Vol. 281, Issue 1, 393-399, 1997

Interaction Between Histamine H₃ Receptors and Other Prejunctional Receptor Systems in the Isolated Guinea Pig Duodenum^1,2

Enzo Poli, Cristina Pozzoli and Giulio Bertaccini

Institute of Pharmacology, School of Medicine, University of Parma, Parma, Italy

The hypothesis that prejunctional histamine H₃ receptors and alpha-2 adrenoceptors interact with each other was assessed on the cholinergic transmission of the guinea pig duodenum. Specific agonists acting at histamine H₃ receptors, alpha-2 adrenoceptors and adenosine A₁ receptors, (R)--methylhistamine (1 nM-1 µM), UK 14,304 (1 nM-1 µM) and N⁶-cyclopentyladenosine (0.1 nM-0.1 µM), respectively, inhibited muscle contractions evoked by electrical stimulation, the effect being antagonized by specific receptor blockers, thioperamide and clobenpropit (H₃ receptors), idazoxan and yohimbine alpha-2 adrenoceptors) and 8-cyclopentyl-1,3-dimethylxanthine (A₁ receptors). The simultaneous activation of H₃ receptors and alpha-2 adrenoceptors, using EC₅₀ values of the specific agonists (UK 14,304: 30 nM; (R)--methylhistamine: 20 nM), produced a combined effect that did not differ from the sum of the individual effects, a result that excluded the occurrence of interactions between these receptors. Conversely, the inhibition evoked by the coadministration of N⁶-cyclopentyladenosine (EC₅₀: 2.5 nm) and (R)--methylhistamine or of N⁶-cyclopentyladenosine and UK 14,304 was significantly lower than the sum of the individual effects, which suggests that the corresponding prejunctional receptors interact with each other. No interaction could be detected when threshold concentrations (EC_10-15) of the different agonists were simultaneously applied. These data show a negative cooperativity between H₃ and A₁ receptors and between A₁ and alpha-2 receptors. Conversely, no evidence of positive cooperativity emerged, even when the different agonists were applied at low or maximum concentrations. The lack of cross-reactivity between the respective agonists excludes an interaction at the recognition sites of the receptor moyeties. Therefore, these phenomena are more likely to reflect interplays between second messengers or effectors involved in modulating the ACh release.