Skip to main content

Advertisement

SpringerLink
Log in

Expression and function of the small-conductance Ca2+-activated K+ channel is decreased in urinary bladder smooth muscle cells from female guinea pig with partial bladder outlet obstruction

  • Urology – Original Paper
  • Published:
International Urology and Nephrology Aims and scope Submit manuscript

Abstract

Purpose

Overactive bladder (OAB), usually accompanied by partial bladder outlet obstruction (PBOO), is associated with detrusor overactivity (DO) which is related to the increased urinary bladder smooth muscle (UBSM) cells excitability. Small-conductance Ca2+-activated K+ (SK) channels play a constitutive regulatory role of UBSM excitability and contractility. PBOO is associated with the decreased SK channels mRNA expression and the attenuated regulative effect of SK channels on UBSM contractility. However, the regulation of SK channels in PBOO UBSM cell excitability is less clear. Here, we tested the hypothesis that PBOO is associated with decreased expression and function of SK channels in UBSM cells and that SK channels are a potential target for the treatment of OAB.

Methods

Cystometry indicated that DO was achieved 2 weeks after PBOO in female guinea pigs. Using this animal model, we conducted single-cell quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and patch-clamp electrophysiology.

Results

The single-cell qRT-PCR experiments indicated the reduced SK channel mRNA expression in PBOO UBSM cells. Patch-clamp studies revealed that NS309 had a diminished effect on resting membrane potential hyperpolarization via the activation of SK channels in PBOO UBSM cells. Moreover, attenuated whole-cell SK channel currents were demonstrated in PBOO UBSM cells.

Conclusions

The attenuated expression and function of SK channels, which results in the increased UBSM cells excitability and contributes to DO, was discovered in PBOO UBSM cells, suggesting that SK channels might be potential therapeutic targets for the control of OAB.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Abrams P, Cardozo L, Fall M, Griffiths D, Rosier P, Ulmsten U, van Kerrebroeck P, Victor A, Wein A (2002) The standardisation of terminology of lower urinary tract function: report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 21(2):167–178

    Article  PubMed  Google Scholar 

  2. Andersson KE (2003) Storage and voiding symptoms: pathophysiologic aspects. Urology 62(5 Suppl 2):3–10

    Article  PubMed  Google Scholar 

  3. Oelke M, Baard J, Wijkstra H, de la Rosette JJ, Jonas U, Hofner K (2008) Age and bladder outlet obstruction are independently associated with detrusor overactivity in patients with benign prostatic hyperplasia. Eur Urol 54(2):419–426. doi:10.1016/j.eururo.2008.02.017

    Article  PubMed  Google Scholar 

  4. Chacko S, Chang S, Hypolite J, Disanto M, Wein A (2004) Alteration of contractile and regulatory proteins following partial bladder outlet obstruction. Scand J Urol Nephrol Suppl 215:26–36. doi:10.1080/03008880410015147

    Article  Google Scholar 

  5. Bing W, Chang S, Hypolite JA, DiSanto ME, Zderic SA, Rolf L, Wein AJ, Chacko S (2003) Obstruction-induced changes in urinary bladder smooth muscle contractility: a role for Rho kinase. Am J Physiol Renal Physiol 285(5):F990–F997. doi:10.1152/ajprenal.00378.2002

    Article  PubMed  Google Scholar 

  6. DiSanto ME, Stein R, Chang S, Hypolite JA, Zheng Y, Zderic S, Wein AJ, Chacko S (2003) Alteration in expression of myosin isoforms in detrusor smooth muscle following bladder outlet obstruction. Am J Physiol Cell Physiol 285(6):C1397–C1410. doi:10.1152/ajpcell.00513.2002

    Article  CAS  PubMed  Google Scholar 

  7. Heppner TJ, Bonev AD, Nelson MT (1997) Ca(2+)-activated K+ channels regulate action potential repolarization in urinary bladder smooth muscle. Am J Physiol 273(1 Pt 1):C110–C117

    CAS  PubMed  Google Scholar 

  8. Hashitani H, Brading AF (2003) Ionic basis for the regulation of spontaneous excitation in detrusor smooth muscle cells of the guinea-pig urinary bladder. Br J Pharmacol 140(1):159–169. doi:10.1038/sj.bjp.0705320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Petkov GV (2011) Role of potassium ion channels in detrusor smooth muscle function and dysfunction. Nat Rev Urol 9(1):30–40. doi:10.1038/nrurol.2011.194

    Article  PubMed  PubMed Central  Google Scholar 

  10. Hristov KL, Chen M, Kellett WF, Rovner ES, Petkov GV (2011) Large-conductance voltage- and Ca2+-activated K+ channels regulate human detrusor smooth muscle function. Am J Physiol Cell Physiol 301(4):C903–C912. doi:10.1152/ajpcell.00495.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hristov KL, Parajuli SP, Soder RP, Cheng Q, Rovner ES, Petkov GV (2012) Suppression of human detrusor smooth muscle excitability and contractility via pharmacological activation of large conductance Ca2+-activated K+ channels. Am J Physiol Cell Physiol 302(11):C1632–C1641. doi:10.1152/ajpcell.00417.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kita M, Yunoki T, Takimoto K, Miyazato M, Kita K, de Groat WC, Kakizaki H, Yoshimura N (2010) Effects of bladder outlet obstruction on properties of Ca2+-activated K+ channels in rat bladder. Am J Physiol Regul Integr Comp Physiol 298(5):R1310–R1319. doi:10.1152/ajpregu.00523.2009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Xin W, Li N, Cheng Q, Petkov GV (2014) BK channel-mediated relaxation of urinary bladder smooth muscle: a novel paradigm for phosphodiesterase type 4 regulation of bladder function. J Pharmacol Exp Ther 349(1):56–65. doi:10.1124/jpet.113.210708

    Article  PubMed  PubMed Central  Google Scholar 

  14. Xin W, Li N, Cheng Q, Fernandes VS, Petkov GV (2014) Constitutive PKA activity is essential for maintaining the excitability and contractility in guinea pig urinary bladder smooth muscle: role of the BK channel. Am J Physiol Cell Physiol 307(12):C1142–C1150. doi:10.1152/ajpcell.00167.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hristov KL, Afeli SA, Parajuli SP, Cheng Q, Rovner ES, Petkov GV (2013) Neurogenic detrusor overactivity is associated with decreased expression and function of the large conductance voltage- and Ca(2+)-activated K(+) channels. PLoS ONE 8(7):e68052. doi:10.1371/journal.pone.0068052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Afeli SA, Rovner ES, Petkov GV (2012) SK but not IK channels regulate human detrusor smooth muscle spontaneous and nerve-evoked contractions. Am J Physiol Renal Physiol 303(4):F559–F568. doi:10.1152/ajprenal.00615.2011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Parajuli SP, Soder RP, Hristov KL, Petkov GV (2012) Pharmacological activation of small conductance calcium-activated potassium channels with naphtho[1,2-d]thiazol-2-ylamine decreases guinea pig detrusor smooth muscle excitability and contractility. J Pharmacol Exp Ther 340(1):114–123. doi:10.1124/jpet.111.186213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Parajuli SP, Hristov KL, Soder RP, Kellett WF, Petkov GV (2013) NS309 decreases rat detrusor smooth muscle membrane potential and phasic contractions by activating SK3 channels. Br J Pharmacol 168(7):1611–1625. doi:10.1111/bph.12049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wulff H, Zhorov BS (2008) K+ channel modulators for the treatment of neurological disorders and autoimmune diseases. Chem Rev 108(5):1744–1773. doi:10.1021/cr078234p

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ni Y, Wang T, Zhuo X, Song B, Zhang J, Wei F, Bai H, Wang X, Yang D, Gao L, Ma A (2013) Bisoprolol reversed small conductance calcium-activated potassium channel (SK) remodeling in a volume-overload rat model. Mol Cell Biochem 384(1–2):95–103. doi:10.1007/s11010-013-1785-5

    Article  CAS  PubMed  Google Scholar 

  21. Coleman N, Brown BM, Olivan-Viguera A, Singh V, Olmstead MM, Valero MS, Kohler R, Wulff H (2014) New positive Ca2+-activated K+ channel gating modulators with selectivity for KCa3.1. Mol Pharmacol 86(3):342–357. doi:10.1124/mol.114.093286

    Article  PubMed  PubMed Central  Google Scholar 

  22. Thorneloe KS, Knorn AM, Doetsch PE, Lashinger ES, Liu AX, Bond CT, Adelman JP, Nelson MT (2008) Small-conductance, Ca(2+)-activated K+ channel 2 is the key functional component of SK channels in mouse urinary bladder. Am J Physiol Regul Integr Comp Physiol 294(5):R1737–R1743. doi:10.1152/ajpregu.00840.2006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Herrera GM, Pozo MJ, Zvara P, Petkov GV, Bond CT, Adelman JP, Nelson MT (2003) Urinary bladder instability induced by selective suppression of the murine small conductance calcium-activated potassium (SK3) channel. J Physiol 551(Pt 3):893–903. doi:10.1113/jphysiol.2003.045914

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Li N, He X, Li Z, Liu Y, Wang P (2016) Partial bladder outlet obstruction is associated with decreased expression and function of the small-conductance Ca2+-activated K+ channel in guinea pig detrusor smooth muscle. Int Urol Nephrol. doi:10.1007/s11255-016-1455-0

    PubMed Central  Google Scholar 

  25. Li L, Jiang C, Song B, Yan J, Pan J (2008) Altered expression of calcium-activated K and Cl channels in detrusor overactivity of rats with partial bladder outlet obstruction. BJU Int 101(12):1588–1594. doi:10.1111/j.1464-410X.2008.07522.x

    Article  CAS  PubMed  Google Scholar 

  26. Yang S, Li YP (2007) RGS10-null mutation impairs osteoclast differentiation resulting from the loss of [Ca2+]i oscillation regulation. Genes Dev 21(14):1803–1816. doi:10.1101/gad.1544107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. He X, Dziak R, Yuan X, Mao K, Genco R, Swihart M, Sarkar D, Li C, Wang C, Lu L, Andreadis S, Yang S (2013) BMP2 genetically engineered MSCs and EPCs promote vascularized bone regeneration in rat critical-sized calvarial bone defects. PLoS ONE 8(4):e60473. doi:10.1371/journal.pone.0060473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Gui L, LaGrange LP, Larson RA, Gu M, Zhu J, Chen QH (2012) Role of small conductance calcium-activated potassium channels expressed in PVN in regulating sympathetic nerve activity and arterial blood pressure in rats. Am J Physiol Regul Integr Comp Physiol 303(3):R301–R310. doi:10.1152/ajpregu.00114.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3(6):1101–1108

    Article  CAS  PubMed  Google Scholar 

  30. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−ΔΔC(T)) method. Methods 25(4):402–408. doi:10.1006/meth.2001.1262

    Article  CAS  PubMed  Google Scholar 

  31. Soder RP, Parajuli SP, Hristov KL, Rovner ES, Petkov GV (2013) SK channel-selective opening by SKA-31 induces hyperpolarization and decreases contractility in human urinary bladder smooth muscle. Am J Physiol Regul Integr Comp Physiol 304(2):R155–R163. doi:10.1152/ajpregu.00363.2012

    Article  CAS  PubMed  Google Scholar 

  32. Kubota Y, Hashitani H, Shirasawa N, Kojima Y, Sasaki S, Mabuchi Y, Soji T, Suzuki H, Kohri K (2008) Altered distribution of interstitial cells in the guinea pig bladder following bladder outlet obstruction. Neurourol Urodyn 27(4):330–340. doi:10.1002/nau.20502

    Article  PubMed  Google Scholar 

  33. Scheepe JR, de Jong BW, Wolffenbuttel KP, Arentshorst ME, Lodder P, Kok DJ (2007) The effect of oxybutynin on structural changes of the obstructed guinea pig bladder. J Urol 178(4 Pt 2):1807–1812. doi:10.1016/j.juro.2007.03.187

    Article  CAS  PubMed  Google Scholar 

  34. Petkov GV, Heppner TJ, Bonev AD, Herrera GM, Nelson MT (2001) Low levels of K(ATP) channel activation decrease excitability and contractility of urinary bladder. Am J Physiol Regul Integr Comp Physiol 280(5):R1427–R1433

    CAS  PubMed  Google Scholar 

Download references

Funding

This study was funded by a Grant from LNCCC of LNCCC-D16-2015 to Ning Li.

Author information

Authors and Affiliations

  1. Department of Urology, Fourth Affiliated Hospital, China Medical University, 4 Chongshan East Road, Shenyang, Liaoning, China

    Ning Li, Honglin Ding, Zizheng Li & Yili Liu

  2. Department of Stomatology, Fourth Affiliated Hospital, China Medical University, 4 Chongshan East Road, Shenyang, Liaoning, China

    Xiaoning He

Authors
  1. Ning Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Honglin Ding
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaoning He
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zizheng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yili Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yili Liu.

Ethics declarations

Conflict of interest

All authors declare that they have no conflicts of interest.

Ethical approval

All applicable international, national, and institutional guidelines for the care and use of animals were followed.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, N., Ding, H., He, X. et al. Expression and function of the small-conductance Ca2+-activated K+ channel is decreased in urinary bladder smooth muscle cells from female guinea pig with partial bladder outlet obstruction. Int Urol Nephrol 49, 1147–1155 (2017). https://doi.org/10.1007/s11255-017-1592-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11255-017-1592-0

Keywords

Search

Navigation