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Publication - Professor Christopher Fry

    Characterisation of nerve‐mediated ATP release from bladder detrusor muscle and its pathological implications

    Citation

    McCarthy, CJ, Ikeda, Y, Skennerton, D, Chakrabarty, B, Kanai, AJ, Jabr, RI & Fry, CH, 2019, ‘Characterisation of nerve‐mediated ATP release from bladder detrusor muscle and its pathological implications’. British Journal of Pharmacology.

    Abstract

    BACKGROUND AND PURPOSE

    To characterise the molecular mechanisms that determine variability of atropine-resistance of nerve-mediated contractions in human and guinea-pig detrusor smooth muscle 

    EXPERIMENTAL APPROACH

    Atropine-resistance of nerve-mediated contractions, and the role of P2X1 receptors, was measured in isolated preparations from guinea-pigs and also humans with or without overactive bladder syndrome, from which the mucosa was removed. Nerve-mediated ATP release was measured directly with amperometric ATP-sensitive electrodes. Ecto-ATPase activity of guinea-pig and human detrusor samples was measured in vitro by measuring the concentration-dependent rate of ATP breakdown. The transcription of ecto-ATPase subtypes in human samples was measured by qPCR.

    KEY RESULTS

    Atropine resistance was greatest in guinea-pig detrusor, absent in human tissue from normally-functioning bladders and intermediate in human overactive bladder. Greater atropine resistance correlated with reduction of contractions by the ATP-diphospho-hydrolase apyrase, directly implicating ATP in their generation. E-NTPDase-1 was the most abundantly transcribed ecto-ATPase of those tested and transcription was reduced in tissue from human overactive, compared to normal, bladders. E-NTPDase-1 enzymatic activity was inversely related to the magnitude of atropine resistance. Nerve-mediated ATP release was continually measured and varied with stimulation frequency over the range 1-16 Hz.

    CONCLUSION AND IMPLICATIONS

    Atropine-resistance in nerve-mediated detrusor contractions is due to ATP release and its magnitude is inversely related to E-NTPDase-1 activity. ATP is released under different stimulation conditions compared to acetylcholine that implies different routes for their release.

    Full details in the University publications repository