Recombinant PAI-1 therapy restores myoendothelial junctions and erectile function in PAI-1-deficient mice.

Myoendothelial junctions are specialised projections of cell : cell contact through the internal elastic lamina between endothelial cells and vascular smooth muscle cells. These junctions allow for endothelial cells and vascular smooth muscle cells to make direct membrane apposition and are involved in cell : cell communication. In this study, we evaluated for the presence of myoendothelial junctions in murine corporal tissue and used plasminogen activator inhibitor (PAI)-1-deficient mice, which lack myoendothelial junctions, to determine whether myoendothelial junctions affect erectile function. Transmission electron microscopy demonstrated the presence of myoendothelial junctions in the corporal tissue of wild-type mice and confirmed the decreased junction numbers in the tissue of PAI-1(-/-) mice. A potential role for myoendothelial junctions in tumescence was established; in that, PAI-1(-/-) mice demonstrated a significantly longer time to achieve maximal intracavernous pressure. Treatment of PAI-1(-/-) mice with recombinant PAI-1 restored the number of myoendothelial junctions in the corporal tissue and also induced a significant decrease in time to maximal corporal pressures. Myoendothelial junctions were similarly identified in the human corporal tissue. These results suggest a critical role for myoendothelial junctions in erectile pathophysiology and therapies aimed at restoring myoendothelial junction numbers in the corporal tissue may provide a novel therapy for erectile dysfunction.

Encouraging scholastic publishing by urologic trainees.

THERE ARE MANY REASONS WHY UROLOGIC TRAINEES SHOULD PUBLISH SCHOLARLY WORK: Personal, professional, and institutional. Publishing by trainees creates an environment that improves the specialty of urology, maintains the quality of our literature, and promotes professionalism of our practitioners. Strategies to encourage scholastic publishing distil down to providing recognition, time, and support to the individual trainee.

Normal preoperative urodynamic testing does not predict voiding dysfunction after Burch colposuspension versus pubovaginal sling.

PURPOSE: Urodynamic studies have been proposed as a means of identifying patients at risk for voiding dysfunction after surgery for stress urinary incontinence. We determined if preoperative urodynamic findings predict postoperative voiding dysfunction after pubovaginal sling or Burch colposuspension. MATERIALS AND METHODS: Data were analyzed from preoperative, standardized urodynamic studies performed on participants in the Stress Incontinence Treatment Efficacy Trial, in which women with stress urinary incontinence were randomized to undergo pubovaginal sling surgery or Burch colposuspension. Voiding dysfunction was defined as use of any bladder catheter after 6 weeks, or reoperation for takedown of a pubovaginal sling or Burch colposuspension. Urodynamic study parameters examined were post-void residual urine, maximum flow during noninvasive flowmetry, maximum flow during pressure flow study, change in vesical pressure at maximum flow during pressure flow study, change in abdominal pressure at maximum flow during pressure flow study and change in detrusor pressure at maximum flow during pressure flow study. The study excluded women with a preoperative post-void residual urine volume of more than 150 ml or a maximum flow during noninvasive flowmetry of less than 12 ml per second unless advanced pelvic prolapse was also present. RESULTS: Of the 655 women in whom data were analyzed voiding dysfunction developed in 57 including 8 in the Burch colposuspension and 49 in the pubovaginal sling groups. There were 9 patients who could not be categorized and, thus, were excluded from the remainder of the analysis (646). A total of 38 women used a catheter beyond week 6, 3 had a surgical takedown and 16 had both. All 19 women who had surgical takedown were in the pubovaginal sling group. The statistical analysis of urodynamic predictors is based on subsets of the entire cohort, including 579 women with preoperative uroflowmetry, 378 with change in vesical pressure, and 377 with change in abdominal and detrusor pressure values. No preoperative urodynamic study findings were associated with an increased risk of voiding dysfunction in any group. Mean maximum flow during noninvasive flowmetry values were similar among women with voiding dysfunction compared to those without voiding dysfunction in the entire group (23.4 vs 25.7 ml per second, p = 0.16), in the Burch colposuspension group (25.8 vs 25.7 ml per second, p = 0.98) and in the pubovaginal sling group (23.1 vs 25.7 ml per second, p = 0.17). Voiding pressures and degree of abdominal straining were not associated with postoperative voiding dysfunction. CONCLUSIONS: In this carefully selected group preoperative urodynamic studies did not predict postoperative voiding dysfunction or the risk of surgical revision in the pubovaginal sling group. Our findings may be limited by the stringent exclusion criteria and studying a group believed to be at greater risk for voiding dysfunction could alter these findings. Additional analysis using subjective measures to define voiding dysfunction is warranted to further determine the ability of urodynamic studies to stratify the risk of postoperative voiding dysfunction, which appears to be limited in the current study.

Nerve growth factor in the urinary bladder of the adult regulates neuronal form and function.

Urethral obstruction produces increased voiding frequency (0.7 +/- 0.06 to 1.1 +/- 0.08 h-1) and hypertrophy of the urinary bladder (89 +/- 1.7 to 708 +/- 40 mg) with profound increments in the dimensions of afferent (4, 6) and efferent neurons (299 +/- 4.7 to 573 +/- 8.6 microns2) supplying this organ in the rat. We discovered that hypertrophied bladders of rat and human contain significantly more nerve growth factor (NGF) per milligram wet weight, protein, and DNA than normal bladders. The temporal correlation between NGF content, neuronal hypertrophy, and bladder weight was consistent with a role for this growth factor in the neurotrophic effects associated with obstruction. Autoimmunity to NGF abolished the hypertrophy of NGF-sensitive bladder neurons in the pelvic ganglion after obstruction. Relief of urethral obstruction reduced bladder size (349 +/- 78 mg), but neuronal hypertrophy (460.2 +/- 10.2 microns2) and elevated NGF levels were only partially reversed. Bladder hypertrophy (133 +/- 4.3 mg) induced by osmotic diuresis slightly increased ganglion cell area (365.2 +/- 6.1 microns2) and only doubled NGF content of the bladder. These findings provide important new evidence that parenchymal cells in the hypertrophied bladder can synthesize NGF and possibly other molecular messengers that act to alter the size and function of neurons in adult animals and man.

Colpocleisis for pelvic organ prolapse: patient goals, quality of life, and satisfaction.

OBJECTIVE: To assess patient-centered colpocleisis outcomes in women. METHODS: This is a prospective cohort study. Between March 2000 and December 2005, 94 patients underwent colpocleisis. Patients completed follow-up questionnaires about their personal postoperative goal attainment satisfaction with care, regrets about surgery, as well as the Incontinence Impact Questionnaire and Urogenital Distress Inventory. RESULTS: Forty patients (42.6% of all patients) returned questionnaires with complete data on study outcomes. Mean age was 75.4 years (+/-6.8 years), and mean weight was 70.9 kg (+/-10.8 kg). Mean follow up was 2.75 years (+/-1.90 years). Most women agreed or strongly agreed that their goals were met for vaginal pressure (100%), urinary incontinence (84.9%), bladder emptying (76.4%), urinary frequency/urgency (91.2%), physical activity (88.6%), restoration of normal anatomy (95 %), colorectal symptoms (65.0%), and self-image (96.9%). Mean goal attainment (1.4+/-0.6) was associated with the postsurgery Urogenital Distress Inventory (r=-0.45, P=.003.) although not the Incontinence Impact Questionnaire. Mean scores improved presurgery to postsurgery for both the Urogenital Distress Inventory (39.9+/-24.9 versus 21.0+/-20.3, P<.01) and the Incontinence Impact Questionnaire (35.4+/-29.3 versus 17.3+/-24.6, P<.01). Ninety-five percent of respondents were either "very satisfied" or "satisfied" with their surgical outcome, while 5% reported postoperative regret. Of the entire series, 19.1% experienced postoperative complications. CONCLUSION: Colpocleisis results in improved quality of life and substantial goal attainment, with a low proportion of regret. LEVEL OF EVIDENCE: II.

Clinical ease of using doxazosin in BPH patients with and without hypertension.

Clinical studies have demonstrated that doxazosin therapy reduced blood pressure (BP) in patients with benign prostatic hyperplasia (BPH) who were hypertensive at baseline but not in patients who were physiologically or pharmacologically normotensive at baseline. In patients with BPH and uncontrolled hypertension, despite treatment with other antihypertensive drugs, the addition of doxazosin resulted in improved control with significant reductions in BP. The new formulation, doxazosin gastrointestinal therapeutic system (GITS), is initiated at a therapeutic dose, simplifying dose titration. Based on its efficacy and pharmacokinetic and tolerability profiles, doxazosin GITS is an effective and well-tolerated treatment for normotensive and hypertensive patients with BPH.

Neural pathways and central sites involved in penile erection: neuroanatomy and clinical implications.

Penile erection occurs in response to tactile, visual, and imaginative stimuli in humans. In animals olfactory and auditory cues are particularly important. The participation of multiple sites with the brain and spinal cord, and coordination of somatic and autonomic pathways make sexual behavior in general, and erection in particular, vulnerable to neurologic injury and disease. Sites within the brain and spinal cord act in concert to process, coordinate, then distribute the neural inputs necessary for sexual behavior including erection. Activation of neurons in some of these regions either pharmacologically or by electrical stimulation has been associated with penile tumescence. This review will provide a geographic framework for understanding the neuroanatomical basis of penile erection based primarily on animal data. Following discussion of the anatomical substrates, a clinical correlation is then provided to confirm and reinforce these experimental observations.

Alterations in afferent pathways from the urinary bladder of the rat in response to partial urethral obstruction.

Afferent pathways from the urinary bladder were examined with axonal tracing techniques in normal female Wistar rats and in those with partial urethral ligation. Following injection of wheat germ agglutinin-horseradish peroxidase (HRP) into the bladder wall, HRP was detected in lumbosacral dorsal root ganglion cells and in afferent projections to the L6-S1 spinal cord at sites in laminae I, II, V-VII, and X known to receive visceral afferent input. Partial urethral ligation (6 weeks) produced a sixfold increase in bladder weight and altered the morphology of bladder afferent pathways. Changes included an increase in the average cross-sectional area of labelled neuronal profiles in L6 and S1 dorsal root ganglia in obstructed (766 +/- 378 microns 2, P less than 0.001) compared to control rats (528 +/- 189 mu 2). The cross-sectional area of the largest profiles also increased by approximately 40%. The mean number of labelled dorsal root ganglion cell profiles was similar in ligated (837 +/- 198) and control (883 +/- 352) groups. When compared to control animals the obstructed animals exhibited a 60% increase in the area of the labelled afferent terminal field in the intermediolateral region of the L6-S1 spinal cord. This increased labelling was even more remarkable given that the volume of tracer per bladder weight injected into the hypertrophied bladder was 87% less than controls. These results provide evidence that bladder afferents project to regions of the spinal cord known to regulate micturition and that these afferents can undergo morphological alterations and/or changes in axoplasmic transport in response to urethral ligation. Changes may occur in response to increased target organ mass, increased neural activity, or alterations in the levels or activity of neurotrophic factors.

Oral trazodone as empirical therapy for erectile dysfunction: a retrospective review.

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.

Nerve growth factor responsiveness of cultured major pelvic ganglion neurons from the adult rat.

The bladder and other pelvic viscera are innervated in the rat by the major pelvic ganglion (MPG), a mixed sympathetic/parasympathetic population of neurons that participates in lower urinary pathophysiology. Neurons from the MPG of adult females were removed, dissociated and cultured in order to test retention of the neuronal phenotype and whether they responded to Nerve Growth Factor (NGF). The bladder-specific subset of MPG neurons were distinguished by retrograde labeling prior to culture. The adult ganglionic neurons adapted to culture with greater than 80% survival in the best cases. The cultured neurons retained excitability, as determined by measuring voltage-activated ionic currents. They were positive for neuron-specific beta-tubulin and many retained immunoreactivity for characteristic peptides and transmitter synthetic enzyme. The proportion of neurons in the different categories tested varied somewhat from that in vivo, but there was no evidence of selective death of a particular population. The cultured MPG neurons were responsive to NGF and anti-NGF antibody. NGF supported neuronal survival and expression of tyrosine hydroxylase. Added NGF also affected the expression of neuropeptide Y. Hypertrophied neurons from animals with experimental bladder outlet obstruction demonstrated increased responsiveness to NGF. The data suggest that NGF participates in adult neural plasticity due to continued responsiveness to the factor. Furthermore, questions concerning regulation of MPG neurons may be addressed in vitro.

Excitatory and inhibitory influences on bladder activity elicited by electrical stimulation in the pontine micturition center in the rat.

Electrical stimulation at various sites in the dorsal pontine tegmentum in urethane anesthetized rats modulated activity of the urinary bladder as well as efferent firing on bladder postganglionic nerves. Electrical stimulation (0.2 ms 50 Hz, 5-20 V or 30-150 microA, 2-5 s train duration) using a microelectrode (tip diameter, 10-20 microns) in an excitatory area located rostral and medial to the locus coeruleus evoked short latency (less than 2 s) large amplitude (greater than 20 cm H2O) bladder contractions and increased firing on the bladder postganglionic nerves. Stimulation at sites adjacent to the excitatory area inhibited bladder postganglionic nerve firing and bladder activity. Inhibitory responses were evident as either a decrease in intravesical pressure, an increased interval between bladder contractions, or an interruption or elimination of bladder contractions. The threshold intensity for excitation using a large electrode (2-4 V) was slightly higher than that for inhibition (1.5-2 V). The optimum sites for evoking bladder contractions were located in and close to the laterodorsal tegmental nucleus (LDT) and in the periaqueductal gray just dorsal or dorsolateral to the LDT. The extent of the area that induced bladder contractions was 0.5-1.2 mm in diameter in each rat when a microelectrode was employed for electrical stimulation. Electrical stimulation in the optimum site for evoking bladder contractions induced relatively little striated muscle activity and produced no short-latency blood pressure changes. The longer latency blood pressure changes associated with a spontaneous bladder contraction were still present following a stimulation of the dorsolateral pons. These data are consistent with the view that neurons in the dorsal pontine tegmentum play an important role in the regulation of urine storage as well as urine release.

Electrophysiological analysis of the ascending and descending components of the micturition reflex pathway in the rat.

Electrophysiological techniques were used to examine the organization of the spinobulbospinal micturition reflex pathway in the rat. Electrical stimulation of afferent axons in the pelvic nerve evoked a long latency (136 +/- 41 ms) response on bladder postganglionic nerves, whereas stimulation in the dorsal pontine tegmentum elicited shorter latency firing (72 +/- 25 ms) on these nerves. Transection of the pelvic nerve eliminated these responses. Firing on the bladder postganglionic nerves was evoked by stimulation in a relatively limited area of the pons within and close to the laterodorsal tegmental nucleus (LDT) and adjacent ventral periaqueductal gray. Stimulation at sites ventral to this excitatory area inhibited at latencies of 107 +/- 11 ms the asynchronous firing on the bladder postganglionic nerves elicited by bladder distension. Electrical stimulation of afferents in the pelvic nerve evoked short latency (13 +/- 3 ms) negative field potentials in the dorsal part of the periaqueductal gray as well as long latency (42 +/- 7 ms) field potentials in and adjacent to the LDT. The responses were not altered by neuromuscular blockade. Similar responses were elicited by stimulation of afferent axons in the bladder nerves. The sum of the latencies of the ascending and descending pathways between the LDT and the pelvic nerve (i.e. 72 ms plus 42 ms = 114 ms) is comparable although somewhat shorter (22 ms) than the latency of the entire micturition reflex. These results provide further evidence that the micturition reflex in the rat is mediated by a spinobulbospinal pathway which passes through the dorsal pontine tegmentum, and that neurons in the periaqueductal gray as well as the LDT may play as important role in the regulation of the micturition.

Neurally mediated hyperactive voiding in spontaneously hypertensive rats.

The development of hypertension in spontaneously hypertensive rats (SHR) and hyperactive voiding in rats with urethral obstruction are characterized by abnormal smooth muscle growth, increased tissue levels of nerve growth factor (NGF) and altered patterns of innervation. The present study was undertaken to determine if bladder smooth muscle from SHRs contains and secretes elevated levels of NGF, and if so, whether the augmented NGF contributes to changes in bladder innervation and function without tissue hypertrophy. Voiding behavior was monitored using specially designed metabolic cages. NGF levels in tissue homogenates and conditioned cell culture media were measured by ELISA. NGF mRNA in cultured bladder smooth muscle cells (BSMCs) was quantified using reverse transcriptase PCR. Noradrenergic innervation was assessed by staining with glyoxylic acid and assaying norepinephrine (NE) content in bladders with high performance liquid chromatography. SHRs voided more frequently than WKY rats. NGF content was higher in bladders from adult SHRs when compared to Wistar-Kyoto normotensive rats (WKYs). No significant difference in NGF mRNA content was observed between SHR and WKY BSMCs. However, SHR BSMCs secreted NGF at a higher rate and amount per unit mRNA than did WKY BSMCs. SHR bladders contained more NE and were more densely stained for catecholaminergic fibers than bladders from WKY rats. The results support the hypothesis that elevated NGF secretion by bladder smooth muscle is associated with hyperinnervation of bladder and hyperactive voiding in SHRs. Thus, the SHR strain may represent a genetic model to study changes in bladder function resulting from altered patterns of innervation.

Treatment of aged rat sensory neurons in short-term, serum-free culture with nerve growth factor reverses the effect of aging on neurite outgrowth, calcium currents, and neuronal survival.

Impaired NGF production and release has been documented in aged animals, suggesting that decreased NGF receptor stimulation may be one factor contributing to neuronal dysfunction with aging. Other studies have suggested that aging may be associated with impaired intracellular responses to NGF. Because aging-associated neuronal dysfunction contributes to morbidity and mortality in the geriatric population, it is important to determine whether the effects of aging on sensory neuron function and survival are reversible. In the present study, we observed significantly decreased neurite outgrowth and neuronal survival in short-term cultures (0-96 h) of dorsal root ganglion (DRG) neurons from aged (>22 months) Fisher 344 x Brown Norway F1 hybrid rats, compared to young (4-6 month) and middle-aged (14 month) animals. From 24 to 96 h in culture, diminished survival of aged neurons appeared to be due to an increased rate of apoptotic cell death. DRG neurons from aged animals also exhibited significantly decreased whole cell, high-threshold voltage-dependent calcium currents, with a larger proportion of L-type current, compared to youthful and middle-aged animals. Treatment of aged DRG neurons with NGF restored neurite outgrowth, neuronal survival and calcium current amplitude and subtype distribution to those observed in youthful DRG neurons.

Alternative approaches to the management of priapism.

Herein we describe the use of intracavernous methylene blue (MB), a guanylate cyclase inhibitor, or internal pudendal artery embolization for the treatment of priapism. Eleven patients with priapism were treated from 1993-1996. Etiologies of priapism included PGE1/papaverine (3), trazodone (2), and sickle cell disease (1), in the other five cases the causes the cause was unknown. The average duration of priapism was 27 h for all patients (6-72 h). Five patients who failed intracavernous MB or an alpha-adrenergic agonist, underwent unilateral or bilateral pudendal artery embolization. The average duration of priapism for patients undergoing embolization was 43 h. Sixty-seven percent of the patients treated with MB responded with immediate detumescence. One-hundred percent of patients with priapism secondary to intracavernous injection therapy or trazodone responded. Of the five patients who underwent embolization, 40% achieved immediate pain relief and subsequent detumescence. The three non-responders exhibited a partial detumescence over 47-72 h. After follow-up of one year embolization available for only two patients revealed that one regained potency while the other remained impotent. These results confirmed that MB is effective for pharmacologically-induced priapism. Embolization is a less invasive option for refractory priapism, although results are less than satisfactory in men with priapism of several days duration.

NGF, bFGF and CNTF increase survival of major pelvic ganglion neurons cultured from the adult rat.

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.

Neurophysiology of micturition and continence.

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.

Stimulation of bladder activity by volume, L-dopa and capsaicin in normal conscious rats--effects of spinal alpha 1-adrenoceptor blockade.

To study possible differences in alpha 1-adrenoceptor involvement in the spinal mechanisms mediating bladder activity induced by volume (bladder filling), central (L-dopa), and peripheral (capsaicin) stimulation, we investigated if these types of bladder activity were modified by intrathecal (i.t.) or intra-arterial (i.a.) administration of the alpha 1-adrenoceptor antagonist, indoramin. Indoramin is selective for the alpha 1A-adrenoceptor subtype, whereas most clinically used alpha 1-adrenoceptor antagonists, including doxazosin, have no subtype selectivity. The drug effects were studied by continuous cystometry in normal, conscious rats and rats with bladder activity evoked by intraperitoneal L-dopa (50 mg/kg after carbidopa pretreatment), or by intravesical capsaicin (30 microM). I.t. indoramin (50 nmol) significantly decreased micturition pressure, and increased bladder capacity and micturition volume. Dribbling incontinence due to urinary retention was observed in one of ten rats. L-dopa-stimulated bladder overactivity was significantly attenuated by i.t. or i.a. indoramin (50 nmol). Similar effects of i.t. and i.a. doxazosin (50 nmol) have been reported previously. Intravesical capsaicin (30 microM) caused bladder activity, which was attenuated by i.t. indoramin (50 nmol), but not by i.t. doxazosin (50 nmol). I.a. indoramin did not reduce capsaicin-induced bladder activity; doxazosin was moderately effective. The results suggest that the bulbospinal micturition reflex evoked by bladder filling and L-dopa involves a descending pathway where transmission is partly mediated by spinal alpha 1-adrenoceptors. Bladder overactivity evoked by intravesical capsaicin, which elicits a vesicospinal-vesical reflex, was not affected by i.t. doxazosin in a dose that attenuates activity mediated through the bulbo-spinal pathway. This suggests less involvement of spinal alpha 1-adrenoceptors in the vesico-spinal-vesical than in the bulbo-spinal voiding reflex.

cGMP mediates corpus cavernosum smooth muscle relaxation with altered cross-bridge function.

We tested the prevailing paradigm that relaxation of corpus cavernosum smooth muscle (CCSM) and penile erection depends upon nitric oxide-induced elevation of myoplasmic cGMP and reduced Ca2+-dependent myosin regulatory light chain phosphorylation levels. This hypothesis invokes a reversal of normal activation pathways. Upon stimulation with 250 microM phenylephrine, phosphorylation of the 20 kD myosin regulatory light chains of rabbit or human CCSM increased approximately 4-fold coincident with contraction. Removal of the agonist was followed by a slow reduction in cross-bridge phosphorylation and force to basal levels. The NO donor, sodium nitroprusside elicited a dose-dependent increase in tissue [cGMP] associated with a rapid relaxation in the continued presence of phenylephrine, although cross-bridge phosphorylation remained significantly elevated. Thus the NO-cGMP inhibitory pathway in CCSM is not simply a reversal of excitatory signal transduction mechanisms. An unidentified mechanism contributes to relaxation by decreasing the rate of cross-bridge recruitment through phosphorylation.

Benign prostatic hyperplasia.

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.