Abstract
BackgroundCimetidine, histamine H2 receptors antagonist, has caused adverse effects on the male hormones and reproductive tract due to its antiandrogenic effect. In the testes, peritubular myoid cells and muscle vascular cells death has been associated to seminiferous tubules and testicular microvascularization damages, respectively. Either androgen or histamine H2 receptors have been detected in the mucosa and smooth muscular layer of vas deferens. Thus, the effect of cimetidine on this androgen and histamine-dependent muscular duct was morphologically evaluated.MethodsThe animals from cimetidine group (CMTG; n=5) received intraperitoneal injections of 100 mg/kg b.w. of cimetidine for 50 days; the control group (CG) received saline solution. The distal portions of vas deferens were fixed in formaldehyde and embedded in paraffin. Masson´s trichrome-stained sections were subjected to morphological and the following morphometrical analyzes: epithelial perimeter and area of the smooth muscular layer. TUNEL (Terminal deoxynucleotidyl-transferase mediated dUTP Nick End Labeling) method, NF-kB (nuclear factor kappa B) and AR (androgen receptors) immunohistochemical detection were also carried out. The birefringent collagen of the muscular layer was quantified in picrosirius red-stained sections under polarized light. The muscular layer was also evaluated under Transmission Electron Microscopy (TEM).ResultsIn CMTG, the mucosa of vas deferens was intensely folded; the epithelial cells showed numerous pyknotic nuclei and the epithelial perimeter and the area of the muscular layer decreased significantly. Numerous TUNEL-labeled nuclei were found either in the epithelial cells, mainly basal cells, or in the smooth muscle cells which also showed typical features of apoptosis under TEM. While an enhanced NF-kB immunoexpression was found in the cytoplasm of muscle cells, a weak AR immunolabeling was detected in these cells. In CMTG, no significant difference was observed in the birefringent collagen content of the muscular layer in comparison to CG.ConclusionsCimetidine induces significant damages in the epithelium; a possible antiandrogenic effect on the basal cells turnover should be considered. The cimetidine-induced muscle cells apoptosis confirms the susceptibility of these cells to this drug. The parallelism between enhanced cytoplasmic NF-kB immunolabeling in the damaged muscular tissue and muscle cell apoptosis suggests that this drug may avoid the translocation of NF-kB to the nucleus and interfere in the control of NF-kB-mediated smooth muscle cell apoptosis. The decreased immunoexpression of ARs verified in the damaged muscular tissue reinforces this possibility.
Highlights
Cimetidine, histamine H2 receptors antagonist, has caused adverse effects on the male hormones and reproductive tract due to its antiandrogenic effect
Light microscopy In the sections stained by Masson's trichrome (Figures 1A1D), the vas deferens of animals from cimetidine group (CMTG) (Figure 1B) showed intensely folded epithelium surrounding a small lumen, and the muscular layer was reduced in comparison to control group (CG) (Figure 1A)
TUNEL labeling In comparison to CG (Figure 2A), numerous TUNELpositive nuclei were observed in the epithelial cells, mainly in the basal cells (Figure 2C), and in the muscular layer of vas deferens (Figures 2B and 2D) in all animals from CMTG
Summary
Cimetidine, histamine H2 receptors antagonist, has caused adverse effects on the male hormones and reproductive tract due to its antiandrogenic effect. Hamilton et al [2] demonstrated alterations in the epithelial cells of vas deferens such as absence of smooth endoplasmic reticulum, reduction in the size of the Golgi apparatus and decreased number of mitochondria. These results indicate that androgens are essential for the structural and functional maintenance of the vas deferens epithelium. The vas deferens muscular contraction has been inhibited by histamine [6,7] This effect was confirmed after the evaluation of the effect of cimetidine (histamine H2 receptor antagonist) on the smooth muscle contraction of vas deferens. The inhibitory response of the muscular contraction was inhibited by this H2 receptor antagonist [8]
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