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

Carly J McCarthy; Youko Ikeda; Deborah Skennerton; Basu Chakrabarty; Anthony J Kanai; Rita I Jabr; Christopher H Fry

doi:10.1111/bph.14840

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

Carly J McCarthy, Youko Ikeda, Deborah Skennerton, Basu Chakrabarty, Anthony J Kanai, Rita I Jabr, Christopher H Fry

School of Physiology, Pharmacology & Neuroscience

Research output: Contribution to journal › Article (Academic Journal)

1 Citation (Scopus)

9 Downloads (Pure)

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.

Original language	English
Number of pages	11
Journal	British Journal of Pharmacology
Early online date	20 Aug 2019
DOIs	https://doi.org/10.1111/bph.14840
Publication status	E-pub ahead of print - 20 Aug 2019

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McCarthy, C. J., Ikeda, Y., Skennerton, D., Chakrabarty, B., Kanai, A. J., Jabr, R. I., & Fry, C. H. (2019). Characterisation of nerve‐mediated ATP release from bladder detrusor muscle and its pathological implications. British Journal of Pharmacology. https://doi.org/10.1111/bph.14840

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abstract = "BACKGROUND AND PURPOSETo characterise the molecular mechanisms that determine variability of atropine-resistance of nerve-mediated contractions in human and guinea-pig detrusor smooth muscle EXPERIMENTAL APPROACHAtropine-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 RESULTSAtropine 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 IMPLICATIONSAtropine-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.",

author = "McCarthy, {Carly J} and Youko Ikeda and Deborah Skennerton and Basu Chakrabarty and Kanai, {Anthony J} and Jabr, {Rita I} and Fry, {Christopher H}",

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AU - McCarthy, Carly J

AU - Ikeda, Youko

AU - Skennerton, Deborah

AU - Chakrabarty, Basu

AU - Kanai, Anthony J

AU - Jabr, Rita I

AU - Fry, Christopher H

PY - 2019/8/20

Y1 - 2019/8/20

N2 - BACKGROUND AND PURPOSETo characterise the molecular mechanisms that determine variability of atropine-resistance of nerve-mediated contractions in human and guinea-pig detrusor smooth muscle EXPERIMENTAL APPROACHAtropine-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 RESULTSAtropine 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 IMPLICATIONSAtropine-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.

AB - BACKGROUND AND PURPOSETo characterise the molecular mechanisms that determine variability of atropine-resistance of nerve-mediated contractions in human and guinea-pig detrusor smooth muscle EXPERIMENTAL APPROACHAtropine-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 RESULTSAtropine 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 IMPLICATIONSAtropine-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.

U2 - 10.1111/bph.14840

DO - 10.1111/bph.14840

M3 - Article (Academic Journal)

C2 - 31430833

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

ER -