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Ovarektomize Dişi Sıçanlarda 1,1-Dimetilbiguanit Hidroklorid (Metformin)'in Detrüsör Kas Kontraktil Yanıtı Üzerine Etkileri

Yıl 2022, Cilt: 6 Sayı: 2, 97 - 103, 31.08.2022
https://doi.org/10.25048/tudod.1066739

Öz

Amaç: Menopoz, yumurtalık foliküler rezervinin tükenmesi ve ardından adet döngüsünün durması olarak tanımlanır. Kadınlarda
gonadal steroid hormonlarının mesane fonksiyonunda önemli rol oynadığı bildirilmiştir. Menopozun bir sonucu olarak idrar düzeninde
değişiklikler meydana gelir. 1,1-dimetilbiguanid hidroklorür, metformin (MET), hepatik glukoz üretimini ve periferik insülin direncini
azaltmak için kullanılan oral bir anti-diyabetik ilaçtır. Son zamanlarda yapılan çalışmalar, MET'in diyabetin neden olduğu mesane
disfonksiyonunda koruyucu etkileri olduğunu ortaya koymuştur. Bu çalışmanın amacı, yumurtalıkları alınmış (OVX) dişi sıçanların
detrusor kasılma fonksiyonunda MET'nin terapötik potansiyelini değerlendirmektir. Gereç ve Yöntemler: Endojen gonadal steroid sekresyonunu ortadan kaldırmak için bilateral ovariektomi yapıldı. Her grupta 8 hayvan
olacak şekilde dört grup tasarlanmıştır: Kontrol, MET uygulanan kontrol, OVX ve MET uygulanan OVX grupları. MET (25 mg/kg) 14
gün boyunca oral gavaj yoluyla günlük olarak uygulandı. İzole mesane kas şeritlerinin kontraktil aktivitesi in vitro organ banyosunda
değerlendirildi. Detrusor şeritlerinin kasılma yanıtları, farklı dozlarda karbakol (10-8-10-2M) ve purinerjik agonist ATP kullanılarak
belirlendi. Striplerin gevşeme yanıtı izoproterenol ile değerlendirildi.
Bulgular: Detrusor kas şeritlerinin 10-5-10-2 M dozlarda karbakole olan kontraktil yanıtları, OVX grubunda, kontrol ve MET ile tedavi
edilen kontrol gruplarına kıyasla azaldı. MET tedavisi, 10-2 ve 10-3 M karbakol dozlarında OVX'in neden olduğu kasılma cevaplarındaki
azalmayı kısmen tersine çevirdi. Deney grupları arasında gevşeme yanıtında istatistiksel olarak anlamlı bir fark yoktu.
Sonuç: Bulgularımız, MET ile tedavinin postmenopozal kadınlarda mesane fonksiyon bozukluğuna karşı yeni potansiyel terapötik ajan
olabileceğini düşündürmektedir. Menopozun neden olduğu detrusor disfonksiyonunda MET'nin terapötik potansiyeli için daha ileri
çalışmalara ihtiyaç vardır.

Kaynakça

  • 1.Bruce D, Rymer J. Symptoms of the menopause. Best Pract Res Clin Obstet Gynaecol. 2009; 23:25–32.
  • 2. Ramos-Filho AC, Faria J, Calmasini FB, Teixeira SA, Mónica FZ, Muscará MN, Gontijo JA, Anhê GF, Zanesco A, Antunes E. The renin-angiotensin system plays a major role in voiding dysfunction of ovariectomized rats. Life Sci. 2013;93(22):820-9.
  • 3. Breyer BN, Wang G, Lin G, Shindel AW, Yang R, Lin CS, Lue TF. The effect of long-term hormonal treatment on voiding patterns during filling cystometry and on urethral histology in a postpartum, ovariectomized female rat. BJU Int. 2010;106(11):1775-81.
  • 4. Chen Y, Yu W, Yang Y, Duan J, Xiao Y, Zhang X, Wu S, Bai W. Association between overactive bladder and peri-menopause syndrome: a cross-sectional study of female physicians in China. Int Urol Nephrol. 2015;47(5):743-9.
  • 5. Medina-Aguiñaga D, Munoz A, Luna M, Martinez-Moreno CG, Quintanar-Stephano A, Quintanar JL. Administration of leuprolide acetate, a GnRH agonist, improves urodynamic parameters in ovariectomized rats. Neurourol Urodyn. 2018;37(5):1574-1582.
  • 6. Liang W, Afshar K, Stothers L, Laher I. The influence of ovariectomy and estrogen replacement on voiding patterns and detrusor muscarinic receptor affinity in the rat. Life Sci. 2002;71(3):351-62.
  • 7. Bonilla-Becerra SM, de Oliveira MG, Calmasini FB, Rojas-Moscoso JA, Zanesco A, Antunes E. Micturition dysfunction in four-month old ovariectomized rats: Effects of testosterone replacement. Life Sci. 2017;179:120-129.
  • 8. Chuang SM, Long CY, Lin RJ, Liu KM, Levin RM, Chang CY, Ho YW, Wu WJ, Chang WC, Juan YS. Protective effects of estrogen on ischemia/reperfusion-induced bladder dysfunction in female rabbits. Menopause. 2013;20(2):209-17.
  • 9. Long CY, Liu CM, Hsu SC, Chen YH, Wu CH, Tsai EM. A randomized comparative study of the effects of oral and topical estrogen therapy on the lower urinary tract of hysterectomized postmenopausal women. Fertil Steril. 2006;85(1):155-60.
  • 10. Shamliyan TA, Kane RL, Wyman J, Wilt TJ. Systematic review: randomized, controlled trials of nonsurgical treatments for urinary incontinence in women. Ann Intern Med. 2008;148(6):459-73.
  • 11. Yang S, Chen X, Xu Y, Hao Y, Meng X. Effects of metformin on lipopolysaccharide-induced depressive-like behavior in mice and its mechanisms. Neuroreport. 2020;31(4):305-310.
  • 12. Shivavedi N, Kumar M, Tej GNVC, Nayak PK. Metformin and ascorbic acid combination therapy ameliorates type 2 diabetes mellitus and comorbid depression in rats. Brain Res. 2017;1674:1-9.
  • 13. Engin S, Barut EN, Soysal AC, Keskin O, Kerimoglu G, Kadioglu M, Sezen S. Double benefit of metformin treatment: improved bladder function in cyclophosphamide-induced cystitis and enhanced cytotoxicity in cancer cells. Naunyn Schmiedebergs Arch Pharmacol. 2021;394(6):1167-1175.
  • 14. Daneshgari F, Liu G, Birder L, Hanna-Mitchell AT, Chacko S. Diabetic bladder dysfunction: current translational knowledge. J Urol 2009;182(Suppl.):S18–S26.
  • 15. Bolat MS, Bilge SS, Akdeniz E, Cinar O, Firat F, Agri AE, Bakirtas M, Alici O, Erdemir F. Effect of a Carbohydrate- Rich Diet on Rat Detrusor Smooth Muscle Contractility: An Experimental Study. Biomed Res Int 2017;2017:5796456.
  • 16. Wróbel A, Łańcut M, Rechberger T. A new model of detrusor overactivity in conscious rats induced by retinyl acetate instillation. J Pharmacol Toxicol Methods. 2015;74:7-16.
  • 17. Ozacmak VH, Barut F, Ozacmak HS. Melatonin provides neuroprotection by reducing oxidative stress and HSP70 expression during chronic cerebral hypoperfusion in ovariectomized rats. J Pineal Res. 2009;47(2):156-163.
  • 18. Ekiz A, Özdemir-Kumral ZN, Erşahin M, Tuğtepe H, Öğünç AV, Akakın D, Kıran D, Özsavcı D, Biber N, Hakan T, Yeğen BÇ, Şener G, Toklu HZ. Functional and structural changes of the urinary bladder following spinal cord injury; treatment with alpha lipoic acid. Neurourol Urodyn. 2017;36(4):1061- 1068.
  • 19. Kume-Kick J, Ferris DC, Russo-Menna I, Rice ME. Enhanced oxidative stress in female rat brain after gonadectomy. Brain Res. 1996; 28;738(1):8-14.
  • 20. Juan YS, Chuang SM, Long CY, Chen CH, Levin RM, Liu KM, Huang CH. Neuroprotection of green tea catechins on surgical menopause-induced overactive bladder in a rat model. Menopause. 2012;19(3):346-354.
  • 21. Kim SO, Song SH, Ahn KY, Kwon DD. Distribution of interstitial cells of cajal in menopausal rat urinary bladder showing detrusor overactivity. Int Neurourol J. 2010; 14(1):48- 53.
  • 22. Zhu Q, Ritchie J, Marouf N, Dion SB, Resnick NM, Elbadawi A, Kuchel GA. Role of ovarian hormones in the pathogenesis of impaired detrusor contractility: Evidence in ovariectomized rodents. J Urol 2001; 166: 1136- 1141.
  • 23. Etiz Sayharman S, Tosun N, Aka N, Köse G, Tekin A, Gören Z. Effects of combined estrogen and progesterone replacement treatment on detrusor contractility and histology in oophorectomized rats. J Obstet Gynaecol Res. 2011;37(11):1638-1644.
  • 24. Rehfuss A, Schuler C, Maxemous C, Leggett RE, Levin RM. Cyclical estrogen and free radical damage to the rabbit urinary bladder. Int Urogynecol J. 2010;21(4):489-494
  • 25. Bassiouni W, Daabees T, Norel X, Senbel AM. Hypoactivity of rat detrusor muscle in a moel of cystitis: exacerbation by nonselective COX inhibitors and amelioration by a selective DP1 receptor antagonist. Naunyn Schmiedebergs Arch Pharmacol. 2019;392(4):437-450.
  • 26. Owen SJ, Rose’Meyer RB, Massa HM. Dietary phytoestrogens maintain contractile responses to carbachol with age in the female rat isolated bladder. Life Sci. 2011; 15;89(7-8):213-220.
  • 27. Fatemi I, Saeed-Askari P, Hakimizadeh E, Kaeidi A, Esmaeil- Moghaddam S, Pak-Hashemi M, Allahtavakoli M. Long-term metformin therapy improves neurobehavioral functions and antioxidative activity after cerebral ischemia/reperfusion injury in rats. Brain Res Bull. 2020;163:65-71.
  • 28. Zakeri M, Fatemi I, Kaeidi A, Zakeri MA, Hakimizadeh E, Hassanipour M, Rahmani M, Hassanshahi J, Ayoobi F, Allahtavakoli M. Pro-neurocognitive and anti-sarcopenic benefits of one-year metformin therapy in ovariectomized aged mice. Clin Exp Pharmacol Physiol. 2019 ;46(12):1133- 1140.
  • 29. Yasmin T, Rahman MM, Khan F, Kabir F, Nahar K, Lasker S, Islam MD, Hossain MM, Hasan R, Rana S, Alam MA. Metformin treatment reverses high fat diet- induced nonalcoholic fatty liver diseases and dyslipidemia by stimulating multiple antioxidant and anti-inflammatory pathways. Biochem Biophys Rep. 2021;28:1-14
  • 30. Deng M, Su D, Xu S, Little PJ, Feng X, Tang L, Shen A. Metformin and Vascular Diseases: A Focused Review on Smooth Muscle Cell Function. Front Pharmacol. 2020;11:635- 645.
  • 31. Wang Z, Cheng Z, Cristofaro V, Li J, Xiao X, Gomez P, Ge R, Gong E, Strle K, Sullivan MP, Adam RM, White MF, Olumi AF. Inhibition of TNF-α improves the bladder dysfunction that is associated with type 2 diabetes. Diabetes. 2012;61(8):2134- 2145.
  • 32. Kullmann FA, Limberg BJ, Artim DE, Shah M, Downs TR, Contract D, Wos J, Rosenbaum JS, de Groat WC. Effects of beta3-adrenergic receptor activation on rat urinary bladder hyperactivity induced by ovariectomy. J Pharmacol Exp Ther. 2009;330(3):704-717.

The Effects of 1,1-Dimethylbiguanide Hydrochloride (Metformin) on Detrusor Muscle Contractile Response in Ovariectomized Female Rats

Yıl 2022, Cilt: 6 Sayı: 2, 97 - 103, 31.08.2022
https://doi.org/10.25048/tudod.1066739

Öz

Aim: Menopause is defined as the depletion of the ovarian follicular reserve followed by the cessation of menstrual cycles. It has been
reported that gonadal steroid hormones play an important role in bladder function in women. Changes in urine pattern including
overactive bladder, stress incontinence and recurrent urinary tract infections occur as a result of menopause. 1,1-dimethylbiguanide
hydrochloride, metformin, (MET) is an oral anti-diabetic drug used to reduce hepatic glucose production and peripheral insulin
resistance. Recent studies have revealed that MET has a protective effects in diabetes induced bladder dysfunction. The aim of this
study was to test the therapeutic potential of MET in detrusor contractile function of ovariectomized (OVX) female rats.
Material and Methods: Bilateral ovariectomy was performed to eliminate endogenous gonadal steroids secretion. Four groups are
designed with 8 animals in each group: Control, MET-administered control, OVX, and MET-administered OVX groups. MET (25 mg/
kg) was administered daily by oral gavage for 14 days. Contractile activity of isolated bladder muscle strips were evaluated in vitro organ
bath. The contractile responses of detrusor strips were determined using different doses of carbachol (10-8-10-2M) and purinergic
agonist ATP. The relaxation response of strips were determined by isoproterenol
Results: The contractile responses of detrusor muscle strips to carbachol at doses 10-5-10-2 M were decreased in the OVX group
compared to control and MET treated control groups. MET treatment partially reversed the reduction in OVX-induced contractile
responses at 10-2 and 10 -3 M carbachol doses. There were no statistically significant difference in relaxation response between the
experimental groups.
Conclusion: Our findings suggest that treatment with MET could be the new potential therapeutic agent against bladder dyfunction
in postmenopausal women. Further studies are needed for the therapeutic potential of MET in detrusor dysfunction induced by
menopause.

Kaynakça

  • 1.Bruce D, Rymer J. Symptoms of the menopause. Best Pract Res Clin Obstet Gynaecol. 2009; 23:25–32.
  • 2. Ramos-Filho AC, Faria J, Calmasini FB, Teixeira SA, Mónica FZ, Muscará MN, Gontijo JA, Anhê GF, Zanesco A, Antunes E. The renin-angiotensin system plays a major role in voiding dysfunction of ovariectomized rats. Life Sci. 2013;93(22):820-9.
  • 3. Breyer BN, Wang G, Lin G, Shindel AW, Yang R, Lin CS, Lue TF. The effect of long-term hormonal treatment on voiding patterns during filling cystometry and on urethral histology in a postpartum, ovariectomized female rat. BJU Int. 2010;106(11):1775-81.
  • 4. Chen Y, Yu W, Yang Y, Duan J, Xiao Y, Zhang X, Wu S, Bai W. Association between overactive bladder and peri-menopause syndrome: a cross-sectional study of female physicians in China. Int Urol Nephrol. 2015;47(5):743-9.
  • 5. Medina-Aguiñaga D, Munoz A, Luna M, Martinez-Moreno CG, Quintanar-Stephano A, Quintanar JL. Administration of leuprolide acetate, a GnRH agonist, improves urodynamic parameters in ovariectomized rats. Neurourol Urodyn. 2018;37(5):1574-1582.
  • 6. Liang W, Afshar K, Stothers L, Laher I. The influence of ovariectomy and estrogen replacement on voiding patterns and detrusor muscarinic receptor affinity in the rat. Life Sci. 2002;71(3):351-62.
  • 7. Bonilla-Becerra SM, de Oliveira MG, Calmasini FB, Rojas-Moscoso JA, Zanesco A, Antunes E. Micturition dysfunction in four-month old ovariectomized rats: Effects of testosterone replacement. Life Sci. 2017;179:120-129.
  • 8. Chuang SM, Long CY, Lin RJ, Liu KM, Levin RM, Chang CY, Ho YW, Wu WJ, Chang WC, Juan YS. Protective effects of estrogen on ischemia/reperfusion-induced bladder dysfunction in female rabbits. Menopause. 2013;20(2):209-17.
  • 9. Long CY, Liu CM, Hsu SC, Chen YH, Wu CH, Tsai EM. A randomized comparative study of the effects of oral and topical estrogen therapy on the lower urinary tract of hysterectomized postmenopausal women. Fertil Steril. 2006;85(1):155-60.
  • 10. Shamliyan TA, Kane RL, Wyman J, Wilt TJ. Systematic review: randomized, controlled trials of nonsurgical treatments for urinary incontinence in women. Ann Intern Med. 2008;148(6):459-73.
  • 11. Yang S, Chen X, Xu Y, Hao Y, Meng X. Effects of metformin on lipopolysaccharide-induced depressive-like behavior in mice and its mechanisms. Neuroreport. 2020;31(4):305-310.
  • 12. Shivavedi N, Kumar M, Tej GNVC, Nayak PK. Metformin and ascorbic acid combination therapy ameliorates type 2 diabetes mellitus and comorbid depression in rats. Brain Res. 2017;1674:1-9.
  • 13. Engin S, Barut EN, Soysal AC, Keskin O, Kerimoglu G, Kadioglu M, Sezen S. Double benefit of metformin treatment: improved bladder function in cyclophosphamide-induced cystitis and enhanced cytotoxicity in cancer cells. Naunyn Schmiedebergs Arch Pharmacol. 2021;394(6):1167-1175.
  • 14. Daneshgari F, Liu G, Birder L, Hanna-Mitchell AT, Chacko S. Diabetic bladder dysfunction: current translational knowledge. J Urol 2009;182(Suppl.):S18–S26.
  • 15. Bolat MS, Bilge SS, Akdeniz E, Cinar O, Firat F, Agri AE, Bakirtas M, Alici O, Erdemir F. Effect of a Carbohydrate- Rich Diet on Rat Detrusor Smooth Muscle Contractility: An Experimental Study. Biomed Res Int 2017;2017:5796456.
  • 16. Wróbel A, Łańcut M, Rechberger T. A new model of detrusor overactivity in conscious rats induced by retinyl acetate instillation. J Pharmacol Toxicol Methods. 2015;74:7-16.
  • 17. Ozacmak VH, Barut F, Ozacmak HS. Melatonin provides neuroprotection by reducing oxidative stress and HSP70 expression during chronic cerebral hypoperfusion in ovariectomized rats. J Pineal Res. 2009;47(2):156-163.
  • 18. Ekiz A, Özdemir-Kumral ZN, Erşahin M, Tuğtepe H, Öğünç AV, Akakın D, Kıran D, Özsavcı D, Biber N, Hakan T, Yeğen BÇ, Şener G, Toklu HZ. Functional and structural changes of the urinary bladder following spinal cord injury; treatment with alpha lipoic acid. Neurourol Urodyn. 2017;36(4):1061- 1068.
  • 19. Kume-Kick J, Ferris DC, Russo-Menna I, Rice ME. Enhanced oxidative stress in female rat brain after gonadectomy. Brain Res. 1996; 28;738(1):8-14.
  • 20. Juan YS, Chuang SM, Long CY, Chen CH, Levin RM, Liu KM, Huang CH. Neuroprotection of green tea catechins on surgical menopause-induced overactive bladder in a rat model. Menopause. 2012;19(3):346-354.
  • 21. Kim SO, Song SH, Ahn KY, Kwon DD. Distribution of interstitial cells of cajal in menopausal rat urinary bladder showing detrusor overactivity. Int Neurourol J. 2010; 14(1):48- 53.
  • 22. Zhu Q, Ritchie J, Marouf N, Dion SB, Resnick NM, Elbadawi A, Kuchel GA. Role of ovarian hormones in the pathogenesis of impaired detrusor contractility: Evidence in ovariectomized rodents. J Urol 2001; 166: 1136- 1141.
  • 23. Etiz Sayharman S, Tosun N, Aka N, Köse G, Tekin A, Gören Z. Effects of combined estrogen and progesterone replacement treatment on detrusor contractility and histology in oophorectomized rats. J Obstet Gynaecol Res. 2011;37(11):1638-1644.
  • 24. Rehfuss A, Schuler C, Maxemous C, Leggett RE, Levin RM. Cyclical estrogen and free radical damage to the rabbit urinary bladder. Int Urogynecol J. 2010;21(4):489-494
  • 25. Bassiouni W, Daabees T, Norel X, Senbel AM. Hypoactivity of rat detrusor muscle in a moel of cystitis: exacerbation by nonselective COX inhibitors and amelioration by a selective DP1 receptor antagonist. Naunyn Schmiedebergs Arch Pharmacol. 2019;392(4):437-450.
  • 26. Owen SJ, Rose’Meyer RB, Massa HM. Dietary phytoestrogens maintain contractile responses to carbachol with age in the female rat isolated bladder. Life Sci. 2011; 15;89(7-8):213-220.
  • 27. Fatemi I, Saeed-Askari P, Hakimizadeh E, Kaeidi A, Esmaeil- Moghaddam S, Pak-Hashemi M, Allahtavakoli M. Long-term metformin therapy improves neurobehavioral functions and antioxidative activity after cerebral ischemia/reperfusion injury in rats. Brain Res Bull. 2020;163:65-71.
  • 28. Zakeri M, Fatemi I, Kaeidi A, Zakeri MA, Hakimizadeh E, Hassanipour M, Rahmani M, Hassanshahi J, Ayoobi F, Allahtavakoli M. Pro-neurocognitive and anti-sarcopenic benefits of one-year metformin therapy in ovariectomized aged mice. Clin Exp Pharmacol Physiol. 2019 ;46(12):1133- 1140.
  • 29. Yasmin T, Rahman MM, Khan F, Kabir F, Nahar K, Lasker S, Islam MD, Hossain MM, Hasan R, Rana S, Alam MA. Metformin treatment reverses high fat diet- induced nonalcoholic fatty liver diseases and dyslipidemia by stimulating multiple antioxidant and anti-inflammatory pathways. Biochem Biophys Rep. 2021;28:1-14
  • 30. Deng M, Su D, Xu S, Little PJ, Feng X, Tang L, Shen A. Metformin and Vascular Diseases: A Focused Review on Smooth Muscle Cell Function. Front Pharmacol. 2020;11:635- 645.
  • 31. Wang Z, Cheng Z, Cristofaro V, Li J, Xiao X, Gomez P, Ge R, Gong E, Strle K, Sullivan MP, Adam RM, White MF, Olumi AF. Inhibition of TNF-α improves the bladder dysfunction that is associated with type 2 diabetes. Diabetes. 2012;61(8):2134- 2145.
  • 32. Kullmann FA, Limberg BJ, Artim DE, Shah M, Downs TR, Contract D, Wos J, Rosenbaum JS, de Groat WC. Effects of beta3-adrenergic receptor activation on rat urinary bladder hyperactivity induced by ovariectomy. J Pharmacol Exp Ther. 2009;330(3):704-717.
Toplam 32 adet kaynakça vardır.

Ayrıntılar

Birincil Dil İngilizce
Konular Sağlık Kurumları Yönetimi
Bölüm Araştırma Makalesi
Yazarlar

İnci Turan 0000-0003-2211-3914

Salih Erdem 0000-0003-3277-0539

Meryem Ergenç Bu kişi benim 0000-0002-0628-4791

Hale Sayan Özaçmak 0000-0002-3564-0468

Yayımlanma Tarihi 31 Ağustos 2022
Kabul Tarihi 8 Haziran 2022
Yayımlandığı Sayı Yıl 2022 Cilt: 6 Sayı: 2

Kaynak Göster

APA Turan, İ., Erdem, S., Ergenç, M., Sayan Özaçmak, H. (2022). The Effects of 1,1-Dimethylbiguanide Hydrochloride (Metformin) on Detrusor Muscle Contractile Response in Ovariectomized Female Rats. Türkiye Diyabet Ve Obezite Dergisi, 6(2), 97-103. https://doi.org/10.25048/tudod.1066739
AMA Turan İ, Erdem S, Ergenç M, Sayan Özaçmak H. The Effects of 1,1-Dimethylbiguanide Hydrochloride (Metformin) on Detrusor Muscle Contractile Response in Ovariectomized Female Rats. Turk J Diab Obes. Ağustos 2022;6(2):97-103. doi:10.25048/tudod.1066739
Chicago Turan, İnci, Salih Erdem, Meryem Ergenç, ve Hale Sayan Özaçmak. “The Effects of 1,1-Dimethylbiguanide Hydrochloride (Metformin) on Detrusor Muscle Contractile Response in Ovariectomized Female Rats”. Türkiye Diyabet Ve Obezite Dergisi 6, sy. 2 (Ağustos 2022): 97-103. https://doi.org/10.25048/tudod.1066739.
EndNote Turan İ, Erdem S, Ergenç M, Sayan Özaçmak H (01 Ağustos 2022) The Effects of 1,1-Dimethylbiguanide Hydrochloride (Metformin) on Detrusor Muscle Contractile Response in Ovariectomized Female Rats. Türkiye Diyabet ve Obezite Dergisi 6 2 97–103.
IEEE İ. Turan, S. Erdem, M. Ergenç, ve H. Sayan Özaçmak, “The Effects of 1,1-Dimethylbiguanide Hydrochloride (Metformin) on Detrusor Muscle Contractile Response in Ovariectomized Female Rats”, Turk J Diab Obes, c. 6, sy. 2, ss. 97–103, 2022, doi: 10.25048/tudod.1066739.
ISNAD Turan, İnci vd. “The Effects of 1,1-Dimethylbiguanide Hydrochloride (Metformin) on Detrusor Muscle Contractile Response in Ovariectomized Female Rats”. Türkiye Diyabet ve Obezite Dergisi 6/2 (Ağustos 2022), 97-103. https://doi.org/10.25048/tudod.1066739.
JAMA Turan İ, Erdem S, Ergenç M, Sayan Özaçmak H. The Effects of 1,1-Dimethylbiguanide Hydrochloride (Metformin) on Detrusor Muscle Contractile Response in Ovariectomized Female Rats. Turk J Diab Obes. 2022;6:97–103.
MLA Turan, İnci vd. “The Effects of 1,1-Dimethylbiguanide Hydrochloride (Metformin) on Detrusor Muscle Contractile Response in Ovariectomized Female Rats”. Türkiye Diyabet Ve Obezite Dergisi, c. 6, sy. 2, 2022, ss. 97-103, doi:10.25048/tudod.1066739.
Vancouver Turan İ, Erdem S, Ergenç M, Sayan Özaçmak H. The Effects of 1,1-Dimethylbiguanide Hydrochloride (Metformin) on Detrusor Muscle Contractile Response in Ovariectomized Female Rats. Turk J Diab Obes. 2022;6(2):97-103.

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