Adenosine A2A receptor-mediated facilitation of myenteric cholinergic neurotransmission is impaired in the ileum of diabetic rats

  • S. Gonçalves-Monteiro
    Affiliations
    Laboratório de Farmacologia e Neurobiologia, Centro de Investigação Farmacológica e Inovação Medicamentosa (MedInUP), Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto (ICBAS-UP), Portugal
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  • M.T. Magalhães-Cardoso
    Affiliations
    Laboratório de Farmacologia e Neurobiologia, Centro de Investigação Farmacológica e Inovação Medicamentosa (MedInUP), Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto (ICBAS-UP), Portugal
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  • P. Correia-de-Sá
    Affiliations
    Laboratório de Farmacologia e Neurobiologia, Centro de Investigação Farmacológica e Inovação Medicamentosa (MedInUP), Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto (ICBAS-UP), Portugal
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  • M. Duarte-Araújo
    Correspondence
    Corresponding author.
    Affiliations
    Laboratório de Farmacologia e Neurobiologia, Centro de Investigação Farmacológica e Inovação Medicamentosa (MedInUP), Instituto de Ciências Biomédicas de Abel Salazar, Universidade do Porto (ICBAS-UP), Portugal
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      Diabetes mellitus causes significant gastrointestinal (GI) symptoms. Purines have been implicated in synaptic transmission deficits in the CNS of diabetics. This prompted us to investigate if purines also play a role in diabetic enteric neuropathy. Adult male Wistar rats injected with streptozotocin (STZ rats, 55 mg/kg, IP) became hyperglycemic (404 ± 56 md/dL, n = 9) in 48 hours. Experiments were performed at day 14 on longitudinal muscle-myenteric plexus (LM-MP) of the ileum of control and STZ rats. By HPLC analysis, we showed that extracellular ATP (30 μM) hydrolysis is faster (t½ 4.33 ± 0.45 min, n = 3) in STZ rats than in control animals (t½ 7.18 ± 1.14 min, n = 6). Despite the faster adenosine formation from ATP in STZ animals, the nucleoside hardly accumulates in the LM-MP because adenosine (30 μM) was inactivated into inosine more rapidly in STZ rats (t½ 13 ± 3 min, n = 4) than in control animals (t½ 34 ± 1, n = 4). The inhibitory effect of the A1 receptor agonist (R-PIA, 300 nM) on evoked [3H]-acetylcholine ([3H]-ACh, 5 Hz, 200 pulses of 1 ms) was similar in control (-36 ± 4%, n = 4) and STZ (-45 ± 8%, n = 3) rats. Conversely, the A2A receptor agonist, CGS 21680C (3 nM), facilitated [3H]-ACh release by 53 ± 10% (n = 4) in control animals but not in diabetics (-19 ± 7%, n = 3). In conclusion, though adenosine formation is faster in the LM-MP of diabetic rats the nucleoside is rapidly inactivated. Low extracellular adenosine levels, together with the functional loss of A2A-receptor-mediated facilitation of cholinergic neurotransmission may contribute to constipation, the most common GI complaint of diabetic patients. Work supported by FCT (PEst-OE/SAU/UI0215/2014).
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