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149Hypercholesterol diet and terazosin treatment: Effects on serum lipid profile and ventral prostate structure in rats
149 HYPERCHOLESTEROL DIET AND TERAZOSIN TREATMENT: EFFECTS ON SERUM LIPID PROFILE AND VENTRAL PROSTATE S T R U C T U R E IN R A T S
~50 POTENTIAL BENEFICIAL EFFECTS ANDROGEN ON THE PROSTATE
OF A NOVEL
SELECTIVE
Attia D., Grootenhuis A. Mitropoulos D. 1 Ploumidou K.2, Kyroudi-Voulgari A. 3, Perea D. ~, Zervas A. ~, Karayaanacos P.-' N.V. Organon, Pharmacology, Oss, The Netherlands 1Athans Medical School, 1st Department of Urology, Athens, Greece, ~Athens Medical School, Department of Experimental Surgel~¢and Surgical Research, Athens, Greece, 3Athens Medical School, Department of Histology and Embryology, Athens, Greece INTRODUCTION & OBJECTIVES: Dietary factors rnay have an effect on benign prostate hyperplasia (BPH) through a variety of mechanisms such as elevation of sympathetic nervous system activity and testosterone concentrations. Alpha 1-adrenoreceptor antagonists are clinically used in patients with symptomatic BPH and besides their effect on smooth muscle tone they may affect the dynamics of prostate growth and the lipid profile. The objective of this research was to examine the impact of hypercholesterol diet (HD) and terazosin (TRZ) administration on serum lipid profile and ventral prostate structure in rats. MATERIAL & METHODS: Forty-five male Wistar rats were fed, beginning at 120 days of age, for 5 months with either standard experimental animals' food (SD) (15 animals) or standard food enriched with 4% cholesterol and 1% cholic acid (30 animals). During the last 2 months of the experimentation period 15 animals of the second group received TRZ (1 mg/Kg body weight diluted in normal saline) orally every second day. The body (BW) and ventral prostate weights (VPW), the serum lipid profile and the ventral prostate structure were determined. RESULTS: BW did not vary among groups. However, VPW of rats fed with HD differed significantly from those receiving SD (0.69±0.13 vs. 0.86:t:0.25) and was further decreased in rats treated with TRZ (0.53±&I1). HD resulted in significant elevation of total cholesterol (464±267 vs. 894-15) and LDL (3214-257 vs. 154-9), while HDL and triglyceride serum levels remained unaffected. TRZ treaUnent of animals under HD resulted in significantlylower total cholesterol, LDL and triglyceride levels (2554-76 vs. 464±267, 192±72 vs. 321±257, and 924-73 vs. 1194-46, respectively), while HDL levels were comparable (39±12 vs. 504-9). Hematoxylin-eosin staining of prostatic tissue in rats fed with SD revealed normal epitheliumlined acini surrounded by a stromal matrix. HD affected almost unanimously, the microscopic structure of the ventral prostate; epithelial cells of the distal area formed papillary projections within the acinar lumen and had more cytoplasm than controls. In most cases vesicular formations within the cytoplasmic area were noted as well. TRZ administration did not result in any obvious alterations. CONCLUSIONS: Our findings suggest that hypercholesterolemia causes marked changes in the rat ventral prostate and could contribute to BPH pathogenesis. Although short-term terazosin treatment did not result in structural alterations, it had a beneficial effect on the lipid profile which may imply that alpha-blockers have a parallel effect on lipid metabolism.
INTRODUCTION & OBJECTIVES: New orally active selective androgens are being developed for male contraception and hormone replacement therapy. Selective androgens suppress LH levels, thus reducing endogenous testosterone/dihydrotestosterone levels. As such, selective androgens are believed to be beneficial for the prostate since endogenous and especially intraprostatic testosterone/dihyrotestosterone levels are replaced by androgens that are not potentiated by 5ct-reduetion, which has been confirtned by in vitro assays (data not shown). MATERIAL & METHODS: In order to test this hypothesis castrated and intact male rats were treated for 6 weeks with either daily p.o. administration of testosterone undecanoate (TU; 40 mg/kg) or daily p.o. administration of the novel androgen (2.5 mg/kg). The androgen replacement capacity of the novel androgen was determined by measuring the maintenance of muscle levator ani (MLA) weight, maintenance of bone mineral density (BMD), suppression of luteinizing hormone (LH) levels and the prostate weight in castrated rats, The beneficial potential for the prostate of the novel androgen was tested by measuring ventral prostate weight in intact male rats (with normal circulating and intraprostatic testosternne/dilaydrotestosterone levels). Fm'thermore, the influence of TU and the novel androgen on prostate epithelial cell proliferation and epithelial cell apoptosis was detemrined in intact male rats. RESULTS: Treatment of castrated rats with TU maintained MLA weight and BMD at intact placebo-treated levels and suppressed serum LH levels. Treatment of castrated rats with the novel androgen maintained MLA weight and BMD even above intact placebo-treated levels and also suppressed serum LH levels. Thus, the novel androgen offered full androgen replacement on MLA, bone and CNS (LH suppression). Treatment of castrated rats with TU increased ventral prostate weight above intact placebo-treated level, whereas treatment with the novel androgen maintained prostate weight at a level far below intact placebo-treated level. In intact male rats TU also increased ventral prostate weight above intact placebotreated level, whereas treatment with the novel androgen reduced prostate weight below intact placebo-treated level. In intact male rats TU increased epithelial cell proliferation and decreased epithelial cell apoptosis, whereas the novel androgen maintained tissue homeostasis. CONCLUSIONS: In summary, the novel selective androgen suppressed LH levels and provided full androgen replacement on muscle mass and bone, but the novel androgen had, as compared to testosterone, a beneficial effect on the prostate. Moreover, in intact animals the novel androgen even reduced prostate weight, which underlines the beneficial effect of the androgen on the prostate. In conclusion tissue selective androgens offer full replacement on MLA, bone and CNS, and have beneficial effects on the prostate.
151
152
FUNCTIONAL RESPONSES OF ISOLATED HUMAN PROSTATE T I S S U E T O D R U G S I N T E R F E R I N G W I T H T H E CGMP-PATHWAY
THE EFFECTS OF PROTEIN AND ENERGY MATERNAL MALNUTRITION DURING LACTATION ON THE PROSTATE GLANDULAR COMPONENT I N RATS. H I S T O M O R P H O M E T R I C ANALYSIS
Kedia G. t, Ockert S. 1, Scheller E 2, Chigogidze T. 3, Jonas U. ~, Managadze L, 3, Truss M. 1 ~Hannover Medical School, Department of Urology, Hannover, Germany, ZHannover Medical School, Department of Nuclear Medicine, Hannover, Germany, 3National Center of Urology, Department of Urology, Tbilisi, Georgia INTRODUCTION & OBJECTIVES: It has been demonstrated that the cyclic nucleotide monophosphates cAMP and cGMP (cNMP) are involved in the control of human urogenital tract smooth musculature. Thus, guanylyl and adenylyl cyclases, as well as cNMP-degrading phosphodiesterases represent important target proteins for the development of potential new drug candidates which might be beneficial in the treatment of lower urinary tract symptomatology (LUTS) and benign prostatic hyperplasia (BPH). The aim of our study was to examine the effects of some nitric oxide (NO) donating agents, as well as C-type natriuretic peptide (CNP), an endogenous ligand of the membrane-bound guanylyl cyclase B, on human prostate tissue isolated from the transition zone. The effects of the drugs were compared to those of sodium nitropmsside (SNP) and forskolin. M A T E R I A L & METHODS: Prostate tissue was obtained from male patients during surgery for localized carcinoma of the prostate or urinary bladder. Using the organ bath technique, the effects of S-nitrosoglutathione (GSNO) and S-nitrosocysteine (SNC), as well as CNP, forskolin, SNP and linsidomine (SIN-I) (1 nM - 1/10 gM) on the tension induced by norepinephrine (NE) of isolated human prostate strips were investigated. Tissue strips were also exposed to increasing concentrations of the dmgs and the production of cGMP and cAMP was determined by means of a radioimmunoassay. RESULTS: The tension induced by NE (40 gM) of the prostate strips was dosedependly reversed by the drugs. The rank order of potency was: Forskolin > SNP > GSNO > SIN-1 > SNC = CNP (1 /xM). Rmax values ranged from 63 % (Forskolin) to 42 % (CNP). From the compounds tested in the experiments, only SNP and the adcnylyl cyclase activator forskolin reached an EC50 value. Relaxing effects of the drugs were paralleled by a 2-fuld to 40-fold increase in tissue levels of cAMP and 2-fold to 45-fold elevation of cGMR CONCLUSIONS: Our results provide evidence that cGMP and cAMP are involved in the control of the normal function of the smooth musculature located in the transition zone of the human prostate. Our findings may provide new options for the furore treatment of LUTS and bladder outlet obstruction (BOO) secondary to BPH. This study was supported by a research grant from the European Association of Urology (EAU), Amhem, The Netherlands.
European Urology Supplements 4 (2005) No. 3, pp. 40
Babinski M., Alba S., Ricardo N., Costa W., Ramos C., Sampaio F. State University of Rio de Janeiro, Urogenital Research Unit, Rio de Janeiro, Brazil I N T R O D U C T I O N & O B J E C T I V E S : The malnutrition is the most prevalent nutritional disorder among children in development countries, since protein malnutrition frequently happens during pregnancy, lactation and the first two months of life. In this way, our goal was to determine the effects of protein and energy restriction during lactation in the morphology of the prostate glandular components of the pups at weaning. M A T E R I A L & M E T H O D S : At parturition, dams were randomly assigned to the following groups: (C) control group, with free access to a standard laboratory diet containing 23% protein; (PR) protein-restricted group, with free access to an isoenergy and protein-restricted diet containing 8% protein; and (ER) energyrestricted group, receiving standard laboratory diet in restricted quantities. At weaning, all pups were sacrificed with pentobarbital and the prostate gland was excised, e m b e d d e d in paraffin and stained with hematoxylin/eosin. The histomorfometric parameters analyzed were luminal area, acinar area, and epithelial area. From each prostate gland, five different sections were selected from five fragments. Then, five random fields were evaluated from each section. Therefore, there were 25 test areas from each prostate. R E S U L T S : The total luminal area (C = 18122.2 -~ 875.2; PR = 16517.4 ± 1787.0; E R = 14.891.4 i 1318.8, p < 0.01) and the total acinar area (C = 5589.8 ± 369.7; PR 3776.4 ± 561.8; E R = 4657.6 ± 443, p < 0.01) were significantly reduced in both PR and E R groups. In spite of a slight decrease, the epithelial area was not significantly different among the groups (C = 24186.6 ± 1602.2; PR = 20294.0 ± 1411.9; E R = 19549.0 ± 1697.0). C O N C L U S I O N S : These results show that protein and energy restriction during lactation leads to an atrophy of the prostatic acini, suggesting a possible alteration in the secretion mechanism.
~50 POTENTIAL BENEFICIAL EFFECTS ANDROGEN ON THE PROSTATE
OF A NOVEL
SELECTIVE
Attia D., Grootenhuis A. Mitropoulos D. 1 Ploumidou K.2, Kyroudi-Voulgari A. 3, Perea D. ~, Zervas A. ~, Karayaanacos P.-' N.V. Organon, Pharmacology, Oss, The Netherlands 1Athans Medical School, 1st Department of Urology, Athens, Greece, ~Athens Medical School, Department of Experimental Surgel~¢and Surgical Research, Athens, Greece, 3Athens Medical School, Department of Histology and Embryology, Athens, Greece INTRODUCTION & OBJECTIVES: Dietary factors rnay have an effect on benign prostate hyperplasia (BPH) through a variety of mechanisms such as elevation of sympathetic nervous system activity and testosterone concentrations. Alpha 1-adrenoreceptor antagonists are clinically used in patients with symptomatic BPH and besides their effect on smooth muscle tone they may affect the dynamics of prostate growth and the lipid profile. The objective of this research was to examine the impact of hypercholesterol diet (HD) and terazosin (TRZ) administration on serum lipid profile and ventral prostate structure in rats. MATERIAL & METHODS: Forty-five male Wistar rats were fed, beginning at 120 days of age, for 5 months with either standard experimental animals' food (SD) (15 animals) or standard food enriched with 4% cholesterol and 1% cholic acid (30 animals). During the last 2 months of the experimentation period 15 animals of the second group received TRZ (1 mg/Kg body weight diluted in normal saline) orally every second day. The body (BW) and ventral prostate weights (VPW), the serum lipid profile and the ventral prostate structure were determined. RESULTS: BW did not vary among groups. However, VPW of rats fed with HD differed significantly from those receiving SD (0.69±0.13 vs. 0.86:t:0.25) and was further decreased in rats treated with TRZ (0.53±&I1). HD resulted in significant elevation of total cholesterol (464±267 vs. 894-15) and LDL (3214-257 vs. 154-9), while HDL and triglyceride serum levels remained unaffected. TRZ treaUnent of animals under HD resulted in significantlylower total cholesterol, LDL and triglyceride levels (2554-76 vs. 464±267, 192±72 vs. 321±257, and 924-73 vs. 1194-46, respectively), while HDL levels were comparable (39±12 vs. 504-9). Hematoxylin-eosin staining of prostatic tissue in rats fed with SD revealed normal epitheliumlined acini surrounded by a stromal matrix. HD affected almost unanimously, the microscopic structure of the ventral prostate; epithelial cells of the distal area formed papillary projections within the acinar lumen and had more cytoplasm than controls. In most cases vesicular formations within the cytoplasmic area were noted as well. TRZ administration did not result in any obvious alterations. CONCLUSIONS: Our findings suggest that hypercholesterolemia causes marked changes in the rat ventral prostate and could contribute to BPH pathogenesis. Although short-term terazosin treatment did not result in structural alterations, it had a beneficial effect on the lipid profile which may imply that alpha-blockers have a parallel effect on lipid metabolism.
INTRODUCTION & OBJECTIVES: New orally active selective androgens are being developed for male contraception and hormone replacement therapy. Selective androgens suppress LH levels, thus reducing endogenous testosterone/dihydrotestosterone levels. As such, selective androgens are believed to be beneficial for the prostate since endogenous and especially intraprostatic testosterone/dihyrotestosterone levels are replaced by androgens that are not potentiated by 5ct-reduetion, which has been confirtned by in vitro assays (data not shown). MATERIAL & METHODS: In order to test this hypothesis castrated and intact male rats were treated for 6 weeks with either daily p.o. administration of testosterone undecanoate (TU; 40 mg/kg) or daily p.o. administration of the novel androgen (2.5 mg/kg). The androgen replacement capacity of the novel androgen was determined by measuring the maintenance of muscle levator ani (MLA) weight, maintenance of bone mineral density (BMD), suppression of luteinizing hormone (LH) levels and the prostate weight in castrated rats, The beneficial potential for the prostate of the novel androgen was tested by measuring ventral prostate weight in intact male rats (with normal circulating and intraprostatic testosternne/dilaydrotestosterone levels). Fm'thermore, the influence of TU and the novel androgen on prostate epithelial cell proliferation and epithelial cell apoptosis was detemrined in intact male rats. RESULTS: Treatment of castrated rats with TU maintained MLA weight and BMD at intact placebo-treated levels and suppressed serum LH levels. Treatment of castrated rats with the novel androgen maintained MLA weight and BMD even above intact placebo-treated levels and also suppressed serum LH levels. Thus, the novel androgen offered full androgen replacement on MLA, bone and CNS (LH suppression). Treatment of castrated rats with TU increased ventral prostate weight above intact placebo-treated level, whereas treatment with the novel androgen maintained prostate weight at a level far below intact placebo-treated level. In intact male rats TU also increased ventral prostate weight above intact placebotreated level, whereas treatment with the novel androgen reduced prostate weight below intact placebo-treated level. In intact male rats TU increased epithelial cell proliferation and decreased epithelial cell apoptosis, whereas the novel androgen maintained tissue homeostasis. CONCLUSIONS: In summary, the novel selective androgen suppressed LH levels and provided full androgen replacement on muscle mass and bone, but the novel androgen had, as compared to testosterone, a beneficial effect on the prostate. Moreover, in intact animals the novel androgen even reduced prostate weight, which underlines the beneficial effect of the androgen on the prostate. In conclusion tissue selective androgens offer full replacement on MLA, bone and CNS, and have beneficial effects on the prostate.
151
152
FUNCTIONAL RESPONSES OF ISOLATED HUMAN PROSTATE T I S S U E T O D R U G S I N T E R F E R I N G W I T H T H E CGMP-PATHWAY
THE EFFECTS OF PROTEIN AND ENERGY MATERNAL MALNUTRITION DURING LACTATION ON THE PROSTATE GLANDULAR COMPONENT I N RATS. H I S T O M O R P H O M E T R I C ANALYSIS
Kedia G. t, Ockert S. 1, Scheller E 2, Chigogidze T. 3, Jonas U. ~, Managadze L, 3, Truss M. 1 ~Hannover Medical School, Department of Urology, Hannover, Germany, ZHannover Medical School, Department of Nuclear Medicine, Hannover, Germany, 3National Center of Urology, Department of Urology, Tbilisi, Georgia INTRODUCTION & OBJECTIVES: It has been demonstrated that the cyclic nucleotide monophosphates cAMP and cGMP (cNMP) are involved in the control of human urogenital tract smooth musculature. Thus, guanylyl and adenylyl cyclases, as well as cNMP-degrading phosphodiesterases represent important target proteins for the development of potential new drug candidates which might be beneficial in the treatment of lower urinary tract symptomatology (LUTS) and benign prostatic hyperplasia (BPH). The aim of our study was to examine the effects of some nitric oxide (NO) donating agents, as well as C-type natriuretic peptide (CNP), an endogenous ligand of the membrane-bound guanylyl cyclase B, on human prostate tissue isolated from the transition zone. The effects of the drugs were compared to those of sodium nitropmsside (SNP) and forskolin. M A T E R I A L & METHODS: Prostate tissue was obtained from male patients during surgery for localized carcinoma of the prostate or urinary bladder. Using the organ bath technique, the effects of S-nitrosoglutathione (GSNO) and S-nitrosocysteine (SNC), as well as CNP, forskolin, SNP and linsidomine (SIN-I) (1 nM - 1/10 gM) on the tension induced by norepinephrine (NE) of isolated human prostate strips were investigated. Tissue strips were also exposed to increasing concentrations of the dmgs and the production of cGMP and cAMP was determined by means of a radioimmunoassay. RESULTS: The tension induced by NE (40 gM) of the prostate strips was dosedependly reversed by the drugs. The rank order of potency was: Forskolin > SNP > GSNO > SIN-1 > SNC = CNP (1 /xM). Rmax values ranged from 63 % (Forskolin) to 42 % (CNP). From the compounds tested in the experiments, only SNP and the adcnylyl cyclase activator forskolin reached an EC50 value. Relaxing effects of the drugs were paralleled by a 2-fuld to 40-fold increase in tissue levels of cAMP and 2-fold to 45-fold elevation of cGMR CONCLUSIONS: Our results provide evidence that cGMP and cAMP are involved in the control of the normal function of the smooth musculature located in the transition zone of the human prostate. Our findings may provide new options for the furore treatment of LUTS and bladder outlet obstruction (BOO) secondary to BPH. This study was supported by a research grant from the European Association of Urology (EAU), Amhem, The Netherlands.
European Urology Supplements 4 (2005) No. 3, pp. 40
Babinski M., Alba S., Ricardo N., Costa W., Ramos C., Sampaio F. State University of Rio de Janeiro, Urogenital Research Unit, Rio de Janeiro, Brazil I N T R O D U C T I O N & O B J E C T I V E S : The malnutrition is the most prevalent nutritional disorder among children in development countries, since protein malnutrition frequently happens during pregnancy, lactation and the first two months of life. In this way, our goal was to determine the effects of protein and energy restriction during lactation in the morphology of the prostate glandular components of the pups at weaning. M A T E R I A L & M E T H O D S : At parturition, dams were randomly assigned to the following groups: (C) control group, with free access to a standard laboratory diet containing 23% protein; (PR) protein-restricted group, with free access to an isoenergy and protein-restricted diet containing 8% protein; and (ER) energyrestricted group, receiving standard laboratory diet in restricted quantities. At weaning, all pups were sacrificed with pentobarbital and the prostate gland was excised, e m b e d d e d in paraffin and stained with hematoxylin/eosin. The histomorfometric parameters analyzed were luminal area, acinar area, and epithelial area. From each prostate gland, five different sections were selected from five fragments. Then, five random fields were evaluated from each section. Therefore, there were 25 test areas from each prostate. R E S U L T S : The total luminal area (C = 18122.2 -~ 875.2; PR = 16517.4 ± 1787.0; E R = 14.891.4 i 1318.8, p < 0.01) and the total acinar area (C = 5589.8 ± 369.7; PR 3776.4 ± 561.8; E R = 4657.6 ± 443, p < 0.01) were significantly reduced in both PR and E R groups. In spite of a slight decrease, the epithelial area was not significantly different among the groups (C = 24186.6 ± 1602.2; PR = 20294.0 ± 1411.9; E R = 19549.0 ± 1697.0). C O N C L U S I O N S : These results show that protein and energy restriction during lactation leads to an atrophy of the prostatic acini, suggesting a possible alteration in the secretion mechanism.