title: Differential functional role of purinergic and nitrergic inhibitory cotransmitters in human colonic relaxation.
abstract: OBJECTIVE
  ATP and nitric oxide (NO) are released from enteric inhibitory motor neurones and are responsible for colonic smooth muscle relaxation. However, how frequency of neural stimulation affects this cotransmission process and the post-junctional responses has not been systematically characterized in the human colon.
  
  
  METHODS
  The dynamics of inhibitory cotransmission were studied using different protocols of electrical field stimulation (EFS) to characterize the inhibitory junction potentials (IJP) and the corresponding relaxation in colonic strips obtained from 36 patients.
  
  
  RESULTS
  Single pulses elicited a fast IJP (IJPf(MAX) = -27.6 ± 1.6 mV), sensitive to the P2Y1 antagonist MRS2500 1 μm, that ran down with frequency increase leaving a residual hyperpolarization at high frequencies (IJPf∞ = -3.7 ± 0.6 mV). Accordingly, low frequencies of EFS caused purinergic transient relaxations that cannot be maintained at high frequencies. Addition of the P2Y1 agonist MRS2365 10 μm during the purinergic rundown did not cause any hyperpolarization. Protein kinase C (PKC), a putative P2Y1 desensitizator, was able to reduce the amplitude of the IJPf when activated, but the rundown was not modified by PKC inhibitors. Frequencies higher than 0.60 ± 0.15 Hz were needed to evoke a sustained nitrergic hyperpolarization that progressively increased reaching IJPs∞ = -13 ± 0.4 mV at high frequencies and leading to a sustained inhibition of spontaneous motility.
  
  
  CONCLUSIONS
  Changes in frequency of stimulation possibly mimicking neuronal firing will post-junctionally determine purinergic vs. nitrergic responses underlying different functional roles. NO will be responsible for sustained relaxations needed in physiological processes such as storage, while purinergic neurotransmission evoking sharp transient relaxations will be dominant in processes such as propulsion.
authors.affiliation: Department of Cell Biology, Physiology and Immunology and Neuroscience Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: N
authors.initials: N
authors.lastname: Mañé
authors.forename: V
authors.initials: V
authors.lastname: Gil
authors.forename: M
authors.initials: M
authors.lastname: Martínez-Cutillas
authors.forename: P
authors.initials: P
authors.lastname: Clavé
authors.forename: D
authors.initials: D
authors.lastname: Gallego
authors.forename: M
authors.initials: M
authors.lastname: Jiménez
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003106:Colon / Q000502:physiology*; D005260:Female; D005769:Gastrointestinal Motility / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009046:Motor Neurons / Q000502:physiology*; D009126:Muscle Relaxation / Q000502:physiology*; D009130:Muscle, Smooth / Q000502:physiology*; D009433:Neural Inhibition / Q000502:physiology; D009469:Neuromuscular Junction / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D058472:Receptors, Purinergic P2Y1 / Q000378:metabolism*; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D018377:Neurotransmitter Agents; D058472:Receptors, Purinergic P2Y1; D009569:Nitric Oxide; D000255:Adenosine Triphosphate
keywords: enteric neurones; inhibitory junction potential; propulsion; relaxation; smooth muscle; storage