Faculty Bibliography

Myelodysplasia represents the most common cause of neurogenic bladder dysfunction in children. The specific histological features associated with myelodysplastic bladders have not been previously characterized. Our objective was to study the relationship between smooth muscle and connective tissue in control and myelodysplastic bladders using classical morphometric analysis with the assistance of an automated image analysis system. Gross histological analysis of the bladder specimens of normal stillborn fetuses showed organized muscle bundles embedded in a small amount of connective tissue. The bladder specimens of myelomeningocele stillborn fetuses showed a marked paucity of muscle bundles as well as a significantly diminished size of the muscle bundles. The myelomeningocele bladder specimens obtained from patients undergoing autopsy and those undergoing augmentation cystoplasty revealed significant interfascicular and pericellular infiltration of the smooth muscle by dense connective tissue. Quantitative morphometric analysis showed that the myelomeningocele stillborn fetuses have a significant increase in the volumetric content of connective tissue compared to control stillborn fetuses. The bladders of myelomeningocele patients who underwent autopsy or augmentation cystoplasty had a 3-fold increase in connective tissue when compared to normal controls. These findings reveal that structural changes in the histological components of the myelodysplastic bladder can be demonstrated not only in patients of varying ages undergoing autopsy or augmentation cystoplasty but also in the developing fetus. These findings enhance our understanding of the relationship of connective tissue proliferation to smooth muscle in the myelodysplastic bladder. We discuss the relationship of these findings to pathological detrusor morphology and detrusor dysfunction

The objective of this study was to compare the binding and functional properties of alpha 1 adrenoceptors in prostate capsules obtained from men with symptomatic and asymptomatic benign prostatic hyperplasia (BPH) undergoing simple retropubic prostatectomy and cystoprostatectomy respectively. Saturation experiments using 125I-Heat demonstrated that the density and binding affinity of alpha 1 adrenoceptors in the prostate capsules obtained from men with symptomatic and asymptomatic BPH were similar. Non-cumulative dose response experiments using phenylephrine demonstrated that the magnitude of the contractile response to phenylephrine was 4-fold greater in the prostate capsules from men with symptomatic BPH than from those with asymptomatic BPH. The EC50 of phenylephrine in the prostate capsules of men with symptomatic and asymptomatic BPH was similar. A correlation between alpha 1 adrenoceptor density and phenylephrine Emax was not observed, implying that either alpha 1 adrenoceptors are not localised exclusively to the prostate smooth muscle or that spare alpha 1 adrenoceptors exist. This study suggests that the neuropharmacological properties of the prostate capsule may play a significant role in the development of infravesical obstruction in the ageing male population

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 +/- 0.11 nM and 0.14 +/- 0.02 nM, respectively. The mean Bmax of 3H-nitrendipine and (+)3H-PN200-110 was 0.57 +/- 0.06 and 0.19 +/- 0.02 fmol/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

Tissue levels of norepinephrine were measured in prostate tissue from 24 men ranging in age between 41 and 83 years. Prostatic tissue was obtained from men with subtle palpable prostate nodules undergoing transperineal needle biopsy. None of the patients were shown to have histologic evidence of adenocarcinoma. The severity of the symptoms of prostatism was evaluated prospectively using a standardized micturition symptom score questionnaire. Norepinephrine levels were quantified using a sensitive radioenzymatic assay (REA). Overall, the prostates contained relatively high levels of norepinephrine (1666 +/- 124 ng./gm.). Inverse correlations were observed between tissue norepinephrine levels and severity of symptoms of prostatism (r = -0.58; p = 0.003); age (r = -0.53; p = .008); and prostate size (r = -0.48; p = .02). Norepinephrine levels were also measured in tissue specimens obtained from men undergoing enucleation prostatectomy and transurethral resection of the prostate (TURP). The level of norepinephrine in these prostatectomy specimens (115 ng./gm.) was only 14% the level of the prostate biopsy specimens. The relatively low level of norepinephrine in the specimens obtained from patients with symptoms necessitating prostatectomy provides further evidence that norepinephrine levels are inversely related to the degree of symptomatic bladder outlet obstruction

The aim of this study was to characterize the binding and functional properties of muscarinic cholinergic (MCh) and alpha 2-adrenergic receptors in the human ileum to provide insight into pharmacologic strategies for managing urinary and fecal incontinence after bladder and rectal replacement with intestinal segments. MCh and alpha 2-adrenergic binding sites were characterized in the epithelium and muscularis of eight human ileal segments with 3H-N-methylscopolamine and 3H-rauwolscine, respectively. The dissociation constant for 3H-N-methylscopolamine in the epithelium and muscularis was 0.32 +/- 0.07 nmol/L and 0.45 +/- 0.10 nmol/L, respectively (p = 0.32). The MCh receptor content was approximately eightfold greater in the muscularis compared with the epithelium (p = 0.008). The dissociation constant for 3H-rauwolscine in the muscularis and epithelium was 2.55 +/- 0.42 nmol/L and 2.03 +/- 0.19 nmol/L, respectively (p = 0.29). The alpha 2-adrenoceptor density was twofold greater in the epithelium compared with the muscularis (p = 0.05). Noncumulative concentration-response experiments were performed with carbachol, an MCh agonist, and UK-14304, a selective alpha 2-adrenergic agonist. The epithelium did not contract in the presence of high concentrations of carbachol and UK-14304. The muscularis preparations were responsive only to carbachol. The muscularis contains primarily MCh receptors mediating smooth muscle contraction. The alpha 2-adrenoceptors are localized primarily to the epithelium and may regulate water secretion in the intestine. The distribution and functional properties of ileal MCh and alpha 2-adrenergic receptors provide a theoretic basis for the treatment of incontinence after bladder and rectal replacement with intestinal segments

Radioligand receptor binding techniques were used to characterize alpha 1 adrenergic, alpha 2 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 (alpha 1 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 less than 0.05). The density of 3H-Ra (alpha 2 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 less than 0.05). The difference in alpha 2 adrenoceptor density was accounted for by an increased receptor density in the open prostatectomy specimens. There was no significant correlation between alpha 2 adrenergic, alpha 1 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 alpha 1 adrenergic or MCh receptor binding sites. The significance of the observed upregulation of alpha 2 adrenoreceptors in the prostate adenomas obtained from men undergoing open prostatectomy is unknown, and requires further investigation

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