (1 mu M), 8-OH-DPAT (1 mu M) further reduced the maximal NKA-induc ed contraction (n=4, P<0.0001), while the contractions of the rat isol ated trachea induced by electrical held stimulation and the concentrat ion-response curve to carbachol were unaffected by pMPPI (0.1 mu M), S DZ 216525 (0.1 mu M), NAN-190 (0.1 mu M) and 8-OH-DPAT (1 mu M) (n=4-6 ). These data demonstrate that the 5-HT1A receptor-mediated potentiati on of contractile responses is not due to nonspecific inhibition of ai rway smooth muscle contraction or to modulation of postganglionic nerv e activation. 6 The selective 5-HT1B/1D receptor antagonist GR 127935, the selective 5-HT3 receptor antagonist tropisetron and the selective 5-HT4 receptor antagonists SE 204070 and GR 113808 (0.1 mu M each) ha d no effect on the concentration-response curve for NKA (n=6-10), ruli ng out the involvement of 5-HT1B/1D, 5-HT3 and 5-HT4 receptors. 7 The alpha-adrenoreceptor antagonist phentolamine (1 mu M) had no effect on the 5-HT-induced contractions (n=4), ruling out the involvement of al pha-adrenoreceptors. 8 In conclusion, the tachykinin-induced contracti on of the F334 rat isolated trachea is mediated by the stimulation of 5-HT2 receptors. Activation of 5-HT1A receptors located on airway smoo th muscle potentiates the direct contractile effects of 5-HT2 receptor activation. The 5-HT1B/1D, 5-HT3 and 5-HT4 receptors are not involved in the NKA-induced contraction of rat airways.