Guanine-based purines affects the enteric cholinergic neurotransmission via a mechanism not involving membrane receptors

Increasing evidence indicate that guanine-based purines, known as modulators of intracellular processes, can exert extracellular effects, raising the possibility of the existence of specific receptors for these compounds. We investigated if guaninebased purine receptors may be present in the rodent gastrointestinal tract modulating intestinal contractility, as the well known adenine-based purine receptors. Experiments were performed in vitro recording spontaneous and neurally-evoked contractile activity, as changes in isometric tension, in mouse distal colon circular muscle. Guanosine up to 3 mM or guanine up to 1 mM, did not affect the spontaneous mechanical activity, but they significantly and reversibly reduced the amplitude of the nerve evoked cholinergic contractions. Both compounds did not affect the direct contractile responses to muscarinic agonist. No desensitization of the response was observed. Guanine-based purine effects were not modified by adenine-based purine receptor antagonists or by adenylyl or guanilyl cyclase inhibitors. Dipyridamole or NBTI, nucleoside uptake inhibitors markedly reduced the guanosine effects whilst guanine effects were prevented in the presence of adenine, competitive inhibitor of nucleobase uptake. Our data indicate that guanosine and guanine are able to modulate negatively the excitatory cholinergic neurotransmission in the mouse colon circular muscle. Guanine-based purines appear to act on prejunctional release of acetylcholine. Their effects are dependent by their cellular uptake, and independent by adenine based purine receptors.