Interactions of new and conventional H3-antagonists with non-histaminergic receptors involved in neurogenic and myogenic contractile responses of guinea-pig ileum.

1. Possible effects of new and conventional H3-receptor antagonists towards various non-histaminergic receptors (alpha2-adrenergic, 5-HT3-serotonin, mu-opiate, A1-adenosine, M1-and M3-muscarinic) involved in neurogenic and myogenic contractile responses of guinea-pig ileum are investigated. 2. When the isolated ileum was contracted by the 5-HT3 receptor agonist, 2-methyl-5-HT (5 x 10(-7)-8 x 10(-6) M), acetylcholine (1 x 10(-9)-1 x 10(-7) M), KCl (3 x 10(-2) M) or electrical stimulation some of the drugs, included thioperamide and clobenpropit, reduced the contractile response when tested at micromolar concentrations (1-3 x 10(-5) M) (only compound IV exhibited an M3 competitive antagonism with a pK(B) = 5.49 +/- 0.18). 3. Ileal twitch responses to electrical stimulation were dose-dependently inhibited by the selective agonists clonidine (3 x 10(-10)-1 x 10(-7) M), dermorphin (1 x 10(-11)-1 x 10(-8) M), R-N6-(2-phenylisopropyl)-adenosine (1 x 10(-9)-3 x 10(-8) M) and McN-A-343 (1 x 10(-7)-1 x 10(-5) M) with different potencies and comparable efficacy (spike amplitude reduction > 85%). All the H3 antagonists under study (up to 1 x 10(-5) M) showed no or minor interactions at the neuronal sites except the compound V which behaved as a weak competitive antagonist at alpha2-adrenoreceptors (pK(B) = 5.96 +/- 0.06). 4. In conclusion, both new and conventional H3-blockers interacted at the enteric neuronal sites here studied with a 1000-30,000 fold lower antagonistic potency than that previously reported for the ileal H3 histamine receptors. Their spasmolytic activity precludes firm conclusions about the non-competitive interaction with 5-HT3 ileal receptor which requires further investigations.