Advertisement

International Urology and Nephrology

, Volume 51, Issue 1, pp 61–72 | Cite as

Effect of high-fat diet-induced obesity on the small-conductance Ca2+-activated K+ channel function affecting the contractility of rat detrusor smooth muscle

  • Ning Li
  • Honglin Ding
  • Zizheng Li
  • Yili LiuEmail author
  • Ping Wang
Urology - Original Paper
  • 91 Downloads

Abstract

Purpose

Obesity usually induces overactive bladder (OAB) associated with detrusor overactivity, which is related to increased contractility of the detrusor smooth muscle (DSM). Small-conductance Ca2+-activated K+ (SK) channels play a constitutive role in the regulation of DSM contractility. However, the role of SK channels in the DSM changes in obesity-related OAB is still unknown. Here, we tested the hypothesis that obesity-related OAB is associated with reduced expression and activity of SK channels in DSM and that SK channels activation is a potential treatment for OAB.

Methods

Female Sprague–Dawley rats were fed a normal diet (ND) or a high-fat diet (HFD) and weighed after 12 weeks. Urodynamic studies, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and isometric tension recording were performed.

Results

Increased average body weights and urodynamically demonstrated OAB were observed in HFD rats. qRT-PCR experiments revealed a decrease in the mRNA expression level of SK channel in DSM tissue of the HFD rats. Isometric tension recordings indicated an attenuated relaxation effect of NS309 on the spontaneous phasic and electrical field stimulation-induced contractions that occurred via SK channel activation in HFD DSM strips.

Conclusions

Reduced expression and activity of SK channels in the DSM contribute to obesity-related OAB, indicating that SK channels are a potential therapeutic target for OAB.

Keywords

SK channel Overactive bladder Detrusor smooth muscle High-fat diet Obesity 

Notes

Acknowledgements

Supported by the LNCCC LNCCC-D16-2015 grant to Ning Li; the National Science Foundation of Liaoning Province 2015020493 grant to Ning Li.

Compliance with ethical standards

Conflict of interest

All authors declare no conflict of interest.

Ethical approval

All applicable International, National, and Institutional Guidelines for the care and use of animals were followed.

References

  1. 1.
    Weisman A et al (2018) Evolving trends in the epidemiology, risk factors, and prevention of type 2 diabetes: a review. Can J Cardiol 34(5):552–564CrossRefGoogle Scholar
  2. 2.
    Murphy M, Robertson W, Oyebode O (2017) Obesity in international migrant populations. Curr Obes Rep 6(3):314–323CrossRefGoogle Scholar
  3. 3.
    Mydlo JH (2004) The impact of obesity in urology. Urol Clin North Am 31(2):275–287CrossRefGoogle Scholar
  4. 4.
    Richter HE et al (2010) The impact of obesity on urinary incontinence symptoms, severity, urodynamic characteristics and quality of life. J Urol 183(2):622–628CrossRefGoogle Scholar
  5. 5.
    Rohrmann S et al (2005) Association between markers of the metabolic syndrome and lower urinary tract symptoms in the Third National Health and Nutrition Examination Survey (NHANES III). Int J Obes (London) 29(3):310–316CrossRefGoogle Scholar
  6. 6.
    Andersson KE (2003) Storage and voiding symptoms: pathophysiologic aspects. Urology 62(5 Suppl 2):3–10CrossRefGoogle Scholar
  7. 7.
    Andersson KE (2009) Prospective pharmacologic therapies for the overactive bladder. Ther Adv Urol 1(2):71–83CrossRefGoogle Scholar
  8. 8.
    Bunn F et al (2015) Is there a link between overactive bladder and the metabolic syndrome in women? A systematic review of observational studies. Int J Clin Pract 69(2):199–217CrossRefGoogle Scholar
  9. 9.
    Ding H et al. (2017) Treatment of obesity-associated overactive bladder by the phosphodiesterase type-4 inhibitor roflumilast. Int Urol Nephrol 49:1723–1730CrossRefGoogle Scholar
  10. 10.
    Oberbach A et al (2014) High fat diet-induced molecular and physiological dysfunction of the urinary bladder. Urologe A 53(12):1805–1811CrossRefGoogle Scholar
  11. 11.
    Fan EW et al (2014) Changes of urinary bladder contractility in high-fat diet-fed mice: the role of tumor necrosis factor-alpha. Int J Urol 21(8):831–835CrossRefGoogle Scholar
  12. 12.
    DiSanto ME et al (2003) Alteration in expression of myosin isoforms in detrusor smooth muscle following bladder outlet obstruction. Am J Physiol Cell Physiol 285(6):C1397–C1410CrossRefGoogle Scholar
  13. 13.
    Li N et al (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 49(1):17–26CrossRefGoogle Scholar
  14. 14.
    Li N et al (2017) 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 49:1147–1155CrossRefGoogle Scholar
  15. 15.
    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–C117CrossRefGoogle Scholar
  16. 16.
    Hristov KL et al (2011) Large-conductance voltage- and Ca2+-activated K+ channels regulate human detrusor smooth muscle function. Am J Physiol Cell Physiol 301(4):C903–C912CrossRefGoogle Scholar
  17. 17.
    Hristov KL et al (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–C1641CrossRefGoogle Scholar
  18. 18.
    Petkov GV (2012) Role of potassium ion channels in detrusor smooth muscle function and dysfunction. Nat Rev Urol 9(1):30–40CrossRefGoogle Scholar
  19. 19.
    GrgicI et al (2009) Endothelial Ca+-activated K+ channels in normal and impaired EDHF-dilator responses–relevance to cardiovascular pathologies and drug discovery. Br J Pharmacol 157(4):509–526CrossRefGoogle Scholar
  20. 20.
    Wulff H, Zhorov BS (2008) K+ channel modulators for the treatment of neurological disorders and autoimmune diseases. Chem Rev 108(5):1744–1773CrossRefGoogle Scholar
  21. 21.
    Kohler M et al (1996) Small-conductance, calcium-activated potassium channels from mammalian brain. Science 273(5282):1709–1714CrossRefGoogle Scholar
  22. 22.
    Parajuli SP et al (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):114–123CrossRefGoogle Scholar
  23. 23.
    Parajuli SP et al (2013) NS309 decreases rat detrusor smooth muscle membrane potential and phasic contractions by activating SK3 channels. Br J Pharmacol 168(7):1611–1625CrossRefGoogle Scholar
  24. 24.
    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–F568CrossRefGoogle Scholar
  25. 25.
    Coleman N et al (2014) New positive Ca2+-activated K+ channel gating modulators with selectivity for KCa3.1. Mol Pharmacol 86(3):342–357CrossRefGoogle Scholar
  26. 26.
    Ni Y et al (2013) Bisoprolol reversed small conductance calcium-activated potassium channel (SK) remodeling in a volume-overload rat model. Mol Cell Biochem 384(1–2):95–103CrossRefGoogle Scholar
  27. 27.
    Soder RP et al (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–R163CrossRefGoogle Scholar
  28. 28.
    Ohya S et al (2000) SK4 encodes intermediate conductance Ca2+-activated K+ channels in mouse urinary bladder smooth muscle cells. Jpn J Pharmacol 84(1):97–100CrossRefGoogle Scholar
  29. 29.
    Herrera GM, Heppner TJ, Nelson MT (2000) Regulation of urinary bladder smooth muscle contractions by ryanodine receptors and BK and SK channels. Am J Physiol Regul Integr Comp Physiol 279(1):R60–R68CrossRefGoogle Scholar
  30. 30.
    Imai T et al (2001) Effects of different types of K+ channel modulators on the spontaneous myogenic contraction of guinea-pig urinary bladder smooth muscle. Acta Physiol Scand 173(3):323–333CrossRefGoogle Scholar
  31. 31.
    Buckner SA et al (2002) Spontaneous phasic activity of the pig urinary bladder smooth muscle: characteristics and sensitivity to potassium channel modulators. Br J Pharmacol 135(3):639–648CrossRefGoogle Scholar
  32. 32.
    Herrera GM et al (2003) Urinary bladder instability induced by selective suppression of the murine small conductance calcium-activated potassium (SK3) channel. J Physiol 551(Pt 3):893–903CrossRefGoogle Scholar
  33. 33.
    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):159–169CrossRefGoogle Scholar
  34. 34.
    Hashitani H, Brading AF (2003) Electrical properties of detrusor smooth muscles from the pig and human urinary bladder. Br J Pharmacol 140(1):146–158CrossRefGoogle Scholar
  35. 35.
    Hashitani H, Brading AF, Suzuki H (2004) Correlation between spontaneous electrical, calcium and mechanical activity in detrusor smooth muscle of the guinea-pig bladder. Br J Pharmacol 141(1):183–193CrossRefGoogle Scholar
  36. 36.
    Thorneloe KS et al (2008) Small-conductance, Ca2+-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–R1743CrossRefGoogle Scholar
  37. 37.
    Haddock RE et al (2011) Diet-induced obesity impairs endothelium-derived hyperpolarization via altered potassium channel signaling mechanisms. PLoS ONE 6(1):e16423CrossRefGoogle Scholar
  38. 38.
    Yang S, Li YP (2007) RGS10-null mutation impairs osteoclast differentiation resulting from the loss of [Ca2+]i oscillation regulation. Genes Dev 21(14):1803–1816CrossRefGoogle Scholar
  39. 39.
    He X et al (2013) BMP2 genetically engineered MSCs and EPCs promote vascularized bone regeneration in rat critical-sized calvarial bone defects. PLoS ONE 8(4):e60473CrossRefGoogle Scholar
  40. 40.
    Gui L et al (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–R310CrossRefGoogle Scholar
  41. 41.
    Xin W et al (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–C1150CrossRefGoogle Scholar
  42. 42.
    Xin W et al (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):56–65CrossRefGoogle Scholar
  43. 43.
    Rohrmann S et al (2004) Associations of obesity with lower urinary tract symptoms and noncancer prostate surgery in the Third National Health and Nutrition Examination Survey. Am J Epidemiol 159(4):390–397CrossRefGoogle Scholar
  44. 44.
    Rahman NU et al (2007) An animal model to study lower urinary tract symptoms and erectile dysfunction: the hyperlipidaemic rat. BJU Int 100(3):658–663CrossRefGoogle Scholar
  45. 45.
    Gharaee-Kermani M et al (2013) Obesity-induced diabetes and lower urinary tract fibrosis promote urinary voiding dysfunction in a mouse model. Prostate 73(10):1123–1133CrossRefGoogle Scholar
  46. 46.
    Oger S et al (2011) Effects of potassium channel modulators on myogenic spontaneous phasic contractile activity in human detrusor from neurogenic patients. BJU Int 108(4):604–611CrossRefGoogle Scholar
  47. 47.
    Andersson KE, Arner A (2004) Urinary bladder contraction and relaxation: physiology and pathophysiology. Physiol Rev 84(3):935–986CrossRefGoogle Scholar
  48. 48.
    Hristov KL et al (2013) Neurogenic detrusor overactivity is associated with decreased expression and function of the large conductance voltage- and Ca2+-activated K+ channels. PLoS ONE 8(7):e68052CrossRefGoogle Scholar
  49. 49.
    Brading AF (1997) A myogenic basis for the overactive bladder. Urology 50(6A Suppl):57–67 (discussion 68–73)CrossRefGoogle Scholar
  50. 50.
    Petkov GV (2011) Role of potassium ion channels in detrusor smooth muscle function and dysfunction. Nat Rev Urol 9(1):30–40CrossRefGoogle Scholar
  51. 51.
    Abrams P, Andersson KE (2007) Muscarinic receptor antagonists for overactive bladder. BJU Int 100(5):987–1006.  https://doi.org/10.1111/j.1464-410X.2007.07205.x CrossRefGoogle Scholar
  52. 52.
    Andersson KE (2016) Potential future pharmacological treatment of bladder dysfunction. Basic Clin Pharmacol Toxicol 119:75–85CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2018

Authors and Affiliations

  • Ning Li
    • 1
  • Honglin Ding
    • 1
    • 2
  • Zizheng Li
    • 1
  • Yili Liu
    • 1
    Email author
  • Ping Wang
    • 1
  1. 1.Department of Urology, Fourth Affiliated HospitalChina Medical UniversityShenyangChina
  2. 2.Department of Urology, Affiliated HospitalChifeng UniversityChifengChina

Personalised recommendations