, Volume 48, Issue 1, pp 2–10 | Cite as

Impact of the Ratio of Metabotropic and Ionotropic Components of Parasympathetic Action on the Excitability of a Urinary Bladder Smooth Muscle Cell: a Simulation Study

  • A. V. Kochenov
  • S. M. Korogod

On a computer model of a smooth muscle cell (SMC) of the urinary bladder detrusor (UBD) having a corresponding set of ion channels and intracellular signaling mechanisms, we investigated the influence of ionotropic (purine, P) and metabotropic (muscarinic, M) components of the parasympathetic stimulus on the membrane potential of the cell and Ca2+ concentration inside it ([Ca2+]i). The P and M components of the stimulus were simulated, respectively, by the increasing conductivity of P2X receptor channels of the SMC membrane (G P2X) and the permeability of calcium channels of the sarcoplasmic reticulum activated by inositol triphosphate (P IP3), considering that IP3 is the end product of the metabotropic chain starting from the M3 cholinergic receptors. The G P2X and P IP3 values, latent periods (LPs) of their activation, and relations of the above parameters were chosen in such a mode that application of a single stimulus evoked the SMC response with the P and M components close to those of the prototype. The normal magnitude and LP of the M component of the concentration response (calcium transient) were significantly greater than the respective parameters of the P component; the M component was accompanied by generation of an action potential (AP) with after-processes analogous to those of the prototype. A decrease in the P IP3 simulating a deficiency of M3 receptors observed under a few pathological conditions led to a decrease in the electric and concentration SMC responses, down to full elimination of AP generation and changes in [Са2+]i. Under such conditions, a significant increase in the G P2X could provide a [Са2+]i increase to a nearly normal level. Using paired parasympathetic stimulation with different interstimulus intervals, ΔТ, allowed us to obtain a situation where the M response to the first stimulus (M1) was preceded by the P response to the second stimulus (P2) with a short adjustable interval. The use of such stimulation with certain values of the ΔТ and conductivity of purinergic channels G P2X can compensate for the attenuation of the M component, due to interaction of the latter with the P component caused by the second stimulus. Thus, pathological attenuation of the M component of the parasympathetic stimulation effect can be compensated in clinical practice (at least partly) by applying purinomimetics and/or paired stimulation.


mathematical model smooth muscle cell urinary bladder detrusor parasympathetic stimulation purinoreceptors muscarinic cholinoreceptors intracellular calcium 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    G. Burnstock, “Purinergic signalling in the urinary tract in health and disease,” Purinergic Signal., 10, No. 1, 103-155 (2014).CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    J. S. Young, E. Meng, T. C. Cunnane, and K. L. Brain, “Spontaneous purinergic neurotransmission in the mouse urinary bladder,” J. Physiol., 586, Pt. 23, 5743-5755 (2008).CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    T. J. Heppner, A. D. Bonev, and M. T. Nelson, “Elementary purinergic Ca2+ transients evoked by nerve stimulation in rat urinary bladder smooth muscle,” J. Physiol., 564, Pt. 1, 201-212 (2005).CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    A. F. Brading and K. L. Brain, “Ion channel modulators and urinary tract function,” in: Urinary Tract. Handbook of Experimental Pharmacology, Vol. 202, Karl-Erik Andersson and Martin C. Michel (eds.), Springer, Heidelberg (2011), pp. 376-389.Google Scholar
  5. 5.
    T. J. Heppner, M. E. Werner, B. Nausch, et al., “Nerveevoked purinergic signalling suppresses action potentials, Ca2+ flashes and contractility evoked by muscarinic receptor activation in mouse urinary bladder smooth muscle,” J. Physiol., 587, Pt. 21, 5275–5288 (2009).CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    T. B. Bolton, “Mechanisms of action of transmitters and other substances on smooth muscle,” Physiol. Rev., 59, No. 3, 606-718 (1979).PubMedGoogle Scholar
  7. 7.
    K. E. Andersson and A. Arner, “Urinary bladder contraction and relaxation: physiology and pathophysiology,” Physiol. Rev., 84, No. 3, 935-986 (2004).CrossRefPubMedGoogle Scholar
  8. 8.
    D. M. Daly, L. Nocchi, M. Liaskos, et al., “Age-related changes in afferent pathways and urothelial function in the male mouse bladder,” J. Physiol. 592, Pt. 3, 537-549 (2014).CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    P. Uvin, M. Boudes, A. Menigoz, et al., “Chronic administration of anticholinergics in rats induces a shift from muscarinic to purinergic transmission in the bladder wall,” Eur. Urol., 64, No. 3, 502-510 (2013).CrossRefPubMedGoogle Scholar
  10. 10.
    A. Kageyama, T. Fujino, Y. Taki, et al., “Alteration of muscarinic and purinergic receptors in urinary bladder of rats with cyclophosphamide-induced interstitial cystitis,” Neurosci. Lett., 436, No. 1, 81-84 (2008).CrossRefPubMedGoogle Scholar
  11. 11.
    H. Hashitani, N. J. Bramich and G. D. Hirst, “Mechanisms of excitatory neuromuscular transmission in the guineapig urinary bladder,” J. Physiol., 524, Pt. 2, 565-579 (2000).CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    A.P.D.W. Ford and D.A. Cockayne, “ATP and P2X purinoceptors in urinary tract disorders,” in: Urinary Tract (Handbook of Experimental Pharmacoljgy, Vol. 202), K.-E. Andersson and M. C. Michel (eds.), Springer-Verlag, Berlin, Heidelberg (2011), pp. 375-393, 487-515.Google Scholar
  13. 13.
    K. E. Creed, R. A. Loxleyand, and J. K. Phillips, “Functional expression of muscarinic and purinoceptors in the urinary bladder of male and female rats and guinea pigs,” J. Smooth Muscle Res., 46, No. 4, 201-215(2010).Google Scholar
  14. 14.
    I. A. Makedonsky, “Immunohistochemical investigation of the M2 and M3 muscarinic receptors in patients with bladder exstrophy,” Eur. Urol., 4, No.2, 182 (2004).CrossRefGoogle Scholar
  15. 15.
    I. A. Makedonsky and E. P. Poddubnaya, “Clinical possibilities of biological feedback systems in the treatment of enuresis in children with urinary bladder exstrophy,” Med. Perspekt., 16, No. 2, 59-65 (2011).Google Scholar
  16. 16.
    C. P. Smith, V. M. Vemulakonda, S. Kiss, et. al., “Enhanced ATP release from rat bladder urothelium during chronic bladder inflammation: effect of botulinum toxin A,” Neurochem. Int., 47, No.4, 291-297 (2005).CrossRefPubMedGoogle Scholar
  17. 17.
    А. V. Kochenov, E. P. Poddubnaya, I. A. Makedonsky, and S. М. Korogod, “Biophysical processes in a urinary detrusor smooth muscle cell during rehabilitation electrostimulation: a simulation study,” Neurophysiology, 47, No. 3, 174-184 (2015).Google Scholar
  18. 18.
    N. T. Carnevale and M. L. Hines, The NEURON Book, Cambridge Univ. Press, Cambridge (2006).CrossRefGoogle Scholar
  19. 19.
    G. D’Agostino, A. M. Condino, V. Calvi, et al., “Purinergic P2X3 heteroreceptors enhance parasympathetic motor drive in isolated porcine detrusor, a reliable model for development of P2X selective blockers for detrusor hyperactivity,” Pharmacol. Res., 65, No. 1, 129-136 (2012).CrossRefPubMedGoogle Scholar
  20. 20.
    T. M. Egan and B. S. Khakh, “Contribution of calcium ions to P2X channel responses,” J. Neurosci., 24, No. 13, 3413-3420 (2004).CrossRefPubMedGoogle Scholar
  21. 21.
    Y. Igawa, X. Zhang, O. Nishizawa, et al., “Cystometric findings in mice lacking muscarinic M2 or M3 receptors,” J. Urol., 172, No. 6, Pt. 1, 2460-2464 (2004).Google Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  1. 1.International Center for molecular physiology (Dnipropetrovsk division)NAS of UkraineDnipropetrovskUkraine
  2. 2.Dnipropetrovsk Medical AcademyMinistry of Public Health of UkraineDnipropetrovskUkraine

Personalised recommendations