Rabbit Prostate Research Articles

Effect of doxazosin on ischemia-induced increased contractility of the rabbit prostate

Effect of doxazosin on ischemia-induced increased contractility of the rabbit prostate

Endogenous nitric oxide‐mediated relaxation and nitrinergic innervation in the rabbit prostate: The changes with aging

Endogenous nitric oxide‐mediated relaxation and nitrinergic innervation in the rabbit prostate: The changes with aging

Z-350, a new chimera compound possessing alpha1-adrenoceptor antagonistic and steroid 5alpha-reductase inhibitory actions.

The effects of Z-350, (S)-4-[3-(4-{1-(4-methyl-phenyl)-3-[4-(2-methoxyphenyl)piperazine-1-yl]propoxy} benzoyl)indole-1-yl]butyric acid hydrochloride, a newly synthesized compound possessing alpha-adrenoceptor antagonistic and steroid 5alpha-reductase inhibitory actions, were studied in vitro. In functional experiments, Z-350 shifted the concentration/response curve for the phenylephrine-induced contraction of rabbit prostate, urethra and aorta to the right with pA2 values of 8.04, 7.57 and 7.13, respectively. The binding affinity of Z-350 for alpha1-adrenoceptors in rabbit prostate, urethra and aorta were estimated by the displacement of [3H]prazosin. The pKi values for this action of Z-350 were 7.53, 7.95 and 7.62 for the prostate, urethra and aorta, respectively. alpha1-Adrenoceptor subtype selectivities were studied in the submaxillary gland (r(1A) and liver (alpha1B) of rat. Z-350 inhibited the specific binding of [3H]prazosin to alpha1A and (alpha1B-adrenoceptors with pKi values of 7.82 and 7.29, respectively. Z-350 inhibited rat prostatic steroid 5alpha-reductase non-competitively with a pIC50 of 8.42. These results indicate that Z-350 is a alpha1-adrenoceptor antagonist and is a steroid 5alpha-reductase inhibitor. It is expected that Z-350 will be a candidate drug for the treatment of benign prostatic hyperplasia.

Effects of the major alkaloid ofHydrastis canadensis L., berberine, on rabbit prostate strips

Previous studies (Palmery et al., 1996) have shown that Hydrastis canadensis L. displays adrenolytic activity possibly ascribable to berberine (Ber), its principal alkaloid. The aim of this study was to compare the activity of H. canadensis extract (HCE) with that of Ber on rabbit prostate strips. Both HCE and Ber inhibited prostate contraction mediated by norepinephrine (NE) and phenilephrine (PHE). The effect of HCE is less pronounced than that of Ber at the same dose on NE-induced prostate contraction. These results suggest that other factors with adrenergic activity may modulate NE response. Moreover, HCE seems to be, at least at some doses, more effective than Ber on PHE-mediated prostate contraction. Studies on the effect of other alkaloids present in the extract will contribute to the understanding of this phenomenon. This study also points to a possible therapeutic use of Ber in prostatic hypertrophy. Copyright © 1998 John Wiley & Sons, Ltd.

Effects of the major alkaloid of Hydrastis canadensis L., berberine, on rabbit prostate strips

Previous studies (Palmery et al., 1996) have shown that Hydrastis canadensis L. displays adrenolytic activity possibly ascribable to berberine (Ber), its principal alkaloid. The aim of this study was to compare the activity of H. canadensis extract (HCE) with that of Ber on rabbit prostate strips. Both HCE and Ber inhibited prostate contraction mediated by norepinephrine (NE) and phenilephrine (PHE). The effect of HCE is less pronounced than that of Ber at the same dose on NE-induced prostate contraction. These results suggest that other factors with adrenergic activity may modulate NE response. Moreover, HCE seems to be, at least at some doses, more effective than Ber on PHE-mediated prostate contraction. Studies on the effect of other alkaloids present in the extract will contribute to the understanding of this phenomenon. This study also points to a possible therapeutic use of Ber in prostatic hypertrophy. Copyright © 1998 John Wiley & Sons, Ltd.

Effects of bovine prostate powder on zinc, glucose, and insulin metabolism in old patients with non—insulin-dependent diabetes mellitus

Since rabbit prostate extract strongly stimulated intestinal zinc absorption and improved the diabetic condition of streptozotocin-induced diabetic rats, we examined the effects of 200 mg bovine prostate powder supplemented with 20 mg zinc (Pro-Z) on the clinical manifestations of older male patients with type II diabetes. Twenty-two male patients who received Pro-Z capsules two to four times per day for 3 months showed reduced mean fasting blood glucose levels from 202 to 169 mg/dL, hemoglobin A 1C-(HbA 1C) concentraitons from 12.2% to 9.5%, and mean values for the 3-hour area response above the fasting glucose concentration (TAFGC) from 141 to 102 mg glucose/dL/h. In eighteen patients who received placebo, mean values for fasting blood glucose decreased from 167 to 165 mg/dL and HbA 1AC from 10.4% to 10.2%, and for TAFGC increased from 121 to 126 mg glucose/dL/h. No detrimental changes occured in the liver and kidney function of patients receiving either Pro-Z or placebo. However, blood cholesterol and low-density lipoprotein in patients receiving Pro-Z decreased slightly, whereas values in the placebo group tended to increase. The mean fasting plasma insulin decreased 15.5 to 13.8 μU/mL in subjects given Pro-Z, while the zinc concentration increased from 1.21 to 1.39 μg/mL. In contrast, the mean value for plasma insulin in the placebo group changed from 14.4 to 15.4 μU/mL (worsened), and for zinc, from 1.24 to 1.30 μg/ml. Interestingly, fasting urinary glucose concentrations in subjects given Pro-Z decreased from 1,249 to 378 mg/dL, whereas in those given were normal, these results suggest that biochemical constituents in the prostate including zinc may be involved in controlling glucose metabolism in patients with non—insulin-dependent diabetes mellitus.

Determination of nitric oxide synthase activity in rat, pig and rabbit prostate glands

The conversion of l-arginine to l-citrulline by nitric oxide synthase and other enzymes was studied in rat, pig and rabbit prostate glands by incubating preparations of the glands with [ 3 H ] l-arginine and measuring [ 3 H ] l-citrulline formation. The nitric oxide synthase inhibitor N G-nitro- l-arginine, (100 μM) reduced [ 3 H ] l-citrulline production in preparations from all three species. The arginase inhibitor l-valine (60 mM) inhibited [ 3 H ] l-citrulline production in rat and pig but not in rabbit prostate preparations. Omission of calcium or NADPH significantly reduced nitric oxide synthase-like activity in preparations from all three species but arginase-like activity was not significantly affected. The results indicate that the rabbit prostate contains the greatest amount of calcium-dependent nitric oxide synthase activity, the rat and pig prostates also have arginase-like enzymatic activity and the rat prostate contains an additional unidentified enzyme that converts l-arginine to l-citrulline.

Characterisation of excitatory and inhibitory transmitter systems in prostate glands of rats, guinea pigs, rabbits and pigs

Excitatory and inhibitory transmitter systems were investigated in strips of prostate glands from rats, guinea pigs, pigs and rabbits. In strips from all species, electrical field stimulation (1 ms pulses at 1–30 Hz for 10 s) produced frequency-dependent contractions which were abolished by tetrodotoxin (1 μM). In strips from rats, guinea pigs and rabbits, contractions were reduced by prazosin (1 μM), guanethidine (10 μM) and atropine (2 μM), indicating the presence of noradrenergic and cholinergic mechanisms. However, the smooth muscle in the pig prostate appears to have a non-(nor)adrenergic non-cholinergic (NANC) excitatory innervation for which the transmitter was not identified. When noradrenergic and cholinergic mechanisms were blocked by guanethidine and atropine, respectively, and tone was raised with noradrenaline or methoxamine, field stimulation produced relaxations only in strips of rabbit prostate, and these were greatly reduced by N G-nitro- l-arginine methyl ester ( l-NAME, 100 μM), providing functional evidence for a nitrergic relaxant innervation. In accord with this, nitric oxide (NO) synthase activity was considerably higher in rabbit than in rat or pig prostates.

The expression of receptors for estrogen and epithelial growth factor in the male rabbit prostate and prostatic urethra following castration.

In the lower urinary tract of the male rabbit, estrogen receptors (ERs) are restricted to the urethra and the prostatic stroma. At present, the function of ERs in these tissues is not known. Epithelial growth factor (EGF) stimulates proliferation of epidermal and epithelial tissues, and several animal studies have indicated that EGF is regulated by estrogen. On this background, we have studied the effect of castration on the expression of ERs and EGF receptors in the rabbit prostatic urethra and prostate. Twelve male rabbits were studied fourteen days after castration, and eight normal rabbits were included as controls. In the control group, ERs were found in the urothelial lining and lamina propria of the prostatic urethra, and in the prostatic stroma. EGF receptors were demonstrated in the epithelial lining of the prostatic urethra and the glandular epithelium of the prostate. Following castration, the expression of ERs, assessed as the increase in the number of positively stained specimens, increased significantly in the lamina propria of the prostatic urethra and the prostatic stroma. EGF receptor expression increased significantly in the epithelial lining of the prostatic urethra. In the prostate, the increase was not significant. The results give no support to the view that ERs play role in the regulation of EGF receptors in the rabbit prostatic urethra nor the prostate.

Comparative regulation of ?1-adrenergic receptor mediated contraction in urogenitally derived smooth muscle

Contractility of smooth muscle within mammalian urogenital organ systems has an established role in physiological/pathophysiological functioning of the component structures. Our aim was to examine the direct effect of epidermal growth factor (EGF) on smooth muscle tone as well as its indirect effects in regulating alpha1-adrenoceptor-mediated contraction of the prostate, the vas deferens and renal arteries. Tissues were mounted isometrically, under controlled conditions, and changes in tension in response to treatment with phenylephrine (PE) with or without pretreatment with EGF were recorded on a physiological recorder via force transducers. In the rabbit prostate, EGF potentiated the magnitude of contraction to PE. The potentiation appeared to be dependent on cyclo-oxygenase products. In the human prostate, EGF potentiated the contractile response to PE. EGF had no effect on the PE-induced contraction of the rabbit renal artery and vas deferens. EGF alone did not alter smooth muscle tone in any of the above-mentioned tissues. The main finding of this study is the difference in the regulation by EGF of the alpha1-adrenoceptor-mediated response in smooth muscle of the prostate, from that by the vas deferens and renal artery. The reasons for this difference in response remain to be elucidated. This study may form the basis for further investigation into receptor transregulation and its relevance to symptomatic benign prostatic hyperplasia (BPH).

Pharmacological evidence that different alpha 1 adrenoceptor subtypes mediate contraction in rabbit prostate and hypogastric artery.

The alpha 1 adrenoceptor subtypes mediating contraction of rabbit prostate and hypogastric artery were pharmacologically characterized using an isolated organ bath technique. The prostate had the same sensitivity to the contractile action of methoxamine and phenylephrine, whereas the hypogastric artery was five times less sensitive to the action of methoxamine in comparison with phenylephrine. Clonidine elicited contraction in the hypogastric artery but not in the prostate. BMY7378 was about 70-fold more potent to antagonize the phenylephrine-induced contraction in the hypogastric artery (pA2 8.14) than in the prostate (pA2 6.28), and 5-methyl-urapidil was about three-fold more potent on prostrate than on hypogastric artery. The potency of different alpha 1-adrenoceptor antagonists tested in the rabbit prostate was significantly correlated with their binding affinity for the expressed recombinant alpha 1A-, but not alpha 1B- or alpha 1D-, adrenoceptor subtype, whereas, the potency of the alpha 1-adrenoceptor antagonists tested in the rabbit hypogastric artery was better correlated with the defined alpha 1D-adrenoceptor. Chloroethylclonidine produced a 10-fold rightward shift in the phenylephrine concentration-response curve in the hypogastric artery but only had a weak effect in the prostate. The results indicate that significant heterogeneity exists among alpha1-adrenoceptor in the rabbit hypogastric artery (alpha 1D-adrenoceptor) and the prostate (alpha 1A-adrenoceptor).

Effect of KMD-3213, an α1a-adrenoceptor-selective antagonist, on the contractions of rabbit prostate and rabbit and rat aorta

KMD-3213, (−)-( R)-1-(3-hydroxypropyl)-5-[2-[[2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]indoline-7-carboxamide, a newly synthesized α 1-adrenoceptor antagonist, has been shown to have potent action toward, and to be selective for human cloned and native α 1-adrenoceptors. In the present study, we characterized the inhibitory effect of KMD-3213 on the phenylephrine ( α 1-adrenoceptor-selective agonist)-induced contraction of rabbit prostate, rabbit thoracic aorta and rat thoracic aorta to functionally confirm the tissue selectivity of KMD-3213. The mean pA 2 value for KMD-3213 for the inhibition of the rabbit prostatic contraction was 10.05, whereas the values for the rabbit and rat aortic contractions were 9.36 and 8.13, respectively. The order of mean pA 2 values for the inhibition of the rabbit prostatic contraction was KMD-3213 ≥ tamsulosin > > prazosin, whereas that for the rabbit and rat aortic contractions was tamsulosin > KMD-3213 > prazosin and tamsulosin ≥ prazosin > > KMD-3213, respectively. KMD-3213 produced a sigmoidal inhibition curve for single-dose phenylephrine-induced contractions of rabbit prostate, whereas it produced a non-sigmoidal curve for that of rabbit aorta. KMD-3213 had no effect on isoproterenol-induced chronotropic action in guinea-pig atria, and 5-hydroxytryptamine-, histamine- and acetylcholine-mediated contractions of rabbit aorta. These results indicate that the potency of the inhibitory activity of KMD-3213 depends on the tissue subtype expression and that KMD-3213 preferentially antagonizes prostatic contraction.

P.1.064 - Responsiveness of rabbit prostate strips to imipramine and trazodone

P.1.064 - Responsiveness of rabbit prostate strips to imipramine and trazodone

P-379 - Further evidence that putative α1L-adrenoceptor is involved in adrenergic contraction of rabbit prostate

P-379 - Further evidence that putative α1L-adrenoceptor is involved in adrenergic contraction of rabbit prostate

Identification of α1 adrenoceptor subtypes in the rabbit prostate

1. The alpha 1-adrenoceptor subtypes of rabbit prostate were characterized in binding and functional experiments. 2. In saturation experiments, [3H]-prazosin bound to two distinct affinity sites in the rabbit prostate (pKD = 11.20 +/- 0.22 and 8.39 +/- 0.11, Bmax = 15.3 and 736 fmol mg protein-1). 3. In the displacement experiments, the binding was inhibited with shallow displacement curves by unlabelled prazosin, WB4101, and 5-methylurapidil, suggesting the presence of two distinct affinity sites for prazosin, WB4101, or 5-methylurapidil. On the other hand, HV723 displaced the [3H]-prazosin binding monophasically with a low affinity. From the results, the presence of two distinct alpha 1-adrenoceptor subtypes was suggested; presumably one is the classical alpha 1A (cloned alpha 1C) subtype with high affinity for prazosin, WB4101 and 5-methylurapidil but not for HV723 and the other corresponds to the alpha 1L subtype, which shows low affinity for the four antagonists. 4. In the functional experiments, prazosin, WB4101, HV723 and 5-methylurapidil competitively antagonized the contractile response to noradrenaline with low affinities close to those for the alpha 1L subtype determined in binding experiments. These results suggest that contractile response to noradrenaline in the rabbit prostate is predominantly mediated through the alpha 1L subtype.

Cloning and partial sequence of the rabbit androgen receptor: expression in fetal urogenital tissues.

Genetic studies indicate that the actions of testosterone and dihydrotestosterone are mediated by a single androgen receptor (AR). The basis for the differential effects of these hormones during development is not known. To address this problem, we have turned to the rabbit, a species in which the endocrine and metabolic events in male sexual differentiation have been studied in detail. As a first step, we have cloned a partial cDNA encoding the rabbit prostate AR and have analyzed the expression of the cDNA in tissues of rabbit embryos at the time during which male phenotypic differentiation takes place. The coding sequence of the rabbit AR cDNA reveals a high degree of conservation with the sequences of the human, mouse, and rat ARs. By Northern analysis the principal transcript expressed in the mesonephros and the anlage of the external genitalia on gestation day 18 appeared to be identical to the mRNA expressed in adult prostate and epididymis.

In vivo and in vitro effects of dexamethasone on pituitary thyrotrophin-releasing hormone-like peptide concentrations in the rat.

The novel peptide, pyroglutamyl-glutamyl-proline amide (pGlu-Glu-ProNH2; EEP), which has structural and immunological similarities to TRH (pGlu-His-ProNH2) has recently been shown to contribute to total TRH-like immunoreactivity (t-TRH-LI) detected in the rabbit prostate and rat and porcine anterior pituitary. In this study, the effects of dexamethasone (DEX) on rat pituitary TRH-like peptide levels in the rat were determined. TRH-like immunoreactivity (TRH-LI) was separated by ion exchange chromatography and detected by TRH RIA. Anion exchange chromatographic analysis suggested that EEP-like immunoreactivity (EEP-LI) accounted for 15.0 +/- 1.2 pmol t-TRH-LI/g (70.4 +/- 3.9%) in the control anterior pituitary with the remaining t-TRH-LI being due to TRH-LI. Following DEX treatment pituitary EEP-LI and TRH-LI increased by 200% and 400% (P < 0.001) respectively, constituting a 2.5-fold increase in t-TRH-LI in the pituitary. TRH-LI now accounted for 45.7 +/- 5.3% of t-TRH-LI compared with 29.6 +/- 4.1% in the controls. TRH-LI, but not EEP-LI, was detected in the hypothalamus and posterior pituitary, suggesting that EEP-LI is synthesised within the anterior pituitary. DEX also caused a 2.6-fold rise (P < 0.001) in t-TRH-LI in dispersed, cultured anterior pituitary cells. Chromatographic analysis of cultured pituitary cell extracts revealed that the majority of t-TRH-LI (> 98%) was due to TRH-LI.(ABSTRACT TRUNCATED AT 250 WORDS)

Gonadal steroids regulate rat anterior pituitary levels of TSH- releasing hormone- and pyroglutamyl-glutamyl-proline amide-like immunoreactivity

The novel peptide, pyroglutamylglutamylprolineamide (pGlu-Glu-ProNH2, EEP), which has structural and immunological similarities to TRH (pGlu-His-ProNH2) has recently been shown to contribute to total TRH-like immunoreactivity (t-TRH-LI) detected in the rabbit prostate and rat and porcine anterior pituitary. This study was undertaken to determine the effects of gonadal steroids on t-TRH-LI and its components in the rat hypothalamus and pituitary. EEP-like immunoreactivity (EEP-LI) was separated from TRH-LI by ion exchange chromatography and detected by TRH RIA. Although male and female posterior pituitary and hypothalamic t-TRH-LI levels were similar, the mean t-TRH-LI in female anterior pituitaries was significantly lower than that in males, 10.3 +/- 2.9 pmol/g vs. 24.4 +/- 2.5 pmol/g (P < 0.01). Anion exchange analysis of control anterior pituitary samples distinguished two peaks of t-TRH-LI, corresponding to [125I]-TRH marker and [3H]-EEP markers. In control female anterior pituitaries EEP-LI accounted for 26.0 +/- 2.4% of t-TRH-LI, whereas in males it accounted for 43.3 +/- 5.3% of the total. Hypothalamic and posterior pituitary samples only contained t-TRH-LI corresponding to [125I]-TRH markers. There was no significant change in hypothalamic and posterior pituitary levels of t-TRH-LI after ovariectomy or orchidectomy. Anterior pituitary levels of t-TRH-LI, however, were increased by an estimated 6-fold after ovariectomy and 2-fold after orchidectomy. After ovariectomy, the proportions of t-TRH-LI accounted for by TRH-LI and EEP-LI were reversed in the female. EEP-LI now accounted for the majority of t-TRH-LI, constituting an increase of approximately 21-fold in pituitary EEP-LI levels. The changes in the levels of pituitary TRH-LI and EEP-LI induced by ovariectomy were reversed by 17-beta-estradiol. As in the ovariectomized samples EEP-LI was increased (2-fold) by orchidectomy. Both TRH-LI, which increased 1.6-fold, and EEP-LI were restored to control values after testosterone replacement. These findings confirm the hypothesis that pituitary TRH-LI and EEP-LI are regulated by gonadal status. The fact that these changes were not observed in the hypothalamus and posterior pituitary suggests that TRH-LI and EEP-LI have specific functional significance in the pituitary gland.

Gonadal steroids regulate rat anterior pituitary levels of TSH-releasing hormone- and pyroglutamyl-glutamyl-proline amide-like immunoreactivity.

The novel peptide, pyroglutamylglutamylprolineamide (pGlu-Glu-ProNH2, EEP), which has structural and immunological similarities to TRH (pGlu-His-ProNH2) has recently been shown to contribute to total TRH-like immunoreactivity (t-TRH-LI) detected in the rabbit prostate and rat and porcine anterior pituitary. This study was undertaken to determine the effects of gonadal steroids on t-TRH-LI and its components in the rat hypothalamus and pituitary. EEP-like immunoreactivity (EEP-LI) was separated from TRH-LI by ion exchange chromatography and detected by TRH RIA. Although male and female posterior pituitary and hypothalamic t-TRH-LI levels were similar, the mean t-TRH-LI in female anterior pituitaries was significantly lower than that in males, 10.3 +/- 2.9 pmol/g vs. 24.4 +/- 2.5 pmol/g (P < 0.01). Anion exchange analysis of control anterior pituitary samples distinguished two peaks of t-TRH-LI, corresponding to [125I]-TRH marker and [3H]-EEP markers. In control female anterior pituitaries EEP-LI accounted for 26.0 +/- 2.4% of t-TRH-LI, whereas in males it accounted for 43.3 +/- 5.3% of the total. Hypothalamic and posterior pituitary samples only contained t-TRH-LI corresponding to [125I]-TRH markers. There was no significant change in hypothalamic and posterior pituitary levels of t-TRH-LI after ovariectomy or orchidectomy. Anterior pituitary levels of t-TRH-LI, however, were increased by an estimated 6-fold after ovariectomy and 2-fold after orchidectomy. After ovariectomy, the proportions of t-TRH-LI accounted for by TRH-LI and EEP-LI were reversed in the female. EEP-LI now accounted for the majority of t-TRH-LI, constituting an increase of approximately 21-fold in pituitary EEP-LI levels. The changes in the levels of pituitary TRH-LI and EEP-LI induced by ovariectomy were reversed by 17-beta-estradiol. As in the ovariectomized samples EEP-LI was increased (2-fold) by orchidectomy. Both TRH-LI, which increased 1.6-fold, and EEP-LI were restored to control values after testosterone replacement. These findings confirm the hypothesis that pituitary TRH-LI and EEP-LI are regulated by gonadal status. The fact that these changes were not observed in the hypothalamus and posterior pituitary suggests that TRH-LI and EEP-LI have specific functional significance in the pituitary gland.

Peptides related to thyrotrophin-releasing hormone (TRH) in human prostate and semen

The TRH-related peptide, pGlu-Glu-ProNH 2, which was first identified in rabbit prostate has recently been named fertilization-promoting peptide (FPP) because of its ability to enhance the in vitro fertilizing potential of mouse epididymal spermatozoa. This study set out to examine the nature of the TRH-related peptides in human prostate and semen but, first, the optimal conditions for collection of semen samples were investigated. FPP was degraded slowly (t 1 2 = 163 min, S.E. ± 5.13, n = 6) in seminal plasma which has allowed us to measure acurrately the concentrations of FPP, after extraction of the peptide in acidified acetone precisely 5 min after ejaculation. In this way, high levels of FPP (mean: 49.5 nmol/1) were detected in normal human semen, from young men, although other TRH-related peptides did not appear to be present. We have also examined the TRH-related peptides present in prostate samples from clinical patients both with and without evidence of benign prostatic hyperplasia (BPH), by ion-exchange chromatography followed by radioimmunoassay. Substantial concentrations of FPP were observed in normal (4.10 pmol/tissue, S.E. ± 1.46) and BPH prostate (6.27 pmol/g tissue, S.E. ± 1.65). In addition, a second, neutral TRH-immunoreactive peptide was always detected in BPH tissie (7.40 pmol/g tissue, S.E. ± 1.98) with only low levels generally present in normal prostate. The possibility that the presence of high levels of the neutral peptide in prostate may be used as an indicator of the onset of BPH deserves further scrutiny.