Summary. Cimetidine, an H 2 receptor antagonist used for treatment of gastric ulcers, exerts antiandrogenic and antiangiogenic effects. In the testes cimetidine impairs spermatogenesis, Sertoli cells and peritubular tissue, inducing apoptosis in the myoid cells. Regarding the importance of histamine and androgens for vascular maintenance, the effect of cimetidine on the structural integrity of the testicular vasculature was evaluated. Adult male rats received cimetidine (CMTG) and saline (CG) for 50 days. The testes were fixed in buffered 4% formaldehyde and embedded in historesin and paraffin. In the PAS-stained sections, the microvascular density (MVD) and the vascular luminal area (VLA) were obtained. TUNEL method was performed for detection of cell death. Testicular fragments embedded in Araldite were analyzed under transmission electron microscopy. A significant decrease in the MVD and VLA and a high number of collapsed blood vessel profiles were observed in CMTG. Endothelial cells and vascular muscle cells were TUNEL-positive and showed ultrastructural features of apoptosis. These results indicate that cimetidine induces apoptosis in vascular cells, leading to testicular vascular atrophy. A possible antagonist effect of cimetidine on the H 2 receptors and/or androgen receptors in the vascular cells may be responsible for the impairment of the testicular microvasculature. Key words: H 2 receptor antagonist, Microvascular density, Vascular atrophy, Cell death, Smooth muscle cell Introduction In the human testes, blood vessels consist of arterioles, metarterioles, capillaries and venules, which interconnect Leydig cell clusters to the adjacent seminiferous tubules and play an important role in the distribution and transport of hormones, nutrients, oxygen and other factors from the interstitium to the seminiferous tubules (Ergün et al., 1997). In this context, it has been suggested that dysfunction in the vasculature, for example, the reduction of blood flow may affects spermatogenic process, resulting in marked decrease in sperm production (Bergh et al., 2001). It is known that histamine induces vasoconstriction and vasodilatation by acting on both H 1 and H 2 receptors, respectively, located in blood vessels (Reinhardt and Ritter, 1979; Gross, 1981; Gross et al., 1981; Heltianu et al., 1982; Edvinsson et al., 1983; Saari, 1986; Guslandi, 1994). Furthermore, regarding the presence of androgen receptors in vascular smooth muscle cells (Vornberger et al, 1994; Welsh et al., 2010), the testicular blood vessels seem to be controlled by testosterone and are involved in endocrine and paracrine control of spermatogenesis (Bergh and Damber, 1992). Cimetidine, an antacid and anti-ulcer drug, is a potent H 2 -receptor antagonist, competing with histamine for H 2 receptors located on gastric parietal cells (Clayman, 1977). Among other effects, cimetidine competitively blocks receptors for dihydrotestosterone (DHT) in the pituitary and hypothalamus (Knigge et al., 1983) and other tissues that require DHT (Winters et al., 1979), causing an antiandrogenic effect (Winters et al., 1979; Pereira, 1987). Studies in rodents have shown that cimetidine causes testicular changes, including significant reduction of the seminiferous tubule diameters, irregular tubules showing disorganized Cimetidine-induced vascular cell apoptosis impairs testicular microvasculature in adult rats Flávia L. Beltrame 1 , Caroline T. Yamauti 2 , Breno H. Caneguim 1 , Paulo S. Cerri 2 , Sandra M. Miraglia 1 and Estela Sasso-Cerri 2 1 Department of Morphology and Genetics, Federal University of São Paulo (UNIFESP), São Paulo/SP, Brazil and 2 Department of Morphology, Laboratory of Histology and Embryology, Dental School – São Paulo State University (UNESP), Araraquara/SP, Brazil Histol Histopathol (2012) 27: 1343-1351 Offprint requests to: Dra. Estela Sasso-Cerri, Faculdade de Odontologia de Araraquara (UNESP/FOAr), Departamento de Morfologia, Laboratorio de Histologia e Embriologia, Rua Humaitá 1680, 14801-903, Araraquara/SP, Brazil. e-mail: esasso@foar.unesp.br http://www.hh.um.es Histology and Histopathology Cellular and Molecular Biology