The Effects of 8-Hydroxy-2-(di-n-propylamino)tetralin on the Cholinergic Contraction in Guinea Pig and Human AirwaysIn Vitro

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Abstract

Electrical field stimulation of guinea pig tracheal strips and human bronchial 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-HT7 agonist. In this study, we have investigated whether 8-OH-DPAT could modulate the cholinergic contraction in guinea pig and human airways in vitro. 8-OH-DPAT (1 to 30 μ M) produced a concentration-dependent inhibition of the cholinergic contraction in guinea pig tracheal strips with a maximal inhibition of 75.8% ± 4.7% (30 μ M, 0.5 Hz). Pretreatment of the tissues with the 5- HT1/2/7 antagonist methysergide (10 to 30 μ M) significantly attenuated the inhibitory effects of 8-OH-DPAT (10 to 30 μ M) on the cholinergic contraction. Pretreatment with ketanserin (10 μ M), a 5-HT2 antagonist, tropisetron (1 μ M), a 5-HT3/4 antagonist, SDZ 216-525 (1 to 10 μ M) and pindobind (10 μ M), both selective 5-HT1A antagonists, or capsaicin (10 μ M), which depletes sensory nerves from neuropeptides, had no effect on the inhibition of the cholinergic contraction by 8-OH-DPAT (10 to 30 μ M). 5-carboxamidotryptamine (5-CT) (10 to 100 μ M), a 5-HT1/2/7 agonist, partially mimicked the inhibitory effects of 8-OH-DPAT on the cholinergic contraction. 8-OH-DPAT (10 to 30 μ M) also inhibited the cholinergic contraction in human bronchial rings in vitro with a maximal inhibition of 46.2% ± 7.2% (30 μ M, 1 Hz). SDZ 216-525 (10 μ M) had no effect, whereas methysergide (30 μ M) partially prevented the effect of 8-OH-DPAT in human airways. 8-OH-DPAT (30 μ M) did not displace the concentration–response curve to acetylcholine (10 nM-30 mM) in guinea pig and human airways in vitro. These results suggest that 8-OH-DPAT inhibits the cholinergic contraction in guinea pig and human airways in vitro through stimulation of prejunctional atypical 5-HT receptors, possibly of the 5-HT7 subtype, located on postganglionic cholinergic nerves.

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