Molecular genetic effects of drugs having the feature of ion channel inhibition on sperm quality

Ca+2, K+, Cl-, Na+, etc. permeable ion channels, located in the cell membrane, are involved in many mechanisms such as sperm motility, flagella localization, sperm-oocyte penetration, acrosome reaction. Studies have shown that ion channel inhibitor drugs used in the treatment of diseases such as anxiety, epilepsy, pain and hypertension inhibit fertilization and sperm function. The aim of this study was to investigate the effects of ion channel inhibitors such as clomipramine, carbamazepine, Verapamil and Diltiazem drugs, on spermiogram, hormone profile and gene expressions determining miRNA, ion channel and sperm quality in testicular tissue and sperm cells at molecular / genetic level. A total of 90 male Wistar albino rats were divided into 6 main groups, 15 animals in each group, control, sham (distilled water 1 ml / day), carbamazepine (25 mg / kg / day), clomipramine (10 mg / kg / day), Verapamil (3.4 mg / kg / day) and Diltiazem (2.57 mg / kg / day). The treatments were performed by oral gavage for a total of 60 days. Effects of ion channel inhibitors on spermatologic parameters were evaluated by spermiogram analysis, on hormone profiles by ELISA, at tissue level by hematoxylin-eosin staining and gene expression by quantitative qRT-PCR. Immunoreactivity analysis was performed to confirm gene expression at the protein level where significant mRNA fold change was detected in qRT-PCR. It was determined that ion channel inhibitors increased follicle stimulating hormone, prolactin, estradiol and testosterone levels. It was observed that carbamazepine and Diltiazem negatively affect sperm parameters. However, when evaluated in terms of all data, it was found that clomipramine had more positive effects on fertility. It was determined that ion channel inhibitor treatments caused a decrease in KCNJ11 and TRPV5 gene expression levels and an increase in CATSPER1 and rno-let-7a gene expression levels in testis samples (p < 0.05). It was also detected that TRPM3 mRNA and rno-miR-92a gene expression levels decreased in sperm samples and CFTR mRNA and rno-mir-27a levels increased (p < 0.05). Although the molecular mechanisms of the effects of ion channel inhibitors on fertility have not yet been fully elucidated, data from the literature and findings from the present study suggest that ion channels and miRNAs play an important role in this process.