Biomedical subjects
Publications and source records attributed to W D Steers.
This article reviews the neuroanatomy, neurophysiology, and neuropharmacology involved in micturition and continence. Knowledge of these topics helps the clinician diagnose and treat voiding disorders that are caused by disease, trauma, drugs, and aging.
PURPOSE: The goal of this investigation was to examine the effect of immunity to nerve growth factor (NGF) on alterations in sensory nerves from the urinary bladder in the dorsal root ganglia (DRG) and their projections to the L6/S1 spinal cord following urethral obstruction in the rat. MATERIALS AND METHODS: Female Wistar rats were immunized to murine 2.5S NGF, then obstructed by partial urethral ligation for 6 weeks. Retrograde axonal tracing with FluoroGold and WGA-HRP was used to measure areas of bladder DRG cells and afferent projections in the sacral spinal cord. Multiunit activity on bladder nerves allowed recording of micturition reflexes. Immunohistochemical staining for growth associated protein (GAP)-43 in the sacral parasympathetic nucleus (SPN) was used to assess potential growth or activity of axons in the spinal cord. Voiding frequencies were then measured in awake obstructed and NGF immune-obstructed rats. RESULTS: Immunity to NGF prevented obstruction-induced hypertrophy of DRG neurons, reduced retrograde axonal labeling of sacral afferent projections, eliminated enhancement of a spinal micturition reflex and abolished the increased GAP-43 expression in the SPN. Immunity to NGF prevented the urinary frequency that accompanies obstruction. CONCLUSIONS: Our results demonstrate that obstruction of the bladder elicits structural and functional plasticity in afferents as a result of ongoing neurotrophic interactions. Neurotrophic interactions offer a potential mechanism whereby symptoms and bladder hyperactivity develop with obstruction associated with benign prostatic hyperplasia.
Explore the source record for details and available documents.
Explore the source record for details and available documents.
Benign prostatic hyperplasia (BPH) is a pathologic disorder that develops in response to the action of dihydrotestosterone on the aging prostate and to changes in stromal and epithelial cells in this exocrine gland. The current therapies for this disorder are chosen after other causes for irritative and obstructive symptoms have been excluded and the status of the urinary tract has been assessed. This evaluation includes a detailed medical history, a thorough genitourinary and neurological examination, assessment of serum prostate specific antigen and creatinine levels, as well as a urinalysis. A urodynamic evaluation consisting of a combined pressure-flow study is required if the diagnosis of obstruction is to be made. Patients with minimal symptoms and normal test results require no therapy. Mild to moderate symptoms can be controlled, at least temporarily, with alpha-adrenergic blockers such as terazosin or doxazosin. A subset of BPH patients with obstructive symptoms respond to the 5 alpha-reductase inhibitor finasteride. Early results with minimally invasive treatments such as laser prostatectomies, hyperthermia, and ultrasonic and radiofrequency ablation appear encouraging for those with moderate symptoms of prostatism. Severe symptoms, urinary retention, gross hematuria, recurrent urinary tract infections, bladder calculi, and hydronephrosis or renal insufficiency warrant transurethral incision, resection, vaporization, or open prostatectomy (for very large neoplasms). Although the morbidities of these latter surgical therapies are not insignificant, these treatments offer the best and most durable results for relief of obstruction and amelioration of symptoms.
OBJECTIVES: Anecdotal reports of increased libido and sexual function in patients taking trazodone have led to its empirical use in patients with erectile dysfunction. A retrospective review of patient-reported responses to trazodone was performed to outline the efficacy and side-effect profile of this agent. METHODS: Between 1989 and 1994, 182 patients were placed on oral trazodone as empirical therapy for erectile dysfunction. Patients ranged in age from 26 to 85 years, with a mean of 60 years. Patients were evaluated before receiving trazodone with a thorough medical history and physical examination. Known risk factors for erectile dysfunction were assigned based on historical information and the findings of the examination. Patients received trazodone for at least 2 consecutive months, with daily doses starting at 25 mg. RESULTS: One hundred twenty-seven patients were available for follow-up by a standardized questionnaire regarding perceived improvement in erectile function, sexual function, and side effects. In patients less than 60 years of age, with no known risk factors for erectile dysfunction, 21 of 27 (78%) showed significant improvement in erectile ability. Smokers and patients older than 60 years with a history of significant peripheral vascular disease responded poorly to trazodone therapy. The duration of erectile dysfunction was inversely related to a response to trazodone. Of patients with a duration of impotence less than 12 months, 48% reported a positive response. Only 16% of patients with duration of erectile dysfunction greater than 60 months reported improvement in erections and sexual function. Trazodone was well tolerated by this population, with 62% reporting no side effects. CONCLUSIONS: Despite the limitations of a nonrandomized, retrospective study, trazodone appears to benefit younger patients with erectile dysfunction with few known risk factors. A prospective, placebo-controlled trial is needed to confirm the observations of this pilot study.
Previous assessments of the autonomic nerve supply of the male genital tract concluded that the testis received sympathetic input primarily from paraaortic ganglia, particularly the spermatic ganglion. We challenged this consensus by using retrograde axonal tracing to examine the source and distribution of efferent fibers reaching the testis of adult rats. We also used immunohistochemical methods to assess putative neurotransmitters in testicular neurons of the abdominal and pelvic ganglia. The results indicate the majority of retrogradely labeled cell profiles were localized within the major pelvic (38%) and pelvic accessory ganglia (37%), and only a few labeled cell profiles were present in the paraaortic and spermatic ganglia. Injection of FluoroGold and Fast Blue dyes into the respective right and left testis demonstrated that 17% of the neurons in pelvic ganglia were labeled when tracers were microinjected beneath the capsule of the contralateral testis. About 8% of the neurons were labeled both with FluoroGold and Fast Blue, suggesting that certain neurons can provide simultaneous input to the left and right testicles. Immunohistochemical results showed that tyrosine hydroxylase, a marker for noradrenergic fibers, was present in over 33% of the cell profiles labeled with either FluoroGold or Fast Blue. Some 27% of the fluorescent-labeled cell profiles were positive for neuropeptide Y, while 22% were immunoreactive for vasoactive intestinal polypeptide. No evidence for vasoactive intestinal polypeptide immunoreactivity was detected within the testis, but neuropeptide Y-immunoreactive fibers were present in the tunica albuginea and testicular vasculature. Catecholamine fluorescent fibers were distributed sparsely throughout the periphery of the testis in association with the capsule, vasculature, and interstitium.(ABSTRACT TRUNCATED AT 250 WORDS)
Cyclic stretch of cultured urinary tract smooth muscle cells has been used to mimic some of the events that occur with bladder obstruction. The stretch stimulus induces production of nerve growth factor (NGF), which has been implicated in changes in bladder innervation. Stretch-induced NGF production was blocked by actinomycin. Involvement of protein kinase C (PKC) in the stretch-induced NGF production is strongly suggested by the following observations. Phorbol ester activators of PKC mimicked the stretch response as did platelet-derived growth factor (PDGF), which acts, in part, through generation of endogenous diacylglycerols. Both stretch- and PDGF-induced NGF production were blocked by prolonged incubation with phorbol ester to downregulate PKC. Western blot analysis confirmed partial downregulation of the Ca(2+)-dependent PKC-alpha and PKC-beta 1 and near complete downregulation of the Ca(2+)-independent PKC isozymes delta, epsilon, and zeta. The involvement of PKC in transducing a physical stimulus (stretch) into a biochemical response (NGF production) has implications for novel types of therapeutic intervention in ailments such as bladder obstruction.
The responsiveness of cultured major pelvic ganglion (MPG) neurons, isolated from adult rats, to nerve growth factor (NGF), basic fibroblastic growth factor (bFGF) and ciliary neuronotrophic factor (CNTF) was tested using in vitro survival assay. MPG neurons respond to NGF with increased survival (+35 +/- 13.3%, mean +/- S.E.), a response completely blocked by antibodies specific to NGF. bFGF (+85 +/- 9.6%) and CNTF (+10.5 +/- 0.5%) also augment survival of MPG neurons in vitro. The effect of bFGF was partially blocked by bFGF antibody. Anti-NGF antibody reduced neuronal survival by 25 +/- 4.1% in conditioned medium from cultures of bladder smooth muscle, suggesting bladder produces NGF. Combining antibodies against NGF and bFGF reduced survival by 19 +/- 0.5% in medium supplemented with bladder extracts, suggesting the extracts contain neurotrophic activity in addition to NGF. These results support the hypothesis that neurons regulating bladder function respond to NGF and other growth factors. Therefore, previously documented changes in bladder neurotrophic factors following hypertrophy, inflammation and injury may elicit growth or change in the autonomic nervous system.
Explore the source record for details and available documents.
Despite the development of molecular and cellular methods for examining physiological processes, the use of the whole animal model remains essential to advance knowledge regarding the integration and coordination of events associated with urinary tract function. The rat offers an inexpensive and versatile species to investigate bladder and urethral responses to drugs or pathology. Models for many disorders have been developed in rodents including diabetes, multiple sclerosis, spinal cord injury, Parkinson's disease, bladder outlet obstruction, pain, and aging. This review examines methodologies to evaluate lower urinary tract function and manipulations used to create pathological models in rodents.
Seminal emission occurs in response to rhythmic contractions of male secondary sex organs, including the vas deferens. Although contraction of the vas is directly due to adrenergic mechanisms, numerous substances modulate the release of norepinephrine from sympathetic pathways. These substances include local endogenous factors and neurotransmitters such as acetylcholine and NPY. Many substances are capable of altering the contractility of the vas deferens by modulating neural transmitter release or the basal tone of this smooth muscle. Because multiple pathways and substrates are capable of affecting its contractility, it is not surprising that drugs and metabolic disorders influence the function of the vas deferens and, ultimately, male fertility.
Voiding dysfunction in diabetics has been attributed to a variety of causes including an axonopathy in autonomic pathways to the urinary bladder. The present study was undertaken to determine whether changes occurred in afferent and efferent neurons supplying bladders of streptozotocin (STZ)-induced diabetic rats. Nine weeks after STZ treatment, the mean cross-sectional area for retrogradely labeled (Fluoro-Gold) bladder neurons in the major pelvic ganglion (MPG) was greater in diabetics (364 microns 2) than controls (300 microns 2). The number of labeled neurons was similar in these groups. In contrast, mean cross-sectional areas of bladder afferent neurons labeled with WGA-HRP in the L6 and S1 dorsal root ganglia (DRG) were smaller (393 microns 2) in diabetics than in normal rats (528 microns 2). In addition, very few DRG neurons were labeled in STZ-treated rats and transganglionic labeling of bladder afferent projections in the L6 and S1 spinal cord with WGA-HRP was sparse. Radioimmunoassay studies revealed that substance P was reduced by 70% in the MPG and by 40% in L6 DRG, yet this peptide was unchanged in the bladders of diabetic rats. The amounts of VIP in the MPG and DRG of diabetics and controls were similar, while VIP in the bladder was increased in diabetics. These observations indicate that both afferent and efferent neurons innervating the urinary bladder are altered in the STZ-induced diabetic rat. In addition, axonal transport in visceral afferent pathways may be disrupted.
To gain insight into the effect of innervation on neurotrophin production, NGF levels in the urinary bladder were measured following unilateral ganglionectomy (bladder denervation) or separation of the post-ganglionic bladder neurons from the central nervous system of the adult rat (bladder and ganglion decentralization). These interruptions of the neural input to half of the bladder caused histological evidence of smooth muscle growth, increased bladder weight (denervation-3 weeks: 98.6 +/- 6 mg; decentralization-3 weeks: 94.0 +/- 7 mg vs. control: 79.6 +/- 4 mg, P < 0.05), transient increases in tissue NGF up to 10-fold (1.99 +/- 0.65 pg NGF/bladder control vs. 20.24 +/- 0.53 (P < 0.05) denervated, ipsilateral, 1 week) and hypertrophy of the neurons in the pelvic ganglia supplying the bladder (control: 340 +/- 4.4 microns2; denervated-3 weeks: 530 +/- 6.8 microns2, P < 0.05; decentralized-3 weeks: 463 +/- 6.8 microns2, P < 0.05). These data suggest that neural input has a significant role in regulating growth of the bladder. Furthermore, the findings show that innervation influences tissue levels of NGF in the bladder.
Cytosolic Ca2+ has been postulated to regulate smooth muscle hypertrophy and growth factor production. Consistent with this hypothesis we report that the Ca2+ channel antagonists verapamil and diltiazem prevent bladder and neuronal growth in rats in response to 3 wk of urethral obstruction. Ca2+ channel blockers prevented 30-45% of the increase in bladder weight, protein, and DNA content found in obstructed animals. Similarly, these drugs produced a 15-27% reduction in area profiles for retrogradely labeled (Fluoro-Gold) motoneurons in the major pelvic ganglia and afferents in the L6-S1 dorsal root ganglia after obstruction. The reduced growth in neuronal areas was attributed, in part, to less nerve growth factor (NGF) in bladders of obstructed rats receiving verapamil (8.5 pg/bladder) or diltiazem (14.5 pg/bladder) compared with obstructed animals not given these drugs (58.2 pg/bladder). The alpha 1-adrenergic antagonist, prazosin, while decreasing voiding frequency in obstructed rats, had no significant impact on bladder weight or neuronal size. These reductions in the increase in bladder hypertrophy and NGF content may be due to altered handling of Ca2+.
Patients with hereditary spastic paraplegia (HSP), a degenerative central nervous system disorder characterized by progressive lower extremity spasticity, frequently experience symptoms of voiding dysfunction. Urodynamic evaluation of patients with HSP has not been reported, and the etiology of voiding dysfunction remains unexplained. We present our evaluation of three men (ages 42-62 years) with this rare syndrome. Urgency of urination was a uniform and dominant complaint, and two patients regularly experienced urge incontinence. Other symptoms included frequency (n = 3), nocturia (n = 3), and diminished force of stream (n = 1). Postvoid residual volumes were less than 25 ml in all patients. On urodynamic evaluation the two patients with urge incontinence displayed cystometric evidence of involuntary detrusor contractions. Pelvic floor EMG recordings suggested detrusor-sphincter dyssynergia (DSD). In addition, one patient exhibited markedly diminished bladder compliance (1.0 ml/cm H2O) and capacity (50 ml). All patients reported marked symptomatic improvement when treated with continuous intrathecal baclofen. Evaluation during baclofen treatment revealed increases in bladder compliance and capacity, with apparent resolution of DSD in one patient. Voiding symptoms in these patients most likely arise from a neurogenic etiology; however, a contributory role for chronic outlet obstruction from striated muscle spasticity may also exist.
Retrograde axonal tracing methods using Fluoro-Gold were used to examine the neuronal input to the vas deferens in the adult Wistar rat. The greatest number of labelled efferent neurons were found in the ipsilateral pelvic accessory ganglion (PAG) (68%) and the major pelvic ganglion (MPG) (15%). Fewer than 3% of labelled neurons were localized to the inferior mesenteric and sympathetic chain ganglia. Labelled neurons were also located in the ipsilateral L1, L2, and L6, S1 dorsal root ganglia (DRG), corresponding to afferents that travel in the hypogastric and pelvic nerves, respectively. Contributions from contralateral neurons in the PAG, MPG and L1 DRG were also documented. The role of afferents supplying the vas deferens is not known but they may relay nociceptive or mechanoreceptive input. Efferent input from peripheral ganglia probably contributes to contractility of the vas deferens based on previous investigations.
Explore the source record for details and available documents.