Poli E, Pozzoli C, Bertaccini G
Institute of Pharmacology, School of Medicine, University of Parma, Italy.
J Pharmacol Exp Ther. 1997 Apr;281(1):393-9.
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.
关于豚鼠十二指肠胆碱能传递，对节前组胺H3受体和α-2肾上腺素能受体相互作用的假说进行了评估。分别作用于组胺H3受体、α-2肾上腺素能受体和腺苷A1受体的特异性激动剂，即（R）-α-甲基组胺（1 nM - 1 μM）、UK 14,304（1 nM - 1 μM）和N6-环戊基腺苷（0.1 nM - 0.1 μM），抑制电刺激诱发的肌肉收缩，该效应被特异性受体阻滞剂硫代哌啶和氯苯丙哌嗪（H3受体）、咪唑克生和育亨宾（α-2肾上腺素能受体）以及8-环戊基-1,3-二甲基黄嘌呤（A1受体）拮抗。使用特异性激动剂的EC50值（UK 14,304：30 nM；（R）-α-甲基组胺：20 nM）同时激活H3受体和α-2肾上腺素能受体，产生的联合效应与各单独效应之和无差异，该结果排除了这些受体之间存在相互作用。相反，同时给予N6-环戊基腺苷（EC50：2.5 nM）与（R）-α-甲基组胺或N6-环戊基腺苷与UK 14,304所诱发的抑制作用显著低于各单独效应之和，这表明相应的节前受体相互作用。当同时应用不同激动剂的阈浓度（EC(10 - 15)）时，未检测到相互作用。这些数据显示H3与A1受体之间以及A1与α-2受体之间存在负协同性。相反，即使以低浓度或最大浓度应用不同激动剂，也未出现正协同性的证据。各激动剂之间缺乏交叉反应排除了受体亚基识别位点处的相互作用。因此，这些现象更可能反映了参与调节乙酰胆碱释放的第二信使或效应器之间的相互作用。
