Assessment of reproductive toxicity profile of ramipril in male wistar rats
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Abstract
Background: Several adverse effects have been associated with the long-time use of antihypertensive drugs in which caution should be taken when administering them.
Objective: To evaluate the effect of 28-days oral administration of ramipril on reproductive functions of male rats.
Methods: Twenty (20) male rats (120 - 150 g) were randomly divided into 4 groups of 5 rats per group and treated orally with distilled-water, 5 mg/kg, 10 mg/kg and 20 mg/kg of ramipril, respectively for 28-days. On day 29, 2 ml of blood samples were collected from the rats in each group through ocular puncture into clean test-tubes and centrifuged at 2500 rpm for 5 mins to obtain the serum for the analysis of testosterone and follicle stimulating hormone (FSH) levels, using enzyme-linked immunosorbent assay (ELISA) technique. All the male rats were later sacrificed by cervical dislocation and the testes removed along with the epididymis for semen analysis.
Results: Oral administration of ramipril produced a significant (P<0.05) decrease in levels of testosterone of the treated rats at all tested doses used and a non-significant (P>0.05) increase in Follicle Stimulating Hormone (FSH) at 5 and 10 mg/kg compared to the distilled water group. There was also a decrease in sperm count, sperm motility and sperm morphology of the treated male rats.
Conclusion: Based on the findings from this study, it can be stated that ramipril may adversely affect fertility as
seen by decrease in testosterone levels, sperm count, sperm motility and sperm morphology in the treated rats.
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References
Whelton PK, Carey RM, Aronow, WS, Casey DE, Collins KJ and Himmelfarb CD (2017).ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH
/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American College of Cardiology. 2018;71(19):e127-e248.
WHO (2021). Hypertension. https://www.who.int/news-room/factsheets/detail/hypertension.
Lackland DT and Weber MA (2015). "Global burden of cardiovascular disease and stroke: hypertension at the core". The Canadian Journal of Cardiology. 31 (5): 569-571. doi:10.1016/j.cjca.2015.01.009. PMID 25795106.
Hernandorena I, Duron E, Vidal JS and Hanon O (2017). "Treatment options and considerations for hypertensive patients to prevent dementia". Expert Opinion on Pharmacotherapy (Review). 18 (10): 989- 1000. doi:10.1080/14656566.2017.1333599. PMID 28532183. S2CID 46601689.
Who (2022). Guideline for the pharmacological treatment of hypertension in adults: summary. https://www.who.int/publications/i/item/9789240050969
Wright JM, Musini VM and Gill R (2018). "First-line drugs for hypertension". The Cochrane Database of Systematic Reviews. 2018 (4): CD001841. doi:10.1002/14651858.CD001841.pub3. PMC 6513559. PMID 29667175.
Lauren Castiello, Tom Rush and Adam Felman (2023). Everything you need to know about hypertension(high blood pressure). https://www.medicalnewstoday.com/articles/150109.
Aronow Wilbert S. (2010). "Cardiac Arrhythmias". Brocklehurst's Textbook of Geriatric Medicine and Gerontology. Elsevier. pp. 327 - 337.
doi:10.1016/b978-1-4160-6231-8.10045-5. ISBN 978-1-4160-6231-8. Angiotensin-converting enzyme inhibitors ACE inhibitors have been
demonstrated to reduce sudden cardiac death in some studies of persons with CHF.24,56
Kester Mark, Karpa Kelly D and Vrana Kent E (2012). "Cardiovascular System". Elsevier's Integrated Review Pharmacology. Elsevier. pp. 125-151. doi:10.1016/b978-0-323-07445-2.00008-2. ISBN 978-0-323-07445-2. ACE inhibitors also slow progression of kidney disease in patients with
diabetic nephropathies. Renal benefits are probably a result of improved renal hemodynamics from decreased glomerular arteriolar resistance.
Chauhan M, Patel JB and Ahmad F (2023). Ramipril. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan.
Drugbank (2023). Ramipril: Uses, Interactions, Mechanism of Action. https://go.drugbank.com/drugs/DB00178.
Zydus Pharmaceuticals USA Inc. (2022). RAMIPRIL - ramipril tablet https://dailymed.nlm.nih.gov/dailymed/fda/fdaDr
ugXsl.cfm?setid=ee92b5bb-77d5-47cd-a8b1- d5f383b94311&type=display.
Fischer J and Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. pp. 469. ISBN 9783527607495.
Hilal-Dandan R (2018). In Goodman & Gilman's: The Pharmacological Basis of Therapeutics. https://go.drugbank.com/drugs/DB00178.
Savarese G, Costanzo P, Cleland JG, Vassallo E, Ruggiero D, Rosano G and Perrone-Filardi P (2013). "A meta-analysis reporting effects of angiotensinconverting enzyme inhibitors and angiotensin receptor blockers in patients without heart failure". Journal of the American College of Cardiology. 61 (2): 131-42. doi:10.1016/j.jacc.2012.10.011. PMID 23219304.
SMPDB (2019). Ramipril Metabolism Pathway. Drug Metabolism Pathway. https://smpdb.ca/view/SMP0000597
Krause AJ, Patel NB and Morgan J (2019). An unusual presentation of ACE inhibitor-induced visceral angioedema. BMJ Case Report. 12(9). [PMC free article] [PubMed]
Eren H, Sivrikaya A, Cobanoglu U, Kalyoncu NI, Karaguzel E, Topbaş M, Kazaz IO, Horsanali MO and Kutlu O (2018). Investigation the effect of propranolol, metoprolol and carvedilol on spermatogenesis in rat testis. International Journal of Research in Medical Sciences. 6(4), 1082-1087. https://doi.org/10.18203/2320- 6012.ijrms20181260
Ayodele OM, Bolanle OI and Olufeyisipe AA (2009). Antireproductive effect of calcium channel blockers on male rats. Reproductive Medicine and Biology. 8(3): 97-102. doi: 10.1007/s12522-009-0018-9. PMCID: PMC5904629PMID: 29699314
Avdatek F, Yeni D, Keleş I, Bozkurt MF, Birdane MK, Gündoğan M (2016). Effects of Amlodipine on Spermatological Parameters and Genital Tract. Atatürk ÜniversitesiVeterinerBilimleriDergisi. 11(3): 267-272. Doi:10.17094/ataunivbd.282980. http://dergipark.ulakbim.gov. tr/ataunivbd.
Hedrich HH and Bullock G (2006). The Laboratory Mouse: The Handbook of Experimental Animals. Elsevier Academic press, UK. pp. 463-492.
Levine JE, Norman RL, Gliessman PM, Oyama TT, Bangsberg DR and Spies HG (1985). InvivoGonadotropin-releasing hormones
measurement in ovariectomized rats. Endocrinology. 117(2):711-721.
World Health Organization (1999). WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction (4th ed.). Cambridge University Press.
Ekaluo UB, Ikpeme EV, Udokpoh AE (2009). Sperm Head Abnormality and Mutagenic Effects of Aspirin, Paracetamol and Caffeine Containing Analgesics in Rats. The Internet Journal of Toxicology. 7(1):1-9.
Laing JA (1979). Fertility and infertility in domestic animals. Bailliere Tindall, a division of Cassell Lt, 3rd edition.
Atli O, Baysal M, Aydogan-Kilic G, Kilic V, Ucarcan S, Karaduman B and Ilgin S (2017). Sertraline-induced reproductive toxicity in male rats: evaluation of possible underlying mechanisms. Asian Journal of Andrology. 19(6): 672-679. Published online 2016 Dec 13. doi: 10.4103/1008-682X.192637. PMCID: PMC5676427PMID: 27976631
Osonuga IO, Adenowo TK, Akindele RA, Idowu G (2020). The effects of P-alaxin on fertility and hematological parameters in male adult wistar rats. African Journal of Science & Nature. Vol. 10, 97-101. DOI: https://doi.org/10.46881/ajsn.v10i0.182. PISSN 2536-6904, E-ISSN 2705-2761.
Loma Linda University (2021). https://lomalindafertility.com/treatments/fertilitytesting/for-men/semen-analysis/
Nassar GN and Leslie SW (2022). Physiology, Testosterone. (https://www.ncbi.nlm.nih.gov/books/NBK526128
/) [Updated 2022 Jan 4]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Accessed 09/02/2022.
Sizar O and Schwartz J (2022). Hypogonadism. (https://www.ncbi.nlm.nih.gov/books/NBK532933 /) [Updated 2022 Jun 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan- . Accessed 09/02/2022.
Peeyush K, Nitish K, Devendra ST and Ajay P (2010). Male hypogonadism: Symptoms and treatment. Journal of Advanced Pharmaceutical Technology & Research. 1(3): 297-301. doi: 10.4103/0110- 5558.72420. PMCID: PMC3255409PMID: 22247861
Khan A, Za B, Mi K, Rahman H and La B (2013). Effect of Neem (Azadirachta Indica) on Fertility in Male Rats. Journal of Shaheed Suhrawardy Medical College. 5(1):39-42.
Oyedeji KO, Robert E, Arubi P and Dare A (2018). Effect of Losartan (Angiotensin II Antagonist) on Reproductive Parameters in Male Wistar Rats. International Journal of Pharmaceutical Sciences Review and Research. 54(1), Article No. 24: 136-140.
Macias-Garcia B, Gonzalez-Fernandez L, Loux SC, Rocha AM, Guimaraes T and Pena FJ (2015). Effect of calcium, bicarbonate, and albumin on Capacitationrelated events in equine sperm. Reproduction. England. 149(1):87- 99.
Walczak-Jedrzejowska R, Wolski JK and Slowikowska-Hilczer J (2013). The role of Oxidative stress and Antioxidants in Male fertility. Central
European Journal of Urology. 66: 60-67.
Arican EY, GökçeoğluKayali D, Ulus Karaca B (2020). Reproductive effects of subchronic exposure to Acetamiprid in Male rats. Scientific
Reports. 10, 8985. https://doi.org/10.1038/s41598-020-65887-0