Skip to main content

Advertisement

SpringerLink
Log in

Does hypercholesterolemia affect the relaxation of the detrusor smooth muscle in rats? In vitro and in vivo studies

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

To evaluate the effects of hypercholesterolemia on the relaxation function of the urinary bladder, we examined the physiological mechanisms involved in the isoproterenol-induced relaxation in isolated detrusor strips in vitro and voiding behavior in vivo in rats. Adult male Sprague–Dawley rats were fed standard (control, N = 16) or 4 % cholesterol diet (hypercholesterolemia, N = 17) for 4 weeks. Concentration–response curves for isoproterenol-induced relaxations in carbachol-precontracted detrusor muscle strips were recorded. The contributions of β2- and β3-adrenoceptors and ATP-dependent and Ca2+-dependent potassium channels to the relaxation response were investigated by using selective adrenergic agonists salbutamol and BRL 37344 and specific potassium channel inhibitors glibenclamide and charybdotoxin, respectively. Cystometrography was performed to assess bladder function. Hypercholesterolemic rats had higher serum cholesterol and low- and high-density lipoprotein levels than the controls with no sign of atherosclerosis. Isoproterenol-induced relaxation was significantly enhanced in the hypercholesterolemia group. Preincubation with the M2 receptor antagonist attenuated the relaxation response in both groups. The relaxation responses to isoproterenol and salbutamol were similar in both groups, while BRL 37344 appeared to produce a greater relaxant effect in the hypercholesterolemic rats. Also, the inhibitory effects of potassium channel inhibitors on relaxation responses were comparable among the groups. The cystometric findings revealed that threshold and basal pressure values were higher in the hypercholesterolemia group compared with controls. We showed that hypercholesterolemia leads to greater relaxation responses to isoproterenol, appears to impair the braking function of M2 cholinergic receptors on adrenoceptor-induced relaxations in the isolated detrusor muscle, and affects the voiding function in rats.

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

Similar content being viewed by others

References

  • Afeli SA, Petkov GV (2013) Functional BK channels facilitate the beta3-adrenoceptor agonist-mediated relaxation of nerve-evoked contractions in rat urinary bladder smooth muscle isolated strips. Eur J Pharmacol 711:50–56

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Afeli SA, Rovner ES, Petkov GV (2013) BRL37344, a beta3-adrenergic receptor agonist, decreases nerve-evoked contractions in human detrusor smooth muscle isolated strips: role of BK channels. Urology 82(744):e741–747

    Google Scholar 

  • Andersson KE (1988) Current concepts in the treatment of disorders of micturition. Drugs 35:477–494

    Article  CAS  PubMed  Google Scholar 

  • Andersson KE (2009) Prospective pharmacologic therapies for the overactive bladder. Ther Adv Urol 1:71–83

    Article  PubMed Central  PubMed  Google Scholar 

  • Andersson KE, Arner A (2004) Urinary bladder contraction and relaxation: physiology and pathophysiology. Physiol Rev 84:935–986

    Article  CAS  PubMed  Google Scholar 

  • Azadzoi KM, Tarcan T, Kozlowski R, Krane RJ, Siroky MB (1999) Overactivity and structural changes in the chronically ischemic bladder. J Urol 162:1768–1778

    Article  CAS  PubMed  Google Scholar 

  • Balkanci ZD, Pehlivanoglu B, Bayrak S, Karabulut I, Karaismailoglu S, Erdem A (2012) The effect of hypercholesterolemia on carbachol-induced contractions of the detrusor smooth muscle in rats: increased role of L-type Ca2+ channels. Naunyn Schmiedeberg’s Arch Pharmacol 385:1141–1148

    Article  CAS  Google Scholar 

  • Cai GJ, Miao CY, Xie HH, Lu LH, Su DF (2005) Arterial baroreflex dysfunction promotes atherosclerosis in rats. Atherosclerosis 183:41–47

    Article  CAS  PubMed  Google Scholar 

  • Cerruto MA, Asimakopoulos AD, Artibani W, Del Popolo G, La Martina M, Carone R, Finazzi-Agro E (2012) Insight into new potential targets for the treatment of overactive bladder and detrusor overactivity. Urol Int 89:1–8

    Article  CAS  PubMed  Google Scholar 

  • Devroey D, Senesael E, Moerenhout T, Van De Vijver E, Vandevoorde J (2011) Follow-up of a cardiovascular prevention campaign. Cent Eur J Public Health 19:190–196

    CAS  PubMed  Google Scholar 

  • Dopico AM, Bukiya AN, Singh AK (2012) Large conductance, calcium- and voltage-gated potassium (BK) channels: regulation by cholesterol. Pharmacol Ther 135:133–150

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ehlert FJ, Griffin MT, Abe DM, Vo TH, Taketo MM, Manabe T, Matsui M (2005) The M2 muscarinic receptor mediates contraction through indirect mechanisms in mouse urinary bladder. J Pharmacol Exp Ther 313:368–378

    Article  CAS  PubMed  Google Scholar 

  • Ekman M, Andersson KE, Arner A (2009) Signal transduction pathways of muscarinic receptor mediated activation in the newborn and adult mouse urinary bladder. BJU Int 103:90–97

    Article  PubMed  Google Scholar 

  • Ferro A (2006) Beta-adrenoceptors and potassium channels. Naunyn Schmiedeberg’s Arch Pharmacol 373:183–185

    Article  CAS  Google Scholar 

  • Frazier EP, Mathy MJ, Peters SL, Michel MC (2005) Does cyclic AMP mediate rat urinary bladder relaxation by isoproterenol? J Pharmacol Exp Ther 313:260–267

    Article  CAS  PubMed  Google Scholar 

  • Frazier EP, Peters SL, Braverman AS, Ruggieri MR Sr, Michel MC (2008) Signal transduction underlying the control of urinary bladder smooth muscle tone by muscarinic receptors and beta-adrenoceptors. Naunyn Schmiedeberg’s Arch Pharmacol 377:449–462

    Article  CAS  Google Scholar 

  • Hall SA, Chiu GR, Link CL, Steers WD, Kupelian V, McKinlay JB (2011) Are statin medications associated with lower urinary tract symptoms in men and women? Results from the Boston Area Community Health (BACH) Survey. Ann Epidemiol 21:149–155

    Article  PubMed Central  PubMed  Google Scholar 

  • Hegde SS, Choppin A, Bonhaus D, Briaud S, Loeb M, Moy TM, Loury D, Eglen RM (1997) Functional role of M2 and M3 muscarinic receptors in the urinary bladder of rats in vitro and in vivo. Br J Pharmacol 120:1409–1418

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Herrera GM, Etherton B, Nausch B, Nelson MT (2005) Negative feedback regulation of nerve-mediated contractions by KCa channels in mouse urinary bladder smooth muscle. Am J Physiol Regul Integr Comp Physiol 289:R402–R409

    Article  CAS  PubMed  Google Scholar 

  • Hristov KL, Cui X, Brown SM, Liu L, Kellett WF, Petkov GV (2008) Stimulation of beta3-adrenoceptors relaxes rat urinary bladder smooth muscle via activation of the large-conductance Ca2+-activated K+ channels. Am J Physiol Cell Physiol 295:C1344–1353

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • 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:e68052

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Huang YC, Shindel AW, Ning H, Lin G, Harraz AM, Wang G, Garcia M, Lue TF, Lin CS (2010) Adipose derived stem cells ameliorate hyperlipidemia associated detrusor overactivity in a rat model. J Urol 183:1232–1240

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kim SC (2000) Hyperlipidemia and erectile dysfunction. Asia J Androl 2:161–166

    CAS  Google Scholar 

  • Kim HW, Kim SC, Seo KK, Lee MY (2002) Effects of estrogen on the relaxation response of rabbit clitoral cavernous smooth muscles. Urol Res 30:26–30

    Article  CAS  PubMed  Google Scholar 

  • Kohan AD, Danziger M, Vaughan ED Jr, Felsen D (2000) Effect of aging on bladder function and the response to outlet obstruction in female rats. Urol Res 28:33–37

    Article  CAS  PubMed  Google Scholar 

  • Kubota Y, Nakahara T, Yunoki M, Mitani A, Maruko T, Sakamoto K, Ishii K (2002) Inhibitory mechanism of BRL37344 on muscarinic receptor-mediated contractions of the rat urinary bladder smooth muscle. Naunyn Schmiedeberg’s Arch Pharmacol 366:198–203

    Article  CAS  Google Scholar 

  • Li G, Li K, Li Z, Wang P (2003) Age-dependent changes in beta-adrenoceptor function in human detrusor and possible mechanisms. Chin Med J 116:1511–1514

    CAS  PubMed  Google Scholar 

  • Longhurst PA, Levendusky M (1999) Pharmacological characterization of beta-adrenoceptors mediating relaxation of the rat urinary bladder in vitro. Br J Pharmacol 127:1744–1750

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Longhurst PA, Levendusky MC, Bezuijen MW (2004) Diabetes mellitus increases the rate of development of decompensation in rats with outlet obstruction. J Urol 171:933–937

    Article  PubMed  Google Scholar 

  • Matsui M, Griffin MT, Shehnaz D, Taketo MM, Ehlert FJ (2003) Increased relaxant action of forskolin and isoproterenol against muscarinic agonist-induced contractions in smooth muscle from M2 receptor knockout mice. J Pharmacol Exp Ther 305:106–113

    Article  CAS  PubMed  Google Scholar 

  • Meredith AL, Thorneloe KS, Werner ME, Nelson MT, Aldrich RW (2004) Overactive bladder and incontinence in the absence of the BK large conductance Ca2+-activated K+ channel. J Biol Chem 279:36746–36752

    Article  CAS  PubMed  Google Scholar 

  • Michel MC, Barendrecht MM (2008) Physiological and pathological regulation of the autonomic control of urinary bladder contractility. Pharmacol Ther 117:297–312

    Article  CAS  PubMed  Google Scholar 

  • Michel MC, Sand C (2009) Effect of pre-contraction on beta-adrenoceptor-mediated relaxation of rat urinary bladder. World J Urol 27:711–715

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Michel MC, Vrydag W (2006) Alpha1-, alpha2- and beta-adrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol 147(Suppl 2):S88–119

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Monica FZ, Bricola AA, Bau FR, Freitas LL, Teixeira SA, Muscara MN, Abdalla FM, Porto CS, De Nucci G, Zanesco A, Antunes E (2008) Long-term nitric oxide deficiency causes muscarinic supersensitivity and reduces beta(3)-adrenoceptor-mediated relaxation, causing rat detrusor overactivity. Br J Pharmacol 153:1659–1668

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Nitti VW, Auerbach S, Martin N, Calhoun A, Lee M, Herschorn S (2013) Results of a randomized phase III trial of mirabegron in patients with overactive bladder. J Urol 189:1388–1395

    Article  CAS  PubMed  Google Scholar 

  • Nomiya M, Yamaguchi O, Andersson KE, Sagawa K, Aikawa K, Shishido K, Yanagida T, Kushida N, Yazaki J, Takahashi N (2012) The effect of atherosclerosis-induced chronic bladder ischemia on bladder function in the rat. Neurourol Urodyn 31:195–200

    Article  CAS  PubMed  Google Scholar 

  • Oger S, Behr-Roussel D, Gorny D, Bernabe J, Comperat E, Chartier-Kastler E, Denys P, Giuliano F (2011) Effects of potassium channel modulators on myogenic spontaneous phasic contractile activity in human detrusor from neurogenic patients. BJU Int 108:604–611

    Article  CAS  PubMed  Google Scholar 

  • Oshita M, Hiraoka Y, Watanabe Y (1997) Characterization of beta-adrenoceptors in urinary bladder: comparison between rat and rabbit. Br J Pharmacol 122:1720–1724

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Parajuli SP, Petkov GV (2013) Activation of muscarinic M3 receptors inhibits large-conductance voltage- and Ca2+-activated K+ channels in rat urinary bladder smooth muscle cells. Am J Physiol Cell Physiol 305:C207–214

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Petkov GV (2012) Role of potassium ion channels in detrusor smooth muscle function and dysfunction. Nat Rev Urol 9:30–40

    Article  CAS  Google Scholar 

  • Petkov GV, Nelson MT (2005) Differential regulation of Ca2+-activated K+ channels by beta-adrenoceptors in guinea pig urinary bladder smooth muscle. Am J Physiol Cell Physiol 288:C1255–1263

    Article  CAS  PubMed  Google Scholar 

  • Rahman NU, Phonsombat S, Bochinski D, Carrion RE, Nunes L, Lue TF (2007) An animal model to study lower urinary tract symptoms and erectile dysfunction: the hyperlipidaemic rat. BJU Int 100:658–663

    Article  PubMed  Google Scholar 

  • Ren YJ, Xu XH, Zhong CB, Feng N, Wang XL (2001) Hypercholesterolemia alters vascular functions and gene expression of potassium channels in rat aortic smooth muscle cells. Acta Pharmacol Sin 22:274–278

    CAS  PubMed  Google Scholar 

  • Shishido T, Tasaki K, Takeishi Y, Takasaki S, Miyamoto T, Itoh M, Takahashi H, Kubota I, Ito T, Katano Y, Wakabayashi I, Tomoike H (2004) Chronic hypertriglyceridemia in young watanabe heritable hyperlipidemic rabbits impairs endothelial and medial smooth muscle function. Life Sci 74:1487–1501

    Article  CAS  PubMed  Google Scholar 

  • Son H, Lee SL, Park WH, Park K, Park S, Kang MS, Kim DY, Kim SW, Paick JS (2007) New unstable bladder model in hypercholesterolemia rats. Urology 69:186–190

    Article  PubMed  Google Scholar 

  • Stevens LA, Chapple CR, Chess-Williams R (2007) Human idiopathic and neurogenic overactive bladders and the role of M2 muscarinic receptors in contraction. Eur Urol 52:531–538

    Article  CAS  PubMed  Google Scholar 

  • Takeda M, Obara K, Mizusawa T, Tomita Y, Arai K, Tsutsui T, Hatano A, Takahashi K, Nomura S (1999) Evidence for beta3-adrenoceptor subtypes in relaxation of the human urinary bladder detrusor: analysis by molecular biological and pharmacological methods. J Pharmacol Exp Ther 288:1367–1373

    CAS  PubMed  Google Scholar 

  • Takeda H, Yamazaki Y, Akahane M, Igawa Y, Ajisawa Y, Nishizawa O (2000) Role of the beta(3)-adrenoceptor in urine storage in the rat: comparison between the selective beta(3)-adrenoceptor agonist, CL316, 243, and various smooth muscle relaxants. J Pharmacol Exp Ther 293:939–945

    CAS  PubMed  Google Scholar 

  • Tanaka Y, Horinouchi T, Koike K (2005) New insights into beta-adrenoceptors in smooth muscle: distribution of receptor subtypes and molecular mechanisms triggering muscle relaxation. Clin Exp Pharmacol Physiol 32:503–514

    Article  CAS  PubMed  Google Scholar 

  • Tyagi P, Thomas CA, Yoshimura N, Chancellor MB (2009) Investigations into the presence of functional Beta1, Beta2 and Beta3-adrenoceptors in urothelium and detrusor of human bladder. Int Braz J Urol : Off J Braz Soc Urol 35:76–83

    Article  Google Scholar 

  • Uchida H, Shishido K, Nomiya M, Yamaguchi O (2005) Involvement of cyclic AMP-dependent and -independent mechanisms in the relaxation of rat detrusor muscle via beta-adrenoceptors. Eur J Pharmacol 518:195–202

    Article  CAS  PubMed  Google Scholar 

  • Vrydag W, Michel MC (2007) Tools to study beta3-adrenoceptors. Naunyn Schmiedeberg’s Arch Pharmacol 374:385–398

    Article  CAS  Google Scholar 

  • Witte LP, de Haas N, Mammen M, Stangeland EL, Steinfeld T, Aiyar J, Michel MC (2011) Muscarinic receptor subtypes and signalling involved in the attenuation of isoprenaline-induced rat urinary bladder relaxation. Naunyn Schmiedeberg’s Arch Pharmacol 384:555–563

    Article  CAS  Google Scholar 

  • Yamaguchi O (2002) Beta3-adrenoceptors in human detrusor muscle. Urology 59:25–29

    Article  PubMed  Google Scholar 

  • Yamazaki Y, Takeda H, Akahane M, Igawa Y, Nishizawa O, Ajisawa Y (1998) Species differences in the distribution of beta-adrenoceptor subtypes in bladder smooth muscle. Br J Pharmacol 124:593–599

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Yoshida M, Masunaga K, Nagata T, Satoji Y, Shiomi M (2010a) The effects of chronic hyperlipidemia on bladder function in myocardial infarction-prone Watanabe heritable hyperlipidemic (WHHLMI) rabbits. Neurourol Urodyn 29:1350–1354

    Article  PubMed  Google Scholar 

  • Yoshida M, Masunaga K, Nagata T, Yono M, Homma Y (2010b) The forefront for novel therapeutic agents based on the pathophysiology of lower urinary tract dysfunction: pathophysiology and pharmacotherapy of overactive bladder. J Pharmacol Sci 112:128–134

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by Hacettepe University Research Foundation (HUBAB; 01-G-019 and 07-D09-101-03) and The Scientific and Technological Research Council of Turkey (TUBITAK: 106-S-244).

The authors wish to thank Gülsen Öner, PhD, Professor of Physiology, for her critical and initiative contribution to this study; Rıfkı Finci, MD, Professor of Pathology, for the histopathological evaluation of the aortic arch; and S. Remzi Erdem, MD, PhD, Professor of Pharmacology, for the critical reading of the manuscript.

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Physiology, Faculty of Medicine, Hacettepe University, 39, 06100, Sihhiye, Ankara, Turkey

    Sibel Bayrak, Zeynep Dicle Balkanci, Bilge Pehlivanoğlu, İsmail Karabulut, Serkan Karaismailoğlu & Ayşen Erdem

Authors
  1. Sibel Bayrak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zeynep Dicle Balkanci
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bilge Pehlivanoğlu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. İsmail Karabulut
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Serkan Karaismailoğlu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ayşen Erdem
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sibel Bayrak.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bayrak, S., Balkanci, Z.D., Pehlivanoğlu, B. et al. Does hypercholesterolemia affect the relaxation of the detrusor smooth muscle in rats? In vitro and in vivo studies. Naunyn-Schmiedeberg's Arch Pharmacol 388, 761–771 (2015). https://doi.org/10.1007/s00210-014-1060-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-014-1060-7

Keywords

Search

Navigation