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Hydrogen sulfide-induced relaxation of the bladder is attenuated in spontaneously hypertensive rats

  • Suo Zou
  • Takahiro ShimizuEmail author
  • Masaki Yamamoto
  • Shogo Shimizu
  • Youichirou Higashi
  • Motoaki Saito
Urology - Original Paper
  • 23 Downloads

Abstract

Purpose

To compare hydrogen sulfide (H2S)-induced relaxation on the bladder between normotensive and spontaneously hypertensive rat (SHR), we evaluated the effects of H2S donors (GYY4137 and NaHS) on the micturition reflex and on the contractility of bladder tissues. We also investigated the content of H2S and the expression levels of enzymes related to H2S biosynthesis [cystathionine β-synthase (CBS), 3-mercaptopyruvate sulfurtransferase (MPST), and cysteine aminotransferase (CAT)] in the bladder.

Methods

Eighteen-week-old male normotensive Wistar rats and SHRs were used. Under urethane anesthesia, the effects of intravesically instilled GYY4137 (10−8, 10−7 and 10−6 M) on the micturition reflex were evaluated by cystometry. The effects of NaHS (1 × 10−8–3 × 10−4 M) were evaluated on carbachol (10−5 M)-induced pre-contracted bladder strips. Tissue H2S content was measured by the methylene blue method. The expression levels of these enzymes were investigated by Western blot.

Results

GYY4137 significantly prolonged intercontraction intervals in Wistar rats, but not in SHRs. NaHS-induced relaxation on pre-contracted bladder strips was significantly attenuated in SHRs compared with Wistar rats. The H2S content in the bladder of SHRs was significantly higher than that of Wistar rats. CBS, MPST and CAT were detected in the bladder of Wistar rats and SHRs. The expression levels of MPST in the SHR bladder were significantly higher than those in the Wistar rat bladder.

Conclusion

H2S-induced bladder relaxation in SHRs is impaired, thereby resulting in a compensatory increase of the H2S content in the SHR bladder.

Keywords

Hydrogen sulfide 3-Mercaptopyruvate sulfurtransferase Spontaneously hypertensive rat Bladder Detrusor overactivity 

Abbreviations

BBF

Bladder blood flow

BBR

Bladder body weight ratio

BL-D

Bladder dome

BL-T

Bladder trigone

CAT

Cysteine aminotransferase

CBS

Cystathionine β-synthase

CSE

Cystathionine γ-lyase

DO

Detrusor overactivity

IACUC

Institutional Animal Care and Use Committees

ICI

Intercontraction intervals

KATP channel

ATP-sensitive potassium channel

LUTS

Lower urinary tract symptoms

MPST

3-Mercaptopyruvate sulfurtransferase

MVP

Maximal voiding pressure

NO

Nitric oxide

OAB

Overactive bladder

SHR

Spontaneously hypertensive rat

Notes

Acknowledgements

This work was supported in part by a Grant-in-Aid for Challenging Exploratory Research (No. 15K15583 to M.S.) from the Japan Society for the Promotion of Science, and GSK Japan Research Grant 2017.

Compliance with ethical standards

Conflict of interest

None of the contributing authors have any conflict of interest.

References

  1. 1.
    Huang CW, Moore PK (2015) H2S synthesizing enzymes: biochemistry and molecular aspects. Handb Exp Pharmacol 230:3–25CrossRefGoogle Scholar
  2. 2.
    Kimura H (2015) Signaling molecules: hydrogen sulfide and polysulfide. Antioxid Redox Signal 22:362–376CrossRefGoogle Scholar
  3. 3.
    Gemici B, Elsheikh W, Feitosa KB et al (2015) H2S-releasing drugs: anti-inflammatory, cytoprotective and chemopreventative potential. Nitric Oxide 46:25–31CrossRefGoogle Scholar
  4. 4.
    Kimura H (2014) The physiological role of hydrogen sulfide and beyond. Nitric Oxide 41:4–10CrossRefGoogle Scholar
  5. 5.
    Yang G, Wu L, Jiang B et al (2008) H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine γ-lyase. Science 322:587–590CrossRefGoogle Scholar
  6. 6.
    Ozatik FY, Teksen Y, Kadioglu E et al (2019) Effects of hydrogen sulfide on acetaminophen-induced acute renal toxicity in rats. Int Urol Nephrol 51:745–754CrossRefGoogle Scholar
  7. 7.
    Fernandes VS, Xin W, Petkov GV (2015) Novel mechanism of hydrogen sulfide-induced guinea pig urinary bladder smooth muscle contraction: role of BK channels and cholinergic neurotransmission. Am J Physiol Cell Physiol 309:C107–C116CrossRefGoogle Scholar
  8. 8.
    Patacchini R, Santicioli P, Giuliani S et al (2005) Pharmacological investigation of hydrogen sulfide (H2S) contractile activity in rat detrusor muscle. Eur J Pharmacol 509:171–177CrossRefGoogle Scholar
  9. 9.
    Fernandes VS, Ribeiro AS, Martínez MP et al (2013) Endogenous hydrogen sulfide has a powerful role in inhibitory neurotransmission to the pig bladder neck. J Urol 189:1567–1573CrossRefGoogle Scholar
  10. 10.
    Gai JW, Wahafu W, Guo H et al (2013) Further evidence of endogenous hydrogen sulphide as a mediator of relaxation in human and rat bladder. Asian J Androl 15:692–696CrossRefGoogle Scholar
  11. 11.
    Zou S, Shimizu T, Shimizu S et al (2018) Possible role of hydrogen sulfide as an endogenous relaxation factor in the rat bladder and prostate. Neurourol Urodyn 37:2519–2526CrossRefGoogle Scholar
  12. 12.
    Azadzoi KM, Tarcan T, Kozlowski R et al (1999) Overactivity and structural changes in the chronically ischemic bladder. J Urol 162:1768–1778CrossRefGoogle Scholar
  13. 13.
    Nomiya M, Sagawa K, Yazaki J et al (2012) Increased bladder activity is associated with elevated oxidative stress markers and proinflammatory cytokines in a rat model of atherosclerosis-induced chronic bladder ischemia. Neurourol Urodyn 31:185–189CrossRefGoogle Scholar
  14. 14.
    Pinggera GM, Mitterberger M, Steiner E et al (2008) Association of lower urinary tract symptoms and chronic ischaemia of the lower urinary tract in elderly women and men: assessment using colour Doppler ultrasonography. BJU Int 102:470–474CrossRefGoogle Scholar
  15. 15.
    Pinggera GM, Mitterberger M, Pallwein L et al (2008) α-Blockers improve chronic ischaemia of the lower urinary tract in patients with lower urinary tract symptoms. BJU Int 101:319–324CrossRefGoogle Scholar
  16. 16.
    Shimizu S, Tsounapi P, Shimizu T et al (2014) Lower urinary tract symptoms, benign prostatic hyperplasia/benign prostatic enlargement and erectile dysfunction: are these conditions related to vascular dysfunction? Int J Urol 21:856–864CrossRefGoogle Scholar
  17. 17.
    Tarcan T, Azadzoi KM, Siroky MB et al (1998) Age-related erectile and voiding dysfunction: the role of arterial insufficiency. Br J Urol 82(Suppl 1):26–33CrossRefGoogle Scholar
  18. 18.
    Yono M, Yamamoto Y, Yoshida M et al (2007) Effects of doxazosin on blood flow and mRNA expression of nitric oxide synthase in the spontaneously hypertensive rat genitourinary tract. Life Sci 81:218–222CrossRefGoogle Scholar
  19. 19.
    Yono M, Tanaka T, Tsuji S et al (2011) Effects of age and hypertension on α1-adrenoceptors in the major source arteries of the rat bladder and penis. Eur J Pharmacol 670:260–265CrossRefGoogle Scholar
  20. 20.
    Jin JH, Lee HJ, Shin HY et al (2011) Development and changes with age of detrusor overactivity in spontaneous hypertensive rats as observed by simultaneous registrations of intravesical and intraabdominal pressures. Int Neurourol J 15:192–198CrossRefGoogle Scholar
  21. 21.
    Persson K, Pandita RK, Spitsbergen JM et al (1998) Spinal and peripheral mechanisms contributing to hyperactive voiding in spontaneously hypertensive rats. Am J Physiol 275:R1366–R1373Google Scholar
  22. 22.
    Steers WD, Clemow DB, Persson K et al (1999) The spontaneously hypertensive rat: insight into the pathogenesis of irritative symptoms in benign prostatic hyperplasia and young anxious males. Exp Physiol 84:137–147CrossRefGoogle Scholar
  23. 23.
    Inoue S, Saito M, Tsounapi P et al (2012) Effect of silodosin on detrusor overactivity in the male spontaneously hypertensive rat. BJU Int 110:E118–E124CrossRefGoogle Scholar
  24. 24.
    Saito M, Ohmasa F, Tsounapi P et al (2012) Nicorandil ameliorates hypertension-related bladder dysfunction in the rat. Neurouro Urodyn 31:695–701CrossRefGoogle Scholar
  25. 25.
    Swan KW, Song BM, Chen AL et al (2017) Analysis of decreases in systemic arterial pressure and heart rate in response to the hydrogen sulfide donor sodium sulfide. Am J Phsiol Heart Circ Physiol 313:H732–H743CrossRefGoogle Scholar
  26. 26.
    Yan H, Du J, Tang C (2004) The possible role of hydrogen sulfide on the pathogenesis of spontaneous hypertension in rats. Biochem Biophys Res Commun 313:22–27CrossRefGoogle Scholar
  27. 27.
    Yu W, Liao Y, Huang Y et al (2017) Endogenous hydrogen sulfide enhances carotid sinus baroreceptor sensitivity by activating the transient receptor potential cation channel subfamily V member 1 (TRPV1) channel. J Am Heart Assoc 6:e004971Google Scholar
  28. 28.
    Saito M, Tsounapi P, Oikawa R et al (2014) Prostatic ischemia induces ventral prostatic hyperplasia in the SHR; possible mechanism of development of BPH. Sci Rep 4:3822CrossRefGoogle Scholar
  29. 29.
    Szabo C, Papapetropoulos A (2017) International union of basic and clinical pharmacology. CII: pharmacological modulation of H2S levels: H2S donors and H2S biosynthesis inhibitors. Pharmacol Rev 69:497–564CrossRefGoogle Scholar
  30. 30.
    Saito M, Shimizu S, Kinoshita Y et al (2010) Bladder dysfunction after acute urinary retention in the rats: a novel over active bladder model. Mol Cell Biochem 333:109–114CrossRefGoogle Scholar
  31. 31.
    Mok YY, Atan MS, Yoke Ping C et al (2004) Role of hydrogen sulphide in haemorrhagic shock in the rat: protective effect of inhibitors of hydrogen sulphide biosynthesis. Br J Pharmacol 143:881–889CrossRefGoogle Scholar
  32. 32.
    Saito M, Tominaga L, Nanba E et al (2005) Expression of HSP 70 and its mRNAS during ischemia-reperfusion in the rat bladder. Life Sci 75:1879–1886CrossRefGoogle Scholar
  33. 33.
    Fukuda S, Tsuchikura S, Iida H (2004) Age-related changes in blood pressure, hematological values, concentrations of serum biochemical constituents and weights of organs in the SHR/Izm, SHRSP/Izm and WKY/Izm. Exp Anim 53:67–72CrossRefGoogle Scholar
  34. 34.
    Berenyiova A, Drobna M, Cebova M et al (2018) Changes in the vasoactive effects of nitric oxide, hydrogen sulfide and the structure of the rat thoracic aorta: the role of age and essential hypertension. J Physiol Pharmacol 69:1–12Google Scholar
  35. 35.
    de Groat WC (1997) Neurologic basis for the overactive bladder. Urology 50:36–56CrossRefGoogle Scholar
  36. 36.
    Leon LA, Hoffman BE, Gardner SD et al (2008) Effects of the β3-adrenergic receptor agonist disodium 5-[(2R)-2-[[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL-316243) on bladder micturition reflex in spontaneously hypertensive rats. J Pharmacol Exp Ther 326:178–185CrossRefGoogle Scholar
  37. 37.
    Sun Y, Huang Y, Zhang R et al (2015) Hydrogen sulfide upregulates KATP channel expression in vascular smooth muscle cells of spontaneously hypertensive rats. J Mol Med 93:439–455CrossRefGoogle Scholar
  38. 38.
    Zhao X, Zhang LK, Zhang CY et al (2008) Regulatory effect of hydrogen sulfide on vascular collagen content in spontaneously hypertensive rats. Hypertens Res 31:1619–1630CrossRefGoogle Scholar
  39. 39.
    Szabo C (2017) Hydrogen sulfide, an enhancer of vascular nitric oxide signaling: mechanisms and implications. Am J Physiol Cell Physiol 312:C3–C15CrossRefGoogle Scholar
  40. 40.
    Fujiwara M, Andersson K, Persson K (2000) Nitric oxide-induced cGMP accumulation in the mouse bladder is not related to smooth muscle relaxation. Eur J Pharmacol 401:241–250CrossRefGoogle Scholar
  41. 41.
    Mamas MA, Reynard JM, Brading AF (2003) Nitric oxide and the lower urinary tract: current concepts, future prospects. Urology 61:1079–1085CrossRefGoogle Scholar
  42. 42.
    Ozawa H, Chancellor MB, Jung SY et al (1999) Effect of intravesical nitric oxide therapy on cyclophosphamide-induced cystitis. J Urol 162:2211–2216CrossRefGoogle Scholar
  43. 43.
    Yu Y, de Groat WC (2013) Nitric oxide modulates bladder afferent nerve activity in the in vitro urinary bladder-pelvic nerve preparation from rats with cyclophosphamide induced cystitis. Brain Res 1490:83–94CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Pharmacology, Kochi Medical SchoolKochi UniversityNankokuJapan

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