Studies on the Action of Calcium Channel Blockers on Reproductive Functions in Male Sprague-Dawley Rats

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Morakinyo, A.O
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Drugs such as nifedipine, verapamil and diltiazem belong to a class of medication called calcium channel blockers (CCB). CCB are first line class of drugs that block the entry of calcium into the muscle cells of the heart and the arteries. They are widely used in the treatment and management of hypertension, arrhythmias, migraine headaches and angina. However, there are conflicting clinical reports of the effect due to the therapeutic administration of nifedipine on fertility in male patients. In addition, while the mechanism of action of these drugs in terms of inhibition of calcium ion influx in the muscle cells of the heart and blood vessels is well documented, there is paucity of information in the literature on other non-specific effects and the mechanism(s) involved in the impairment of fertility in males. The present study was therefore designed to experimentally elucidate the sub-chronic effect of calcium channel blockers nifedipine, verapamil and diltiazem on reproductive functions and the possible biological mechanism(s) of action in the male Sprague-Dawley rats. Male rats were divided into four groups of twelve rats each. Group 1 (control) received distilled water; Group 2, received nifedipine 0.57mg/kg body weight (BW); Group 3, were given verapamil 3.40mg/kg BW and Group 4 were given diltiazem 2.57mg/kg BW. The treatment of experimental rats was done daily intra-gastrically via oral cannula and it lasted for 30 days. At the end of drug-treatment, six (6) rats from each group were randomly selected and sacrificed by cervical dislocation. The remaining six (6) rats in each drug treated group were discontinued from drug-treatment and served as the recovery group. The recovery rats were kept for another 30 days after drug withdrawal before experimental measurements were carried out. All rats were weighed twice weekly and their weights recorded. Semen evaluation was done on caudal epididymal sperm sample. Blood samples were collected for hormonal assay of follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone. Reproductive organs like the testes, epididymis, prostate gland and seminal vesicles were carefully removed, weighed immediately and passed through routine histological preparations. In addition, mating study or fertility test was performed. Other studies such as oxidative enzyme activities and lipid peroxidation level (in both the testicular and sperm samples) as well as sperm capacitation process were conducted so as to establish the basis or mechanism of action of the CCB. The result obtained revealed that nifedipine, verapamil and diltiazem significantly (P<0.05) decrease sperm count and motility in drug treated groups. Treatment with each of these CCB produced no gross and biologically meaningful histological change in the male reproductive organs. Similarly, there was no significant change in the levels of serum testosterone, follicle stimulating hormone and luteinizing hormone. However, oxidative studies indicated that CCB significantly increased the level of lipid peroxidation shown by increased malondialdehyde (MDA) level and a concomitant decrease in enzymatic anti-oxidants like catalase (CAT), superoxide dismutase (SOD) and reduced glutathione (GSH) in both the testicular tissue and spermatozoa cell samples. Thus, the disruption of the balance between the protective antioxidant enzymes and free radicals generation in the reproductive milieu is indicative of oxidative stress. Furthermore, epididymal sperm capacitation process (which confers on the mammalian sperm the intrinsic capacity to bind and fuse with the oocyte) was significantly suppressed by CCB treatment. These results therefore suggest that each of the CCB used, namely, nifedipine, verapamil and diltiazem has reversible anti-fertility effects on reproductive functions in male rats. The impairment of fertility by these CCB is possibly mediated by inducing oxidative stress in the reproductive milieu, and consequently suppressing the sperm capacitation process thereby compromising sperm intrinsic capacity for fertilization. These changes suggest the anti-fertility mechanism of CCB in the male rats.
A Thesis Submitted to the School of Postgraduate Studies, University of Lagos
Drugs , Calcium Channel Blockers , Reproductive Functions , Experimental Rats , Research Subject Categories::MEDICINE::Physiology and pharmacology
Morakinyo, A.O (2010). Studies on the Action of Calcium Channel Blockers on Reproductive Functions in Male Sprague-Dawley Rats. A Thesis Submitted to University of Lagos School of Postgraduate Studies Phd Thesis and Dissertation, 188pp.