Human Prostatic Adenoma Research Articles

Abstract ED04-03: Interleukins at the crossroad of inflammation, senescence, and cancer

Abstract ED04-03 Benign lesions commonly contain one or more ‘driver’ mutations that may cause an initial phase of proliferation. Several mechanisms including apoptosis and lack of vessel formation, account for their failure to continue growing and to undergo full malignant transformation. As is illustrated by the absence of mitotic figures often seen in longstanding benign tumors, proliferative arrest represents an effective mechanism suppressing continued outgrowth and transformation to overt cancer. The proliferative arrest of long-term benign lesions, such as melanocytic nevi, shares a number of characteristics with cellular senescence, originally defined as a mechanism accounting for the cellular response to telomere attrition-dependent DNA damage in vitro. Recent evidence has implicated Oncogene-Induced cellular Senescence (OIS), which is induced prematurely (that is, before telomeric shortening can account for it), as a critical cause of arrest of benign neoplasms. It can be triggered by an activated oncogene like BRAFE600 or RASV12, or by the loss of a tumor suppressor gene, like PTEN or NF1, and occurs in a variety of cell types. OIS is associated with a largely irreversible loss of proliferative activity that is often accompanied by the upregulation of tumor suppressors like p16INK4A (a CDK4/6 inhibitor) and p21CIP1, an increase in Senescence-Associated β-Galactosidase (SA-β-Gal) activity, and elevated levels of PAI-1. A further hallmark of OIS is the formation of Senescence-Associated Heterochromatic Foci (SAHF), corresponding to subnuclear structures that contain heterochromatin proteins such as HP1. SAHF are associated with methylation of lysine 9 of histone H3 (K9M-H3) and are thought to contribute to the irreversible cell cycle exit of senescent cells by repressing the promoters of proliferation-associated genes. In addition to telomere dysfunction and oncogenic genetic events, senescence can be triggered by oxidative stress and by exposure to DNA-damaging agents. In vivo, OIS has been correlated with DNA replication stress and DNA hyper-replication. Convincing evidence of the importance of OIS as a physiologically relevant mechanism limiting tumorigenesis is rapidly emerging. Senescence markers have been identified in various in vivo lesions, including human melanocytic nevi, murine lung adenomas, human dermal neurofibromas, human and murine prostatic adenomas, pancreatic intraductal neoplasias, murine lymphomas and early murine melanomas. In aggregate, indications are that the role of OIS in the prevention of cancer is substantial. In recent years, unbiased experimental approaches including function-based genome-wide screens have unraveled unanticipated tumorigenic mechanisms. Despite such recent progress, we are only beginning to unveil the molecular mechanism of OIS and to identify the key players involved. By using a combination of gene expression microarrays and RNA interference, we asked whether we could uncover novel pathways that relay OIS. Combined microarray expression and Gene Ontology analysis revealed that OIS is specifically linked to an inflammatory transcriptome. Induced genes included interleukin 6 (IL-6), a pleiotropic cytokine often associated with cancer-promoting paracrine effects. Indeed, upon secretion by senescent cells IL-6 acted mitogenically in a paracrine fashion. Unexpectedly, in OIS IL-6 had a cell-autonomous role, being required in an autocrine fashion both for the induction and maintenance of cell cycle arrest of cells exposed to oncogenic stress. Upon IL-6 depletion, the inflammatory network collapsed and cells bypassed senescence. The transcription factor C/EBPβ was identified as an OIS integrator, acting with IL-6 to amplify the activation of the inflammatory network, including IL-8. In human colon adenomas, IL-8 specifically co-localized with arrested, p16INK4A-positive epithelium. On the basis of these results we propose a model in which the antagonistic functions of interleukins contribute to connect senescence with an inflammatory phenotype and cancer. Citation Information: Cancer Prev Res 2008;1(7 Suppl):ED04-03.

Alfuzosin, a selective alpha 1-adrenoceptor antagonist in the lower urinary tract.

1. Phenylephrine-induced contractions of rabbit isolated trigone and urethra were antagonized in a competitive manner by alfuzosin (pA2 7.44 and 7.30, respectively) and prazosin. 2. The characteristics of [3H]-prazosin binding to human prostatic adenoma tissue were evaluated. [3H]-prazosin was potently displaced by alpha 1-adrenoceptor specific agents including alfuzosin, its (+)- and (-)-enantiomers and prazosin (IC50 0.035, 0.023, 0.019 and 0.004 microM, respectively), but only weakly by alpha 2-adrenoceptor selective agents, for example, yohimbine (IC50 = 6.0 microM). 3. In the pithed rat, alfuzosin (0.03-0.3 mg kg-1, i.v.) markedly inhibited pressor responses produced by the alpha 1-selective agonist, cirazoline but inhibited only slightly responses to the alpha 2-selective agonist, UK 14,304. Alfuzosin (1 mg kg-1, i.v.) had minimal effects against responses mediated by stimulation of prejunctional alpha 2-receptors (UK 14,304-induced inhibition of sympathetic tachycardia). 4. In the anaesthetized cat, alfuzosin (0.001-1 mg kg-1, i.v.) and prazosin (0.001-0.3 mg kg-1, i.v.) produced dose-related inhibition of the increases in urethral pressure caused by stimulation of sympathetic hypogastric nerves. Prazosin was approximately 5 fold more potent than alfuzosin. When phenylephrine was employed to induce urethral and vascular alpha 1-mediated tone simultaneously, prazosin inhibited both stimuli with similar potency whereas alfusozin was 3-5 fold more potent against elevated urethral pressure. This functional uroselectivity of alfuzosin was more evident by the intraduodenal route, since doses of 0.03 and 0.1 mg kg-1 alfuzosin inhibited urethral pressure with minimal effects on arterial blood pressure. 5. Alfuzosin is a potent selective alpha1-adrenoceptor antagonist in tissues of the lower urinary tract including the human prostate. This provides a pharmacological basis for its use in the treatment of benign prostatic hypertrophy.

Subtypes of alpha 1-adrenoceptors in urinary bladder and urethral smooth muscle and prostatic adenoma

Two alpha 1-adrenoceptor subtypes (alpha 1A and alpha 1B) have been distinguished by competitive antagonists and alkylating agent chloroethylclonidine (CEC). The CEC-insensitive subtype (alpha 1A) had been suggested to selectively activate Ca2+ influx through Ca-channels in smooth muscle cell membrane. We examined the effects of WBC4101, CEC and verapamil on contractile responses to phenylephrine in rabbit aorta, urinary bladder and urethral smooth muscle and in human prostatic adenoma to examine the alpha 1-adrenoceptor subtypes in these tissue. Pretreatment with WB4101 caused a large shift to the right for phenylephrine-induced dose response curves and verapamil decreased the phenylephrine-induced contractions of rabbit aorta, urinary bladder and urethral smooth muscles and human prostatic adenomas. CEC inhibited only phenylephrine induced contractions of human prostatic adenomas. The pA2 value for WB4101 was significantly lower in human prostate than in rabbit aorta, urinary bladder and urethra. These results suggest that functional alpha 1-adrenoceptor subtypes involve alpha 1A and alpha 1B in human prostatic adenoma, while only alpha 1A in rabbit aorta, urinary bladder and urethral smooth muscles.

High-intensity focused ultrasound experimentation on human benign prostatic hypertrophy.

High intensity-focused ultrasound (HIFU) has been used transrectally to induce an intraprostatic coagulation necrosis lesion in human prostatic adenoma. The device to produce HIFU combines a firing system (power amplifier and therapy transducer) and an imaging system (ultrasound scanner). Nine patients have been treated on epidural anaesthesia with an ultrasound intensity similar to or higher than the acoustic intensity used in previous experiments on canine prostates. Intraprostatic lesions were obtained without any damage to the rectal wall. These lesions were also histologically determined to be coagulation necrosis with a complete destruction of the glandular tissue. These studies confirm the possibility of creating irreversible lesions in the prostatic tissue through the rectal wall. The destruction of localised prostatic cancer would seem to be possible in the near future by using HIFU delivered by the transrectal route.

Needle Ablation Using Radio Frequency Current as a Treatment for Benign Prostatic Hyperplasia: Experimental Results in ex vivo Human Prostate

Transurethral needle ablation of the prostate using low level radiofrequency (RF) energy was investigated in a human ex vivo model. RF power applications at a variety of power levels for various treatment times elicited marked thermal lesions of consistent sizes in prostatic adenomas. Tissue temperature was found to be the fundamental lesioning parameter. Lesions were created whenever tissue temperature exceeded 45 degrees C. Lesion size correlated with RF power delivery and electrode length. Monitoring of the tissue impedance assisted in controlling efficacious lesioning. RF power applications of 5-7.5 W for 3 min are suggested as the 'ideal' setting to treat human prostatic adenomas, taking into consideration the lesion size and time to achieve ablative temperatures.

Alpha 1-adrenoceptor properties of terazosin HCl and its enantiomers in the human prostate and canine brain.

The objective of the present study was to characterize the alpha 1-adrenoceptor binding properties of terazosin and its enantiomers in human prostate and canine brain. Human prostate adenomas were obtained from 7 males undergoing prostatectomy for symptomatic BPH and canine cerebral cortices were obtained from 6 male beagles. Competitive displacement experiments were carried out on these tissue homogenates in the presence of a constant concentration ([180 pM]) of 125I-Heat and varying concentrations of unlabelled terazosin and its enantiomers. The Ki of terazosin and its enantiomers were determined from these binding studies. The mean Ki of rac-terazosin, R(+)-terazosin, and S(-)-terazosin in human prostate was 3.6 nM, 3.8 nM, and 2.8 nM, respectively. The differences between these mean Ki values were not statistically significant. The mean Ki of rac-terazosin, R(+)-terazosin, and S(-)-terazosin in canine brain were 6.7 nM, 8.4 nM, and 5.6 nM, respectively. The differences between these mean Ki values were not significantly different. The mean Ki of terazosin and its enantiomers were consistently lower in the human prostate compared to canine brain (P less than 0.05). The present study does not provide any evidence suggesting differential effects of terazosin enantiomers on the human prostate. The twofold difference between the Ki values in the prostate and brain suggests that different subtypes of the alpha 1-receptor might be present in these tissues.

Antispasmodic effects of flavoxate, MFCA,and REC 15/2053 on smooth muscle of human prostate and urinary bladder

The antispasmodic effects of the flavone compounds flavoxate hydrochloride, 3-methylflavone carboxylic acid (MFCA), and REC 15/2053 (and in the case of the detrusor, oxybutynin), on the human detrusor, prostatic adenoma, prostatic capsule, and bladder neck, were studied by the in vitro isometric method. All the compounds inhibited, in different orders of potency, potassium-induced contractions of the tissues. Flavoxate showed a slightly greater activity than the other two compounds in the prostatic and bladder neck tissues. However, REC 15/2053 displayed greater activity in the detrusor than in the other tissues. The relaxant effect on the prostatic tissues suggests a potential use for these compounds in benign prostatic obstruction.

Characterization of 1,4, Dihydropyridine Calcium Channel Binding Sites in the Human Prostate

The binding and functional properties of calcium channel receptors have not been previously characterized in the normal or hyperplastic prostate. Dihydropyridine (DHP) binding sites have been characterized in other tissues using the ligands 3H-nitrendipene and (+)3H-PN200-110. Saturation experiments were performed on homogenates obtained from five human prostate adenomas using these ligands. The binding of 3H-nitrendipine and (+)3H-PN200-110 in the prostate was saturable and of high affinity. The mean Kd of 3H-nitrendipine and (+)3H-PN200-110 was 0.92 ± 0.11nM and 0.14 ± 0.02nM, respectively. The mean Bmax of 3H-nitrendipine and (+)3H-PN200-110 was 0.57 ± 0.06 and 0.19 ± 0.02fmol/mg. wet wt., respectively. The percent specific binding of 3H-nitrendipene and (+)3H-PN200-110 was 18 ± 1% and 38 ± 4%, respectively. The pharmacology of (+)3H-PN200-110 binding sites was further characterized using competition displacement experiments. The IC50 corrected values for Bay K 8644, nifedipine, verapamil, and diltiazem in the human prostate and other tissues are of the same order of magnitude. The prostate contains an abundance of high affinity DHP binding sites. The physiologic significance of the DHP binding sites in the prostate requires further investigation.

Binding and functional properties of doxazosin in the human prostate adenoma and canine brain

The binding and functional properties of doxazosin were characterized in the canine brain and human prostate. 3H-Doxazosin binding sites were characterized in canine brain and human prostate homogenates using saturation experiments. The binding of 3H-doxazosin in the canine brain was consistently saturable and of high affinity. The mean equilibrium dissociation constant (Kd) and density (Bmax) of 3H-doxazosin binding sites in the canine brain were 0.19 nM and 2.17 fmol/mg wet wt, respectively. The binding of 3H-doxazosin in human prostate homogenates was not consistently linear owing to a relatively high proportion of nonspecific doxazosin binding sites. The mean Kd and Bmax of 3H-doxazosin binding sites in the prostate determined from the saturation experiments yielding linear Scatchard plots were 0.2 nM and 0.51 fmol/mg wet wt. The pharmacology of doxazosin binding sites was further characterized in the canine brain using competitive binding experiments. The rank order of IC50corr values for norepinephrine, clonidine, yohimbine, terazosin, and prazosin indicated that doxazosin binds selectively to alpha 1 and alpha 2 adrenergic binding sites. The relative affinity of unlabeled doxazosin for alpha 1 and alpha 2 binding sites in the human prostate was determined by displacing 125I-Heat or 3H-rauwolscine with varying concentrations of unlabeled doxazosin. The affinity of doxazosin for alpha 1 binding sites in the prostate adenoma was approximately 100-fold greater than its affinity for alpha 2 binding sites. The potency of doxazosin for inhibiting phenylephrine-induced contractions in the prostate indicated that prostate smooth muscle contraction is mediated by alpha 1 adrenoceptors.

Autonomic Receptors in Human Prostate Adenomas

Radioligand receptor binding techniques were used to characterize alpha1 adrenergic, alpha2 adrenergic and muscarinic cholinergic (MCh) binding sites in human prostate adenomas obtained from men with symptomatic and asymptomatic benign prostatic hyperplasia (BPH). Prostate adenoma specimens were obtained from nine men with asymptomatic BPH undergoing cystoprostatectomy, 11 men with symptomatic BPH undergoing open prostatectomy, and 11 men with symptomatic BPH undergoing transurethral resection of the prostate (TURP). A quantitative symptoms score analysis and urinary flow rate determinations documented the absence of bladder outlet obstruction in men undergoing cystoprostatectomy and confirmed the presence of bladder outlet obstruction in men undergoing prostatectomy. The mean equilibrium dissociation constants (Kd) and the mean densities of 125I-Heat (alpha1 adrenergic) and 3H-NMS (MCh) binding sites were similar in tissue homogenates obtained from men with asymptomatic and symptomatic BPH. The mean Kd of 3H-Rauwolscine (3H-Ra) was significantly greater in the prostatectomy specimens obtained from men with symptomatic BPH compared to the specimens obtained from men with asymptomatic BPH (p < 0.05). The density of 3H-Ra (alpha2 adrenergic) binding sites was significantly greater in the prostate adenomas obtained from men with symptomatic BPH compared to the prostate adenomas obtained from men with asymptomatic BPH (p < 0.05). The difference in alpha2 adrenoceptor density was accounted for by an increased receptor density in the open prostatectomy specimens. There was no significant correlation between alpha2 adrenergic, alpha1 adrenergic, and MCh receptor densities and prostate weight or patient age. This study indicates that the development of infravesical obstruction in men with BPH is not related to upregulation or altered binding affinity of alpha1 adrenergic or MCh receptor binding sites. The significance of the observed upregulation of alpha2 adrenoreceptors in the prostate adenomas obtained from men undergoing open prostatectomy is unknown, and requires further investigation.

Contractile properties of human prostate adenomas and the development of infravesical obstruction

The contractile response of human prostate adenomas to KCl, phenylephrine (alpha 1 adrenergic agonist), UK 14304 (alpha 2 adrenergic agonist), and carbachol (muscarinic cholinergic agonist) was evaluated in tissue specimens obtained from men with symptomatic and asymptomatic BPH. Prostate specimens were obtained from 5 men with asymptomatic BPH undergoing cystoprostatectomy, 11 men with symptomatic BPH undergoing open prostatectomy, and 11 men with symptomatic BPH undergoing transurethral resection of the prostate (TURP). Quantitative symptom score analysis and urinary flow rate determination documented the absence of bladder outlet obstruction in men undergoing cystoprostatectomy and confirmed the presence of bladder outlet obstruction in men undergoing prostatectomy. The magnitude of the contractile response (Emax) and the potency of phenylephrine-induced contractions (EC50) in prostatic preparations obtained from men with symptomatic and asymptomatic BPH were similar. The IC50 for the inhibition of phenylephrine-induced contractions by prazosin was 3.2 nM, confirming that phenylephrine-induced contraction in the human prostate is mediated by the alpha 1 adrenoceptor. The contractile responses of prostate adenomas to muscarinic cholinergic and alpha 2 agonists were negligible. This study demonstrates that the development of bladder outlet obstruction in men with BPH is not related to alterations in the functional response of the smooth muscle component of the prostate adenoma.

The Alpha Adrenergic Binding Properties of Terazosin in the Human Prostate Adenoma and Canine Brain

Clinical trials are currently underway to evaluate the efficacy of terazosin for the treatment of symptomatic benign prostatic hyperplasia (BPH). Terazosin is a potent and selective alpha1 adrenergic blocking agent structurally similar to prazosin. The alpha adrenergic binding properties of terazosin were studied in human prostate adenomas and canine brains using radioligand receptor binding methods.Saturation analyses were performed at varying concentrations of [125I]-Heat and [3H]rauwolscine ([3H]Ra) in human prostate adenomas and canine brains. The binding of [125I]-Heat and [3H]Ra in the human prostates and canine brains was consistently saturable and of high affinity. The equilibrium dissociation constant (Kd) for [125I]-Heat binding in the canine brains and human prostate adenomas was 84.4 ± 4.3pM and 65.4 ± 19.2pM, respectively (p>0.05). The (Kd) for [3H] Ra binding in the human prostate adenomas and canine brains was 1.21 ± 0.23nM and 1.52 ± 0.28nM, respectively (p>0.05). The density of alpha1 (0.37 ± 0.15fmol/mg. wet wt.) and alpha2 (0.29 ± 0.09fmol/mg. wet wt. adrenergic binding sites in the human adenomas were similar (p>0.05). The IC50 corrected (IC50 corr) of terazosin for [125I]-Heat and [3H]Ra binding sites in the human prostate was 2.5nM and 1.0μm., respectively. The IC50 corr of terazosin for [125I]-Heat and [3H]Ra binding sites in the canine brain was 2.0nM and 0.8μM, respectively. The competitive binding assays indicate that terazosin binds selectively to alpha1 adrenergic binding sites in the human prostate and canine brain. (J. Urol., 140: 664–667, 1988)

The stereospecificity of LY253352 for alpha 1-adrenoceptor binding sites in the brain and prostate.

1. The stereospecificity of the enantiomers of LY253352, a potent and selective alpha 1-adrenoceptor antagonist, were studied in the human prostate and canine brain using radioligand receptor binding methods. 2. The mean equilibrium dissociation constant (KD) in the canine brain and human prostatic adenoma was 84.4 pM and 65.4 pM, respectively. 3. The alpha 1-adrenoceptor density in the canine brain was approximately eight fold greater than in the human prostatic adenoma. 4. The mean Ki values of (-)-LY253352 and (+)-LY253352 in the prostate were 0.19 nM and 5.79 nM, respectively. 5. The mean Ki values of (-)-LY253352 and (+)-LY253352 in the brain were 0.29 nM and 34.7 nM, respectively. 6. This study indicates that the stereochemical specificity of the optical isomers of LY253352 is a manifestation of differential affinities of the enantiomers for alpha 1-adrenoceptor binding sites. 7. The differential affinities of (+)-LY253352 in the brain and prostate are suggestive of subtle unique properties of adrenoceptor binding sites in these tissues.

Identification and Characterization of Alpha1 Adrenergic Receptors in the Canine Prostate Using [125I]-Heat

We have recently utilized radioligand receptor binding methods to characterize muscarinic cholinergic and alpha adrenergic receptors in human prostate adenomas. The primary advantages of radioligand receptor binding methods are that neurotransmitter receptor density is quantitated, the affinity of unlabelled drugs for receptor sites is determined, and receptors can be localized using autoradiography on slide-mounted tissue sections. Recently, [125I]-Heat, a selective and high affinity ligand with high specific activity (2200Ci/mmole) has been used to characterize alpha1 adrenergic receptors in the brain. In this study alpha1 adrenergic receptors in the dog prostate were characterized using [125I]-Heat. The Scatchard plots were linear indicating homogeneity of [125I]-Heat binding sites. The mean alpha1 adrenergic receptor density determined from these Scatchard plots was 0.61 ± 0.07fmol/mg. wet wt. ± S.E.M. The binding of [125I]-Heat to canine prostate alpha1 adrenergic binding sites was of high affinity (Kd = 86 ± 19pM). Steady state conditions were reached following an incubation interval of 30 minutes and specific binding and tissue concentration were linear within the range of tissue concentrations assayed. The specificity of [125I]-Heat for alpha1 adrenergic binding sites was confirmed by competitive displacement assays using unlabelled clonidine and prazosin. Retrospective analysis of the saturation experiments demonstrated that Bmax can be accurately calculated by determining specific [125I]-Heat binding at a single ligand concentration. [125I]-Heat is an ideal ligand for studying alpha1 adrenergic receptors in the prostate and its favorable properties should facilitate the autoradiographic localization of alpha1 adrenergic receptors in the prostate.

Alpha2 Adrenergic Receptors in Canine Prostate: Biochemical and Functional Correlations

The sympathetic innervation of human prostate adenomas has been previously demonstrated using fluorescence microscopy and in vitro isometric studies. A clinical implication of these observations is that bladder outlet obstruction in men with benign prostatic hypertrophy may be subject to pharmacologic manipulation using adrenergic drugs. Randomized clinical trials have demonstrated the efficacy of alpha adrenergic antagonists for symptomatic BPH.We have previously characterized the alpha1 and alpha2 adrenergic receptors in the human prostate using [3H]prazosin and [3H]rauwolscine, respectively. The mean alpha1 and alpha2 receptor densities in the adenomas studied were equivalent. The effect of alpha2 adrenergic drugs on prostatic urethral pressure has not been examined in the human or in an animal model. In this study a canine model was used to define the effect of alpha2 drugs on prostatic urethral pressure. Intravenous administration of clonidine, a selective alpha2 agonist, resulted in a dose dependent increase in prostatic urethral pressure. The maximal increase in urethral pressure ranged between 18 to 30cm. H20. The maximal response to clonidine was approximately 50% less than the response to epinephrine, indicating that clonidine acts as a partial agonist. Pretreatment with yohimbine, a selective alpha2 adrenergic antagonist, abolished the effects of clonidine and epinephrine. The alpha2 adrenergic receptors were then studied in the canine prostates using [3H]rauwolscine. The equilibrium dissociation constant, Kd, ranged between 0.68 to 1.80nM and the receptor density ranged between 14.8 to 69.3fmol./mg. protein. The receptor density was homogeneous in specimens obtained from the proximal, midportion, and distal canine prostate suggesting that the effect of alpha2 drugs is not sphincter mediated. These in vitro and in vivo studies provide the basis for investigating the effects of alpha2 antagonists in men with symptomatic BPH.

Nuclear retinoic acid binding protein in human prostate adenomas.

A retinoic acid binding protein has been detected in salt extracts of nuclei obtained from human prostate adenoma. The binding was characterized by competition experiments, temperature/time studies and saturation analysis. Substantial binding was only observed after sonication of nuclei and charcoal-pretreatment of a salt extract. The binding of radiolabelled all-trans-retinoic acid was displaced by all-trans-retinoic acid, retinol and to a lesser extent retinal and two synthetic retinoids, RO 10-1670 and RO 13-7410. Testosterone and dihydrotestosterone, at a 100-fold excess, had little effect on the binding. The association between retinoic acid and nuclear protein was both temperature and time dependent. At 37 degrees C, equilibrium was rapidly reached (30 min) whereas at 4 and 25 degrees C, ligand binding occurred at a slower rate. Saturation analysis performed under steady-state conditions yielded a dissociation constant of 15 +/- 2 nmol/l. Metabolism studies failed to show conversion of either radiolabelled all-trans-retinol or [3H]retinoic acid in vitro; these data suggest that both acid and alcohol forms of vitamin A are recognized by the extracted nuclear protein. The effect of three enzyme inhibitors on [3H]retinoic acid binding was studied. Binding was unaltered in the presence of aprotinin and phenylmethylsulphonyl fluoride but sodium molybdate (10 mmol/l) increased binding by 18%. The presence of a specific retinoid binding protein in prostate nuclei suggests that retinoids may play some role in the function of the gland.

Characterization of Alpha1 Adrenergic Receptors in Human Benign Prostatic Hyperplasia

Bladder outlet obstruction in men with benign prostatic hyperplasia is decreased following administration of prazosin, a selective alpha1 adrenergic antagonist. Prazosin presumably binds and antagonizes alpha1 adrenergic receptors on the smooth muscle cells of the prostatic adenoma. This study represents the first identification and characterization of alpha1 adrenergic receptors in the prostate using radioligand receptor binding methods.The binding of [3H] prazosin in homogenates obtained from human prostatic adenomas was saturable and a single high affinity prazosin binding site was identified (Kd = 0.29 ± 0.09nM). The alpha1 adrenergic receptor concentration in these homogenates ranged between 0.28 to 2.05fmol./mg. wet wt. prostate. The equilibrium dissociation constant and density of prazosin binding sites were similar in different regions of an enucleated prostate suggesting homogeneity of receptor density and receptor binding sites within an adenoma. The receptor density was not directly proportional to the weight of the surgically removed adenoma. The pharmacology of the prazosin binding sites was characterized by competitive binding experiments using [3H] prazosin and several unlabelled adrenergic analogs. The IC50’s determined from competitive binding experiments using [3H] prazosin and alpha-methylnorepinephrine, rauwolscine and corynanthine were characteristic of alphai adrenergic receptor binding.

Identification and characterization of the binding properties of steroid hormone receptors in the nuclear fraction of adenomas of the human prostate gland.

1. Specific binding of 5α-DHT, corresponding to the androgen receptors according to the value of the measurable Kα and hormonal specificity of affinity, was detected in 0.4 M KC1 extracts of human prostate adenoma nuclei. 2. Specific binding of progesterone, corresponding in its characteristics to the progestin receptors, was detected in the same material. 3. A very low level of specific binding of estradiol is detected in nuclear extracts of prostate adenomas. 4. Receptors for glucocorticoids are not detected in nuclei of prostate adenomas.

The alpha-adrenergic blocking effect of prazosin on the human prostate.

The effect of prazosin on the adrenergic receptors in the human prostatic adenoma and prostatic capsule was investigated by an in vitro isometric technique. The results showed an alpha-adrenergic blocking action on both tissues. The cholinergic response of the capsule and the direct response of the adenoma were not affected. It is suggested that prazosin may prove preferable to phenoxybenzamine for clinical use as a prostatic alpha blocking agent, because of the selective action on the alpha1 receptors.

The pharmacological action of bromocriptine on the human prostate.

In-vitro isometric studies of the effects of bromocriptine on the human prostatic capsule and prostatic adenoma reveal transient direct stimulant actions, alpha-adrenergic blocking effects and anticholinergic effects. The mechanism of the latter effect is discussed. It is suggested that these direct pharmacological actions may at least partly explain the clinical improvement reported in some cases of benign prostatic obstruction and detrusor instability treated with bromocriptine.