Skip to main content
SpringerLink
Log in

Enalapril reduces germ cell toxicity in streptozotocin-induced diabetic rat: investigation on possible mechanisms

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

Abstract

Diabetes mellitus, a state of persistent hyperglycemia, is a major cause of micro- and macrovascular diseases. It affects nearly every system in the body including the reproductive system. Abnormalities in spermatogenesis and sexual function have been documented in animal models for both types of diabetes. The purpose of the present study is to determine the possible protective effects of enalapril against the germ cell toxicity in diabetic rat. Sprague–Dawley rats were divided into four groups: (1) control, (2) control + enalapril, (3) diabetic, and (4) diabetic + enalapril. Enalapril was administered per orally for 4 and 8 weeks continuously. After the treatment, animals were sacrificed and blood glucose level, sperm count, sperm DNA damage, apoptotic cell death, immunohistochemistry of 8-oxo- 7,8-dihydro- 2′-deoxyguanosine, and the cellular toxicity were performed. Furthermore, western blotting was performed to evaluate the expression of NFκB and COX-2 in testes. The results of the present study indicate that intervention of enalapril ameliorates the sperm DNA damage, reduces the oxidative stress, and down-regulates the expression of NFκB and COX-2 expression in streptozotocin-induced diabetic rat.

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
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Agarwal A, Said TM (2005) Oxidative stress, DNA damage and apoptosis in male infertility: a clinical approach. BJU Int 95(4):503–507

    Article  PubMed  CAS  Google Scholar 

  • Agarwal A, Gupta S, Sikka S (2006) The role of free radicals and antioxidants in reproduction. Curr Opin Obstet Gynecol 18(3):325–332

    Article  PubMed  Google Scholar 

  • Agbaje IM, Rogers DA, McVicar CM, McClure N, Atkinson AB, Mallidis C, Lewis SE (2007) Insulin dependant diabetes mellitus: implications for male reproductive function. Hum Reprod 22(7):1871–1877

    Article  PubMed  CAS  Google Scholar 

  • Aitken RJ, Gordon E, Harkiss D, Twigg JP, Milne P, Jennings Z, Irvine DS (1998) Relative impact of oxidative stress on the functional competence and genomic integrity of human spermatozoa. Biol Reprod 59(5):1037–1046

    Article  PubMed  CAS  Google Scholar 

  • Al-Aubaidy HA, Jelinek HF (2010) 8-Hydroxy-2-deoxy-guanosine identifies oxidative DNA damage in a rural prediabetes cohort. Redox Rep 15(4):155–160

    Article  PubMed  CAS  Google Scholar 

  • Arun KH, Kaul CL, Ramarao P (2005) AT1 receptors and L-type calcium channels: functional coupling in supersensitivity to angiotensin II in diabetic rats. Cardiovasc Res 65(2):374–386

    Article  PubMed  CAS  Google Scholar 

  • Bain SC, Le Guen CA, Lunec J, Barnett AH (1991) Comparison of the free radical scavenging activity of captopril versus enalapril: a three month in vivo study in hypertensive diabetic patients. J Hum Hypertens 5(6):511–515

    PubMed  CAS  Google Scholar 

  • Baluchnejadmojarad T, Roghani M, Imani A (2004) Protective effect of enalapril on vascular reactivity of the rat aorta. Vascul Pharmacol 40(6):301–307

    Article  PubMed  CAS  Google Scholar 

  • Blankfield RP (2002) Angiotensin-receptor blockers, type 2 diabetes, and renoprotection. N Engl J Med 346(9):705–707

    Article  PubMed  Google Scholar 

  • Brown CD, Forman CL, McEuen SF, Miller MG (1994) Metabolism and testicular toxicity of 1,3-dinitrobenzene in rats of different ages. Fundam Appl Toxicol 23(3):439–446

    Article  PubMed  CAS  Google Scholar 

  • Burruel VR, Yanagimachi R, Whitten WK (1996) Normal mice develop from oocytes injected with spermatozoa with grossly misshapen heads. Biol Reprod 55(3):709–714

    Article  PubMed  CAS  Google Scholar 

  • Burul-Bozkurt N, Pekiner C, Kelicen P (2010) Diabetes alters aromatase enzyme levels in gonadal tissues of rats. Naunyn Schmiedebergs Arch Pharmacol 382(1):33–41

    Article  PubMed  CAS  Google Scholar 

  • Cai L, Chen S, Evans T, Deng DX, Mukherjee K, Chakrabarti S (2000) Apoptotic germ-cell death and testicular damage in experimental diabetes: prevention by endothelin antagonism. Urol Res 28(5):342–347

    Article  PubMed  CAS  Google Scholar 

  • Caneguim BH, Cerri PS, Spolidorio LC, Miraglia SM, Sasso-Cerri E (2009) Structural alterations in the seminiferous tubules of rats treated with immunosuppressor tacrolimus. Reprod Biol Endocrinol 7:19

    Article  PubMed  Google Scholar 

  • Ceriello A, Motz E (2002) Angiotensin-receptor blockers, type 2 diabetes, and renoprotection. N Engl J Med 346(9):705–707

    Article  PubMed  Google Scholar 

  • Chen SX, Song T, Zhou SH, Liu YH, Wu SJ, Liu LY (2008) Protective effects of ACE inhibitors on vascular endothelial dysfunction induced by exogenous advanced oxidation protein products in rats. Eur J Pharmacol 584(2–3):368–375

    Article  PubMed  CAS  Google Scholar 

  • Costa JC, Costa RS, Silva CG, Coimbra TM (2006) Enalapril reduces the expression of nuclear factor-kappaB and c-Jun N-terminal kinase in the renal cortices of five-sixths-nephrectomized rats. Am J Nephrol 26(3):281–286

    Article  PubMed  CAS  Google Scholar 

  • Cozzoli A, Nico B, Sblendorio VT, Capogrosso RF, Dinardo MM, Longo V, Gagliardi S, Montagnani M, De Luca A (2011) Enalapril treatment discloses an early role of angiotensin II in inflammation- and oxidative stress-related muscle damage in dystrophic mdx mice. Pharmacol Res 64(5):482–492

    Article  PubMed  CAS  Google Scholar 

  • de Cavanagh EM, Inserra F, Ferder L, Romano L, Ercole L, Fraga CG (1995) Superoxide dismutase and glutathione peroxidase activities are increased by enalapril and captopril in mouse liver. FEBS Lett 361(1):22–24

    Article  PubMed  Google Scholar 

  • de Cavanagh EM, Inserra F, Ferder L, Fraga CG (2000) Enalapril and captopril enhance glutathione-dependent antioxidant defenses in mouse tissues. Am J Physiol Regul Integr Comp Physiol 278(3):R572–R577

    PubMed  Google Scholar 

  • de Cavanagh EM, Inserra F, Toblli J, Stella I, Fraga CG, Ferder L (2001) Enalapril attenuates oxidative stress in diabetic rats. Hypertension 38(5):1130–1136

    Article  PubMed  Google Scholar 

  • de Cavanagh EM, Piotrkowski B, Basso N, Stella I, Inserra F, Ferder L, Fraga CG (2003) Enalapril and losartan attenuate mitochondrial dysfunction in aged rats. FASEB J 17(9):1096–1098

    PubMed  Google Scholar 

  • de Cavanagh EM, Flores I, Ferder M, Inserra F, Ferder L (2008) Renin–angiotensin system inhibitors protect against age-related changes in rat liver mitochondrial DNA content and gene expression. Exp Gerontol 43(10):919–928

    Article  PubMed  Google Scholar 

  • Duarte J, Martinez A, Bermejo A, Vera B, Gamez MJ, Cabo P, Zarzuelo A (1999) Cardiovascular effects of captopril and enalapril in obese Zucker rats. Eur J Pharmacol 365(2–3):225–232

    Article  PubMed  CAS  Google Scholar 

  • Eidem I, Stene LC, Henriksen T, Hanssen KF, Vangen S, Vollset SE, Joner G (2010) Congenital anomalies in newborns of women with type 1 diabetes: nationwide population-based study in Norway, 1999–2004. Acta Obstet Gynecol Scand 89(11):1403–1411

    Article  PubMed  Google Scholar 

  • Evans MD, Cooke MS (2004) Factors contributing to the outcome of oxidative damage to nucleic acids. Bioessays 26(5):533–542

    Article  PubMed  CAS  Google Scholar 

  • Ghorbanihaghjo A, Veisi P, Argani H, Aghaeishahsavari M, Noroozianavval M, Rashtchizadeh N, Mesgari M, Safa J, Babaei H (2008) Prevention of DNA damage in renal transplantation by losartan and enalapril: the role of renin–angiotensin system polymorphisms. Clin Exp Nephrol 12(1):65–73

    Article  PubMed  CAS  Google Scholar 

  • Griveau JF, Dumont E, Renard P, Callegari JP, Le Lannou D (1995) Reactive oxygen species, lipid peroxidation and enzymatic defence systems in human spermatozoa. J Reprod Fertil 103(1):17–26

    Article  PubMed  CAS  Google Scholar 

  • Haines GA, Hendry JH, Daniel CP, Morris ID (2002) Germ cell and dose-dependent DNA damage measured by the comet assay in murine spermatozoaa after testicular X-irradiation. Biol Reprod 67(3):854–861

    Article  PubMed  CAS  Google Scholar 

  • Ishikawa T, Fujioka H, Ishimura T, Takenaka A, Fujisawa M (2007) Increased testicular 8-hydroxy-2′-deoxyguanosine in patients with varicocele. BJU Int 100(4):863–866

    Article  PubMed  CAS  Google Scholar 

  • Jackson G (2004) Sexual dysfunction and diabetes. Int J Clin Pract 58(4):358–362

    Article  PubMed  CAS  Google Scholar 

  • Kakimoto M, Inoguchi T, Sonta T, Yu HY, Imamura M, Etoh T, Hashimoto T, Nawata H (2002) Accumulation of 8-hydroxy-2′-deoxyguanosine and mitochondrial DNA deletion in kidney of diabetic rats. Diabetes 51(5):1588–1595

    Article  PubMed  CAS  Google Scholar 

  • Kishikawa H, Tateno H, Yanagimachi R (1999) Chromosome analysis of BALB/c mouse spermatozoa with normal and abnormal head morphology. Biol Reprod 61(3):809–812

    Article  PubMed  CAS  Google Scholar 

  • Kodama H, Yamaguchi R, Fukuda J, Kasai H, Tanaka T (1997) Increased oxidative deoxyribonucleic acid damage in the spermatozoa of infertile male patients. Fertil Steril 68(3):519–524

    Article  PubMed  CAS  Google Scholar 

  • Koh PO (2007a) Streptozotocin-induced diabetes increases apoptosis through JNK phosphorylation and Bax activation in rat testes. J Vet Med Sci 69(9):969–971

    Article  PubMed  CAS  Google Scholar 

  • Koh PO (2007b) Streptozotocin-induced diabetes increases the interaction of Bad/Bcl-XL and decreases the binding of pBad/14-3-3 in rat testis. Life Sci 81(13):1079–1084

    Article  PubMed  CAS  Google Scholar 

  • Kushwaha S, Vikram A, Jena GB (2011) Protective effects of enalapril in streptozotocin-induced diabetic rat: studies of DNA damage, apoptosis and expression of CCN2 in the heart, kidney and liver. J Appl Toxicol

  • Mughal MZ, Eelloo J, Roberts SA, Maresh M, Ward KA, Ashby R, Sibley CP, Adams JE (2010) Body composition and bone status of children born to mothers with type 1 diabetes mellitus. Arch Dis Child 95(4):281–285

    PubMed  CAS  Google Scholar 

  • Munzel T, Keaney JF Jr (2001) Are ACE inhibitors a "magic bullet" against oxidative stress? Circulation 104(13):1571–1574

    Article  PubMed  CAS  Google Scholar 

  • Murray FT, Cameron DF, Orth JM (1983) Gonadal dysfunction in the spontaneously diabetic BB rat. Metabolism 32(7 Suppl 1):141–147

    Article  PubMed  CAS  Google Scholar 

  • National High Blood Pressure Education Program (NHBPEP) Working Group (1994) National High Blood Pressure Education Program Working Group report on hypertension in diabetes. Hypertension 23(2):145–158

    Google Scholar 

  • Neeraja S, Sreenath AS, Reddy PR, Reddanna P (2003) Expression of cyclooxygenase-2 in rat testis. Reprod Biomed Online 6(3):302–309

    Article  PubMed  CAS  Google Scholar 

  • Ricci G, Catizone A, Esposito R, Pisanti FA, Vietri MT, Galdieri M (2009) Diabetic rat testes: morphological and functional alterations. Andrologia 41(6):361–368

    Article  PubMed  CAS  Google Scholar 

  • Rossi A, Kapahi P, Natoli G, Takahashi T, Chen Y, Karin M, Santoro MG (2000) Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase. Nature 403(6765):103–108

    Article  PubMed  CAS  Google Scholar 

  • Sakai Y, Aminaka M, Takata A, Kudou Y, Yamauchi H, Aizawa Y, Sakagami H (2010) Oxidative stress in mature rat testis and its developmental changes. Dev Growth Differ 52(7):657–663

    Article  PubMed  CAS  Google Scholar 

  • Savoia C, Schiffrin EL (2007) Vascular inflammation in hypertension and diabetes: molecular mechanisms and therapeutic interventions. Clin Sci (Lond) 112(7):375–384

    Article  CAS  Google Scholar 

  • Scarano WR, Messias AG, Oliva SU, Klinefelter GR, Kempinas WG (2006) Sexual behaviour, sperm quantity and quality after short-term streptozotocin-induced hyperglycaemia in rats. Int J Androl 29(4):482–488

    Article  PubMed  CAS  Google Scholar 

  • Schmid U, Stopper H, Schweda F, Queisser N, Schupp N (2008) Angiotensin II induces DNA damage in the kidney. Cancer Res 68(22):9239–9246

    Article  PubMed  CAS  Google Scholar 

  • Shanmugam N, Gaw Gonzalo IT, Natarajan R (2004) Molecular mechanisms of high glucose-induced cyclooxygenase-2 expression in monocytes. Diabetes 53(3):795–802

    Article  PubMed  CAS  Google Scholar 

  • Sikka SC (2001) Relative impact of oxidative stress on male reproductive function. Curr Med Chem 8(7):851–862

    PubMed  CAS  Google Scholar 

  • Sun JG, Jurisicova A, Casper RF (1997) Detection of deoxyribonucleic acid fragmentation in human sperm: correlation with fertilization in vitro. Biol Reprod 56(3):602–607

    Article  PubMed  CAS  Google Scholar 

  • Tattersall R (1982) Sexual problems of diabetic men. Br Med J (Clin Res Ed) 285(6346):911–912

    Article  CAS  Google Scholar 

  • Tokunaga I, Gotohda T, Ishigami A, Kitamura O, Kubo S (2003) Toluene inhalation induced 8-hydroxy-2′-deoxyguanosine formation as the peroxidative degeneration in rat organs. Leg Med (Tokyo) 5(1):34–41

    Article  CAS  Google Scholar 

  • Tripathi DN, Jena GB (2009) Intervention of astaxanthin against cyclophosphamide-induced oxidative stress and DNA damage: a study in mice. Chem Biol Interact 180(3):398–406

    Article  PubMed  CAS  Google Scholar 

  • Varin R, Mulder P, Tamion F, Richard V, Henry JP, Lallemand F, Lerebours G, Thuillez C (2000) Improvement of endothelial function by chronic angiotensin-converting enzyme inhibition in heart failure: role of nitric oxide, prostanoids, oxidant stress, and bradykinin. Circulation 102(3):351–356

    PubMed  CAS  Google Scholar 

  • Vikram A, Tripathi DN, Ramarao P, Jena GB (2008) Intervention of d-glucose ameliorates the toxicity of streptozotocin in accessory sex organs of rat. Toxicol Appl Pharmacol 226(1):84–93

    Article  PubMed  CAS  Google Scholar 

  • Walser M (2002) Angiotensin-receptor blockers, type 2 diabetes, and renoprotection. N Engl J Med 346(9):705–707

    Article  PubMed  Google Scholar 

  • Yamazaki T, Tanimoto M, Gohda T, Ohara I, Hagiwara S, Murakoshi M, Matsumoto M, Kaneko S, Aoki T, Toyoda H, Ishikawa Y, Funabiki K, Horikoshi S, Tomino Y (2009) Combination effects of enalapril and losartan on lipid peroxidation in the kidneys of KK-Ay/Ta mice. Nephron Exp Nephrol 113(2):e66–e76

    Article  PubMed  CAS  Google Scholar 

  • Yao LS, Wang YT, Chen Y, Dai YT (2009) Expressions of NOS isoforms in the cavernous tissues of diabetic rat models. Zhonghua Nan Ke Xue 15(10):915–919

    PubMed  CAS  Google Scholar 

  • Zemel P (1988) Sexual dysfunction in the diabetic patient with hypertension. Am J Cardiol 61(16):27H–33H

    Article  PubMed  CAS  Google Scholar 

  • Zhang BQ, Huang YS, Zhang JP, Zhang DX, Dang YM, Wang G, Hu JY, Lei ZY, Xiao R (2007) Protective effects of administration of enalapril maleate on rat myocardial damage in early stage of burns. Zhonghua Shao Shang Za Zhi 23(5):335–338

    PubMed  CAS  Google Scholar 

  • Zhu JH, Jia RP, Xu LW, Wu JP, Wang ZZ, Wang SK, Bo CJ (2010) Reduced expression of SK3 and IK1 channel proteins in the cavernous tissue of diabetic rats. Asian J Androl 12(4):599–604

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We wish to acknowledge the financial assistance received from the Department of Science and Technology (DST), India (vide letter no. SR/SO/HS-83/2008) for the present work. Furthermore, the financial assistance received from the National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar, Mohali, Punjab, India is duly acknowledged.

Author information

Authors and Affiliations

  1. Facility for Risk Assessment & Intervention Studies Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S, Nagar, Punjab, 160062, India

    S. Kushwaha & G. B. Jena

Authors
  1. S. Kushwaha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. B. Jena
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G. B. Jena.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kushwaha, S., Jena, G.B. Enalapril reduces germ cell toxicity in streptozotocin-induced diabetic rat: investigation on possible mechanisms. Naunyn-Schmiedeberg's Arch Pharmacol 385, 111–124 (2012). https://doi.org/10.1007/s00210-011-0707-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-011-0707-x

Keywords

Search

Navigation