1 The coexistence of both inhibitory A 1 and facilitatory A 2 adenosine receptors in the rat myenteric plexus prompted the question of how adenosine activates each receptor subtype to regulate cholinergic neurotransmission. 2 Exogenously applied adenosine (0.3-300 mM) decreased electrically evoked [ 3 Increasing endogenous adenosine levels, by the addition of (1) the adenosine precursor AMP (30-100 mM), (2) the adenosine kinase inhibitor 5 0 -iodotubercidin (10 mM) or (3) inhibitors of adenosine uptake (dipyridamole, 0.5 mM) and of deamination (erythro-9(2-hydroxy-3-nonyl)adenine, 50 mM), enhanced electrically evoked [ ) attenuated endogenous adenosine formation from AMP, analysed by HPLC, the corresponding reduction in [ 3 H]ACh release only became evident when stimulation of the myenteric plexus was prolonged to over 250 s. 5 In summary, we found that endogenously generated adenosine plays a predominantly tonic facilitatory effect mediated by prejunctional A 2A receptors. Extracellular deamination and cellular uptake may restrict endogenous adenosine actions to the neuro-effector region near the release/ production sites.

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Background and purpose:The relative contribution of distinct ecto-nucleotidases to the modulation of purinergic signalling may depend on differential tissue distribution and substrate preference. Experimental approach: Extracellular ATP catabolism (assessed by high-performance liquid chromatography) and its influence on [

Mitoxantrone (MTX) is a pharmaceutical drug used in the treatment of several cancers and refractory multiple sclerosis (MS). Despite its therapeutic value, adverse effects may be severe, namely the frequently reported cardiotoxicity, whose mechanisms need further research. This work aimed to assess if inflammation or oxidative stress-related pathways participate in the cardiotoxicity of MTX, using the mouse as an animal model, at two different age periods (infant or adult mice) using two therapeutic relevant cumulative doses. Histopathology findings showed that MTX caused higher cardiac toxicity in adults. In MTX-treated adults, at the highest dose, noradrenaline cardiac levels decreased, whereas at the lowest cumulative dose, protein carbonylation increased and the expression of nuclear factor kappa B (NF-κB) p65 subunit and of M1 macrophage marker increased. Moreover, MTX-treated adult mice had enhanced expression of NF-κB p52 and tumour necrosis factor (TNF-α), while decreasing interleukin-6 (IL-6). Moreover, while catalase expression significantly increased in both adult and infant mice treated with the lowest MTX cumulative dose, the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and glutathione peroxidase only significantly increased in infant animals. Nevertheless, the ratio of GAPDH to ATP synthase subunit beta decreased in adult animals. In conclusion, clinically relevant doses of MTX caused dissimilar responses in adult and infant mice, being that inflammation may be an important trigger to MTX-induced cardiotoxicity.