Interaction between histamine H3 receptors and other prejunctional receptor systems in the isolated guinea pig...

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)-alpha-methylhistamine (1 nM-1 microM), UK 14,304 (1 nM-1 microM) and N6-cyclopentyladenosine (0.1 nM-0.1 microM), 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)-alpha-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)-alpha-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.