An investigation into the effects and possible mechanisms of action of cimetidine and ranitidine on the sexual behaviour of male rats.
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The development of a new class of antihistamines, the H2-receptor antagonists, introduced a new era in the treatment of peptic ulcer diseases. Cimetidine, the first clinically effective H2-blocker, was introduced in 1976. Recently ranitidine, a second member approved for clinical use, has been found to be as effective as cimetidine in the management of peptic ulcer diseases. Soon after the introduction of cimetidine several reports of loss of libido, impotence and gynaecomastia were described in male patients who were on normal or high therapeutic doses of cimetidine. A few unsubstantiated reports of loss of libido and gynaecomastia attributed to ranitidine therapy have also appeared in literature. This study was undertaken to examine in detail the effects of acute and subchronic treatment with cimetidine and ranitidine on mating behaviour in sexually active male rats. Motor activity counts were recorded immediately before sexual behaviour observations. The animals were tested on every third day and observations were terminated after the first intromission of the next series of copulations. In the single dose study, mating behaviour tests were commenced 2 hours after treatment; mating tests during the subchronic dose studies were done 4 to 7 hours after the 6hOO dose. The following measures were used in the analysis of data: mount latency, intromission latency, mount frequency, intromission frequency, ejaculation latency, and the postejaculatory intromission latency. At the termination of the subchronic dose studies blood samples were collected by cardiac puncture and the animals were subsequently autopsied. Cauda epididymal sperm counts and motility were determined, testes and accessory sex organs were weighed, and one testis was processed for histological examination. Cimetidine in the low dose, 128.6 mg/kg, significantly shortened the ejaculatory latency and to a lesser extent the postejaculatory intromission latency. At the higher dose, 257.1 mg/kg, cimetidine markedly prolonged the postejaculatory intromission latency and to a lesser extent increased the ejaculation latency. The inhibitory effect of cimetidine on copulatory behaviour at the higher dose level was accompanied by significant depression in motor activity. At the conclusion of the subchronic dose studies marked reductions in serum testosterone levels and decreased testes and accessory organ weights were observed in the cimetidine group. No significant changes in sperm counts were observed, although the sperm counts in the cimetidine group were lower than the control values. Histological examination of testes showed apparently normal spermatogenesis in all three treatment groups. However, in spite of the reduced testosterone levels and decreased testes and accessory sex organ weights in the cimetidine group, no impairment in mating behaviour was observed. In both the acute and the subchronic dose studies, similar to placebo, treatment with ranitidine showed no effect on mating behaviour. On final analysis of the results it is concluded that cimetidine, and not ranitidine, disrupts sexual behaviour in male rats. Furthermore, it is concluded that the effect of cimetidine on sexual behaviour is not related to H2-receptor blockade as equipotent doses of ranitidine did not produce similar effects. The mechanism of cimetidine-induced impairment of sexual performance in the male rat may possibly be attributed to some non-specific, direct or indirect action of cimetidine on some neurotransmitter system responsible for the control of sexual behaviour. It is further suggested that the effect may possibly be mediated by a blockade of central dopamine receptors. However, it must be stressed that further experimentation is necessary to elucidate the mechanism of action of cimetidine on sexual behaviour.