THE EFFECTS OF 8-HYDROXY-2-(DI-N-PROPYLAMINO)TETRALIN ON THE CHOLINERGIC CONTRACTION IN GUINEA-PIG AND HUMAN AIRWAYS IN-VITRO

Electrical field stimulation of guinea pig tracheal strips and human b ronchial rings, in vitro, evokes a cholinergic contraction mediated by the release of acetylcholine. 8-hydroxy-2-(di-n-propylamino)tetralin( 8-OH-DPAT) is a 5-HT1A and 5-MT7 agonist. In this study, we have inves tigated whether 8-OH-DPAT could modulate the cholinergic contraction i n guinea pig and human airways in vitro. 8-OH-DPAT (1 to 30 mu M) prod uced a concentration-dependent inhibition of the cholinergic contracti on in guinea pig tracheal strips with a maximal inhibition of 75.8% +/ - 4.7% (30 mu M, 0.5 Hz). Pretreatment of the tissues with the 5-HT1/2 /7 antagonist methysergide (10 to 30 mu M) significantly attenuated th e inhibitory effects of 8-OH-DPAT (10 to 30 mu M) on the cholinergic c ontraction. Pretreatment with ketanserin (10 mu M), a 5-HT2 antagonist , tropisetron (1 mu M), a 5-HT3/4 antagonist, SDZ 216-525 (1 to 10 mu M) and pindobind (10 mu M), both selective 5-HT1A antagonists, or caps aicin (10 mu M), which depletes sensory nerves from neuropeptides, had no effect on the inhibition of the cholinergic contraction by 8-OH-DP AT (10 to 30 yM). 5-carboxamidotryptamine (5-CT) (10 to 100 mu M), a 5 -HT1/2/7 agonist, partially mimicked the inhibitory effects of 8-OH-DP AT on the cholinergic contraction. 8-OH-DPAT (10 to 30 mu M) also inhi bited the cholinergic contraction in human bronchial rings in vitro wi th a maximal inhibition of 46.2% +/- 7.2% (30 mu M, 1 HZ). SDZ 216-525 (10 mu M) had no effect, whereas methysergide (30 mu M) partially pre vented the effect of 8-OH-DPAT in human airways. 8-OH-DPAT (30 mu M) d id not displace the concentration-response curve to acetylcholine (10 nM-30 mM) in guinea pig and human airways in vitro. These results sugg est that 8-OH-DPAT inhibits the cholinergic contraction in guinea pig and human airways in vitro through stimulation of prejunctional atypic al 5-HT receptors, possibly of the 5-HT7 subtype, located on postgangl ionic cholinergic nerves.