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Autonomic innvervation of rabbit urinary bladder following estrogen
Abstract
The effects of estrogen administration on the autonomic innervation of the rabbit urinary bladder were studied. Immature female white rabbits were injected twice daily with estrogen (150 microgram./Kg.) for four consecutive days. Control animals received injections of vehicle alone. The adrenergic innervation was identified using the glyoxalic acid method of catecholamine histofluorescence. The cholinergic innervation was visualized utilizing specific acetylcholinesterase staining. Additionally, the effect of estrogen administration on the response of smooth muscle strips of urinary bladder to specific autonomic agonists was determined. Estrogen administration induced a moderate increase in the adrenergic innervation of the rabbit bladder detrusor, whereas no change could be observed in the cholinergic innervation. It should be noted, however, that whereas the adrenergic innervation in the bladder of the control animal was sparse, the cholinergic innervation in the bladder body was quite dense. Estrogen induced a marked increase in the response to alpha-adrenergic (methoxamine) and muscarinic cholinergic (bethanechol) agonists. No alterations were noted in the response to beta-adrenergic agonists (isoproterenol). These findings indicate that the urinary bladder responds as a target organ for estrogen-induced alterations in autonomic innervation.
... Polyestradiol treatment of mature female rabbits caused increased α-adrenergic receptor density in the rabbit urethra. 26 Levin et al. 28,29 found that treating immature female rabbits with estradiol caused an increased bladder-body response to α-adrenergic stimulation that corresponded to an increase in α-adrenergic receptor density. Shapiro 30 found that low-dose estradiol treatment after ovariectomy caused no change in bladder muscarinic receptor density. ...
The incidence of lower urinary tract dysfunctions (LUTDs) in women increases with age. These dysfunctions include incontinence, recurrent urinary bladder infection, and poor bladder and urethral contraction. There is a corresponding progressive decrease in mean circulating estrogen as women age. We have data indicating that the rate at which LUTDs develop and progress is directly related to the decrease in circulating estrogen. Our studies on rabbits indicate that low circulating estrogen mediates a de crease in blood flow to the bladder and urethra. This in turn results in mucosal and smooth muscle hypoxia and the generation and release of free radicals. The end result is slow progressive oxidation damage of cellular and subcellular membranes (protein, lipids, and phospholipids), which relates directly to the etiology of age-related progressive LUTD. Estrogen administration to ovariectomized rabbits reverses these effects while causing smooth muscle hypertrophy, mucosal hyperplasia, increased vascularity and blood flow, fully oxygenated tissue, and reduced oxidative damage.
Symptomatic bladder outlet obstruction due to prostatic enlargement is a common problem in urological practice. Hyperactive detrusor function, "detrusor instability", occurs in up to 80% of patients presenting with prostatic obstruction and in most cases it resolves post-operatively when the obstruction has been relieved. This dysfunction is generally regarded as a modern concept but, in 1786, John Hunter recognised the complex nature of prostatic obstruction and reported: “The disease of the bladder arising from obstruction alone, is increased irritability, and its consequences, by which the bladder becomes quick in its action and thick and strong in its coats." Animal models have confirmed the relationship between obstruction and instability. Several hypotheses have been proposed to explain this link and include; (1) post-junctional hypersensitivity possibly related to denervation, (2) altered adrenoceptor function, (3) afferent nerve dysfunction, (4) an imbalance of peptide neuro-transmitters, and (5) a primary or acquired myogenic deficit. The principal motor control of the intraprostatic musculature is mediated by the sympathetic nervous system; however, the mechanism of action and specific localisation of prostatic adrenoceptors and the importance of non-adrenergic neurotransmission in man is poorly understood. A study of patients with symptomatic prostatic obstruction was undertaken to investigate the influence of neural pathways in determining the pathogenesis and clinical presentation of prostatic and detrusor dysfunction. Sixty-two patients were investigated using modern urodynamic techniques and sub-divided into three groups; control, stable obstructed and unstable obstructed. Biopsies of prostate, bladder neck and bladder muscle were taken at the time of surgery, and pharmacological, autoradiographic and histochemical studies performed. The prostate, bladder and bladder neck were found to be innervated by a complex network of noradrenaline-, acetylcholine-, neuropeptide-, and amine-containing nerves. Separate quantitative analyses of these neurons were carried out and corrections applied to compensate for muscle hypertrophy and hyperplasia. The histological findings were complemented wherever possible by biochemical assay of neuro transmitters. There was a significant reduction in the acetylcholinesterase positive innervation of the obstructed bladder compared with control, which was most marked in tissue from patients with detrusor instability. A similar reduction in the non-adrenergic, non-cholinergic sensorimotor neurotransmitters was evident. Biochemical changes within the detrusor included an increase in noradrenaline content and a decrease in the putative sensory neurotransmitter substance P. Detrusor muscle strips from obstructed patients showed increased contraction in response to acetylcholine, suggesting that denervation hypersensitivity might contribute to the pathogenesis of post-obstructive detrusor instability. Normal detrusor muscle relaxed in response to noradrenaline. In contrast, detrusor muscle from unstable obstructed patients contracted; a response most marked in detrusor muscle from patients who had presented in acute retention. In vitro prostatic muscle-strip experiments confirmed that contraction of prostatic muscle is produced by adrenoceptor stimulation. Radioligand binding assays endorsed the results of these experiments by demonstrating a clear excess of α1 receptors over α2 receptors in histologically normal and adenomatous prostate. Auto-radiography showed the precise localization of the two types of adrenoceptor and confirmed the predominance of α1 receptors within prostatic musculature. The complexity and potential importance of the autonomic nervous system in the pathogenesis and symptomatic expression of prostate-mediated bladder outflow obstruction, is demonstrated by this work. Marked changes in the innervation of both the prostate and bladder accompany obstructive benign enlargement of the prostate. The characterisation and localisation of the prostatic adrenoceptor is of considerable relevance since it validates the therapeutic use of selective prostatic α1 blockade in the clinical management of obstructed patients. Preliminary immunohistochemical studies of bladder, bladder neck and prostate are presented, which provide an histological basis for further functional investigative studies.
The lower urinary tract performs two functions: the storage and emptying of urine. The physiology of the cycle of micturition has been described by many qualified authors, each of whom has given his own particular concept of the neuroanatomy and neurophysiology of the smooth and striated muscular structures, the peripheral autonomic and somatic neural factors, and the spinal and supraspinal influences which are necessary for the normal micturition cycle. There are significant disagreements regarding the finer details of the relevant neuromorphology, neurophysiology and neuropharmacology. Perhaps the best example of this is the current controversy over the influence of the sympathetic nervous system on the physiology of micturition and the interrelationships, if any, of the parasympathetic and sympathetic influences on the smooth muscle of the urinary bladder and its outlet.
In order logically to understand the actions of the many pharmacological agents in use today which produce their effects on the urinary musculature via its autonomic control, it is desirable first of all to give a brief review of presentday thinking concerning the structure and functions of the autonomic nervous system in relation to the urinary tract.
As a result of the renewed interest in the neuropharmacology and neurophysiology of the urinary bladder and its outlet, pharmacological therapy now exists which is effective in the management of many types of voiding dysfunction. It is the intention of this chapter to summarise briefly the pharmacological principles on which this drug therapy is based, and to show how pharmacological treatment fits into a functional scheme of therapy for disorders of micturition, specifically related to the female patient with urinary incontinence.
Pelvic floor disorders are common and bothersome problems that include a variety of conditions. These conditions greatly affect the performance of daily activities and social function such as work, traveling, physical exercise, sleep and sexual function. Aging is a well-known factor affecting the pelvic floor and lower urinary tract anatomy and function. It is clear that the pelvic organs and their surrounding muscular and connective tissue support are estrogen-responsive. Treatment of pelvic floor disorders requires significant health-care resources and their impact is likely to increase in the near future. This literature review aims to provide an overview of both research and clinical aspects of the pathophysiology of urogenital estrogen deficiency and the role of local estrogen therapy as part of the management strategy of different pelvic floor disorders. The safety and risk concerns regarding the use of local estrogen therapy are addressed as well.
The term vesical outlet is used herein in a broad sense to include the base region of the bladder and the prediaphragmatic urethra, represented by its prostatic segment in the male. So defined, the outlet performs four essential functions in micturition in both sexes:47,49 1) continence, by sustained closure during bladder filling (collection phase); 2) opening to initiate the urine stream at the onset of voiding (expulsion phase); 3) sustained opening to maintain the urine stream until the bladder is empty; and 4) closure to terminate voiding and restore its resting status in preparation for the oncoming micturition cycle. In addition, the vesical outlet in the male functions in such a way that seminal emission and ejaculation can occur while the vesicourethral junction remains closed to prevent retrograde ejection of semen into the bladder (retrograde ejaculation).
The menopause is defined by the World Health Organization as the point in time of permanent cessation of menstruation due to loss of ovarian function [1]. Clinically, the menopause is characterized by persistent amenorrhea for a period of 12 months. The perimenopause is defined as the time period of changing ovarian function preceding the menopause to 1 year following the final menses, generally lasting between 2 and 8 years. Today, the average age of menopause is approximately 51 years [2-5]. Laboratory findings in the menopause generally reveal serum estradiol levels of less than 40 pg/mL, with follicle-stimulating hormone (FSH) levels more than 40 mIU/mL. These values may vary depending on the assay used.
Pregnancy induces morphological as well as functional changes in the urinary tract. Urinary frequency, incontinence, and an increase in residual urine are common clinical findings during gestation. Previous studies from this laboratory have shown a decreased cholinergic response and cholinergic receptor density in the urinary bladders of pregnant rabbits.
In the present study, the adrenergic functions of the bladders of pregnant and virgin New Zealand White rabbits were compared using isolated muscle strips. Dose-response curves showed that the contractile responses to epinephrine (alpha and beta agonist) and methoxamine (alpha agonist) were significantly reduced in tissues from the base and the mid-segment, but not the body of the pregnant rabbit bladders. No significant difference was observed in the degree of isoproterenol (beta agonist) induced relaxations between the two groups. Thus, the results demonstrated a decreased alpha responsiveness in the midsegment and base of the pregnant bladders.
Physiologically, a decrease in alpha tone at the bladder base would be advantageous for bladder emptying as the resultant relaxation at the bladder outlet theoretically would alleviate the effect of decreased bladder body contractility as well as any mechanical stress imposed on the urethra by the enlarging uterus.
The effects of ATP, adenosine (ADS), β,γ-methylene ATP (APPCP), norepinephrine (NE), and hypogastric nerve stimulation (HGS) on urinary bladder responsiveness have been studied in male and female cats. Recent studies indicated binding sites for estradiol and testosterone in the urinary tract of animals. Other studies have demonstrated that estrogen alters the effects of certain agonists in urinary tract smooth muscle, although the mechanism of this effect is not known. The present study was designed to determine if differences occurred in the response of bladder smooth muscle in male vs. female cats to various stimuli and if surgical or drug pretreatment alters the response.
The results of these experiments indicate differences between the response of the urinary bladder in female and male cats to various stimuli and that various pretreatments can alter the detrusor response to selected stimuli. In particular, detrusor of female cats was less responsive to most stimuli than detrusor of male cats, including stimuli that induced inhibition of pelvic-nerve-evoked bladder contractions (such as norepinephrine) and stimuli which induced bladder contractions (such as ATP). Also, gonadectomy altered the response of the detrusor making it more responsive to purine inhibitory stimuli, while having a mixed effect on detrusor responsiveness to excitatory stimuli. Pretreatment of cats with a gonadotropin-releasing hormone antagonist also altered detrusor responsiveness, both inhibitory and excitatory agonists in a variable manner, increasing the magnitude of most responses. In addition to the above-stated differences, the data also proved to underscore some similarities in the response of male and female cats to adrenergic and cholinergic stimuli. These studies imply that sex hormones influence detrusor response to certain purinergic stimuli and that alteration of sex hormone levels by surgery or medication can impact lower urinary tract function.
In vitro isometric studies of bladder dome muscle taken at operation from 47 patients with benign prostatic obstruction, revealed an alpha-adrenergic response instead of the normal beta response in 23 per cent. The relationship between this finding and the presence of irritative symptoms and an unstable detrusor is examined. This finding may explain the beneficial effect of alpha-blockers on these symptoms in many patients with prostatic obstruction.
The effects of ovarian hormones on β-adrenergic receptor-mediated responses in female rabbit detrusor smooth muscles were
investigated. Ovariectomized mature female New Zealand white rabbits were untreated or treated with estrogen and/or progesterone
for 2 weeks. The contractile responses to carbachol and KCl in the detrusor strips were not significantly different in all
groups. As compared with dobutamine and GS-332, isoproterenol and procaterol significantly relaxed the detrusor strips derived
from all groups on KCl-induced tonic contractions. Combined with estrogen treatment, isoproterenol, procaterol and GS-332
caused a significant increase in this muscle relaxation. Furthermore, estrogen treatment caused a significant increase in
relaxation as a result of forskolin and the cyclic AMP (cAMP) production that was induced by isoproterenol, procaterol and
GS-332. However, estrogen treatment did not affect the relaxant response to dibutyryl cyclic AMP. Progesterone treatment did
not affect β-adrenergic receptor-mediated responses. These results suggest that estrogen treatment causes the increased relaxant
responses mediated by β2- and β3-adrenergic receptor subtypes, which may be related to the increased cAMP content in female rabbit detrusor smooth muscles.
Pharmacological therapy has been developed which can have significant impact in the management of many forms of urinary incontinence and voiding dysfunction. In general the clinical laboratory studies which have supported or challenged the efficacy of many of the commonly prescribed drugs for voiding dysfunction are often difficult to interpret and contradictory. The available clinical studies often do not demonstrate a lack of bias. Nor do they include an adequate number of subjects, use appropriate and sensitive methods of evaluation, employ double-blind placebo-controlled design, or appear statistically valid. Although the contribution of laboratory research has been of unquestionable value in the development of our current knowledge of lower urinary tract pharmacology it is difficult to interpret the results of in vitro pharmacological studies because of the array of experimental models used and the need to extrapolate to in vivo activity. This paper utilizes a functional scheme which classifies agents by their effects on urinary storage and emptying. The purpose of this review is to promote discussion of the application of uropharmacological investigation to the development of newer, more efficacious forms of drug therapy.
An understanding of normal bladder function provides a basis for the interpretation of disturbances of micturition, notably where they are caused by trauma. Knowledge of the underlying mechanisms can contribute significantly to diagnosis, prognosis and treatment although it remains true that both bladder physiology and its disturbances are incompletely understood. This paper aims to provide a reasonably concise survey of the relevant physiology and pharmacology and its implications for those dealing with urological abnormalities.
The treatment options of patients with urge incontinence are behavioral therapy, drug therapy and surgery. The evaluation and reported efficacy of these treatments, with particular reference to the potential placebo response in treatment is discussed.
Urinary complaints such as urinary incontinence, urinary tract infections, nocturia, and urinary urgency are common in women. The prevalence of these urinary conditions increases with age. Factors which are related to a rise in urinary complaints include age-related changes in bladder and urethral function, comorbid medical conditions, medications, and changes in the hormonal milieu. In fact, some studies have shown a distinct rise in the prevalence of urinary incontinence after menopause
[30] and [52]; however, others
[24] and [67] have not found menopause to be an independent risk factor for urinary incontinence. It is tempting to place blame on the hormonal changes associated with menopause when considering etiologic factors for urinary complaints. Several researchers have shown that the urethra and bladder contain a rich supply of estrogen receptors in women, which presumably would affect urogenital function. Whether research confirms this hypothesis and whether estrogen therapy can be used to treat these common urinary complaints are the main subjects of this article. In addition, we briefly review the evaluation of urinary incontinence, nocturia, and urgency that is required before beginning therapy and other nonsurgical modalities for treating incontinence. The use of estrogen replacement therapy for the prevention of urinary tract infection is also discussed.
Postmenopausal estrogen deprivation has been suggested as a risk factor for lower urinary tract dysfunction including stress incontinence, overactive bladder and recurrent urinary tract infection. These symptoms could have enormous effects on individuals and health-care providers in terms of impact on quality of life and cost. Recent randomized, controlled trials suggested that systemic hormone replacement therapy does have a negative effect on female lower urinary tract function, probably because of the progestogen component. Further, it may be unacceptable for many women because of concerns about breast cancer or the return of withdrawal bleeding. Topical vaginal estrogen preparations reverse urogenital atrophic changes and may relieve associated urinary symptoms while avoiding systemic and progestogenic effects. This article provides an up-to-date overview of the role, effectiveness and safety of topical vaginal estrogen therapy for the treatment of lower urinary tract symptoms in postmenopausal women.
Micturition characteristics, collagen composition, and in vitro urinary bladder strip contractility were examined in young adult (six month) and old (24 month) male and female Fischer 344 rats. Although young female rats consumed significantly less water than young males, there were no differences in volumes of urine excreted. Old females excreted significantly more urine than old males, but there were no differences in volumes of water consumed. Old male rats had similar micturition frequencies during the light and dark cycles, in contrast to females and young males, where the number of micturitions during the dark cycle was significantly greater than those during the light cycle. The mean and maximal micturition volumes were significantly greater in old males compared to young males and old females during both the light and dark cycles.
We studied the bladders of 24-month-old intact rats, rats that had been ovariectomized at the age of 6 months, and intact and ovariectomized rats treated by estrogen from the age of 16 months. The study thus comprized four groups: group I: bilaterally ovariectomized rats; group II: intact rats; group III: ovariectomized rats treated with estrogen; group IV: intact rats treated with estrogen. The weight and collagen concentration of the bladders were determined. The ovariectomized bladders weighed significantly less and had a higher collagen concentration than the intact bladders. Estrogen substitution for ovariectomized rats reversed these parameters. Detrusor strips were also used for organ bath studies. All bladders were similar in regard to the nerve-mediated frequency-response relationship. The atropine-resistant response was studied by adding scopolamine to the organ bath. Strips from ovariectomized rats had a significantly diminished atropine-resistant response, which was abolished by estrogen substitution. The present study suggests that micturition problems in menopause might have a structural as well as a pharmacological explanation.
Recent advances in imaging technology have allowed for the diagnosis of many congenital urologic abnormalities through the use of antenatal ultrasonography. There is controversy in the literature as to whether antenatally detected dilatations of the urinary tract are always secondary to obstruction or if in select cases the dilatations are physiologic in nature and will spontaneously regress. Benign dilatations of the fetal urinary tract are postulated to be secondary to the increased fetal diuresis and a more compliant fetal urinary tract. No one has investigated the possibility that such dilatations might be a consequence of the hormonal changes seen with pregnancy. In this study we present evidence for a change in bladder function with pregnancy. A summary of our results shows that in the presence of bethanechol, strips from the urinary bladders of pregnant rabbits generate 50% less tension in response to calcium than those from nonpregnant rabbits. Such a suppression in smooth muscle function might also help explain the benign dilatations of the upper urinary tract which are seen frequently during pregnancy.
The effects of castration and testosterone on the autonomic receptor density and contractility in the urinary bladder smooth muscle of male rabbits were compared to untreated animals. Four groups of rabbits were studied over a similar time span with Group 1 animals serving as the untreated controls. Two groups (Groups 2 and 3) were castrated 28 days prior to sacrifice, Group 2 animals received corn oil for 14 days, and Group 3 animals received testosterone, 10 mg./day, for 14 days. The Group 4 animals were non-operated and received testosterone 10 mg./day for 14 days. Ligand saturation binding studies for alpha adrenoceptors in the bladder base and proximal urethra were performed with [³H]dihydroergocryptine ([³H]DHE). Muscarinic cholinergic receptors (MChR) were assayed with [³H]quinuclidinyl benzilate ([³H]QNB) and beta adrenoceptors with [¹²⁵I]iodo-cyanopindolol ([¹²⁵I]CYP) on the detrusor smooth muscle. Castrated Group 2 animals showed no significant change in receptor density with either [³H]QNB or [¹²⁵I]CYP in detrusor muscle, but did exhibit a significant reduction (59%) of alpha adrenoceptors in the bladder base-urethra. The testosterone treated castrate and testosterone treated non-operated animals had significant increases in the MChR density, but no change in the alpha adrenergic, or beta adrenergic receptor density as compared to untreated controls.
Symptomatic clinical changes and urodynamic changes are apparent in the female urinary tract system during pregnancy, the menstrual cycle and following the menopause. The sex hormones exert physiological effects on the female urinary tract, from the ureters to the urethra, with oestrogens having an additional influence on the structures of the pelvic floor. High affinity oestrogen receptors have been identified in bladder, trigone, urethra and pubococcygeus muscle of women. Oestrogen pretreatment enhances the contractile response of animal detrusor muscle to a-adrenoceptor agonists, cholinomimetics and prostaglandins, as well as enhancing the contractile response to a-agonists in ureter and urethra. Progesterone on the other hand decreases tone in the ureter, bladder and urethra by enhancing β-adrenergic responses.
The dependence on oestrogens of the tissues of the lower urinary tract contributes to increased urinary problems in postmenopausal women. Urinary symptoms due to atrophic mucosal changes respond well to oestrogen replacement therapy. However, because they recur when treatment is stopped, continuous therapy with low dose natural oestrogens is recommended. Oestrogens may be of benefit in postmenopausal women with stress incontinence but the doses necessary for clinical effect are higher than for the treatment of atrophic urethritis. The practice of adding a progestagen to long term oestrogen therapy to reduce the risk of endometrial carcinoma may, however, exacerbate stress incontinence by decreasing urethral pressure. Cyclical therapy with oestrogens may therefore be more appropriate particularly in women who are not suitable for surgery or have a mild degree of stress incontinence, along with other conservative measures such as pelvic floor exercises and a-adrenoceptor agonists. The place of oestrogen therapy in motor urge incontinence has not been determined.
The risk of developing endometrial carcinoma as a result of long term high dose oestrogen replacement therapy must be borne in mind but remains to be clarified. However, oestriol has less of a uterotrophic effect compared to other oestrogens in standard therapeutic doses and is to be preferred. Side effects are usually dose related and tend not to be a problem with low dose therapy.
Because of renewed interest in the neuropharmacology and neurophysiology of the urinary bladder and its outlet, drug therapy can now help manage many types of voiding dysfunction. This article summarizes the scientific foundations on which this type of therapy is based and the current drug usage in this area.
The ability of mixed spinal nerve roots to regenerate and reinnervate the urinary bladder was examined in young adult female cats. Using microsurgical technique, a unilateral extradural spinal nerve root anastomosis of a lumbar (L7) to a sacral root (S1) either with or without a nerve graft was performed. Remaining ipsilateral sacral roots were transected. The contralateral normal sacral roots remained intact and allowed the animals adequate urination during the period necessary for axonal regeneration. At the time of restudy seven months later, stimulation of the anastomosed nerve root proximal to the anastomosis (isolated from the spinal cord) elicited a bladder contraction. Significant lumbar axonal regeneration was substantiated by compound action potentials recorded across the anastomosis. In addition, redirection of axons from a lumbar to a sacral distribution was demonstrated. The contralateral normal sacral roots provided control cystometric and electrophysiological data against which responses from the previously anastomosed nerve roots were compared. In conclusion, significant bladder reinnervation can occur after an anastomosis of a lumbar and sacral root with or without a nerve graft. This technique, or variations thereof, may have a clinical role in selected patients with neurogenic bladder dysfunction to reinnervate the bladder and restore central control.
Summary— Phenylpropanolamine, and alpha receptor stimulant, was found effective in 11 of 13 female and 6 of 7 male patients with sphincteric incontinence. In all the male patients except 1, the incontinence has followed prostatectomy.
Side effects occurred in only 1 patient.
As a rule, the beneficial response depended on the therapy being continued. The results are consistent with the distribution of alpha receptors and their effect in the proximal urethra.
STEROID hormones alter sympathetic function and modulate responses to catecholamines1-3. The gonadal steroids, oestrogen and progesterone, can affect sympathetic response by altering catecholamine metabolism, and, in addition, they produce qualitative changes in the contractile response of smooth muscle to stimulation by adrenaline and noradrenaline4-6. The response of human oviduct and uteri from several species changes from contraction to relaxation depending upon the concentrations of gonadal steroids. Contraction, which is mediated by alpha-adrenergic receptors, is observed in uteri from oestrogen-treated humans or rabbits, while relaxation, a beta-adrenergic response, predominates during pregnancy or with progesterone treatment. Conversion between alpha and beta response, depending on hormonal or other environmental factors, has prompted the hypothesis that alpha- and beta-adrenergic receptors may be interconvertible7-9. We used the radioligands 3H-dihydroergocryptine (DHE) and 125I-iodohydroxybenzylpindolol ([125I] IHYP) to quantitate alpha- and beta-adrenergic receptors respectively in subcellular preparations of uteri from rabbits treated with oestrogen or oestrogen followed by progesterone. alpha-Adrenergic binding sites were three times greater in uteri from the oestrogen-treated animals in which alpha-adrenergic response was predominant than in uteri from animals treated with oestrogen followed by progesterone in which beta-adrenergic response predominates. The number of beta-adrenergic binding sites was unchanged by the different treatments and these sites were only 5% as numerous as alpha-adrenergic sites. These findings suggest that gonadal steroids may alter smooth muscle adrenergic response by alterations of adrenergic receptor number and do not support the hypothesis that alpha- and beta-adrenergic receptors are simply interconvertible.
The urethra is innervated by adrenergic fibres and its smooth muscle is equipped mainly with alpha-adrenoreceptors. Norephedrine chloride, which is an alpha-stimulating agent, has been proposed as therapy for stress incontinence, since it was shown to increase the maximum urethral pressure at rest. For further study of the effect of norephedrine chloride on the urethal closure pressure at rest and in a dynamic situation, we examined ten severely stress-incontinent women before and after three weeks of treatment with this agent (100 mg by mouth twice daily). The urethral closure pressure at rest, between coughs of varied strength and at the precise moment of stress were recorded. The margin to leakage, the tone of the urethral wall and the transmission of pressure from abdomen to urethra were also among the estimated factors. No improvement was found in any of these respects. Alpha stimulation in this form therefore seems ineffective in severe stress incontinence and is not an alternative to surgical treatment.
Studies of the response of isolated rabbit urinary bladder strips to adrenergic agents indicate the presence of both alpha and beta-adrenergic receptors in bladder smooth muscle. Using [3H]dihydroergocryptine and [3H]dihydroalprenolol, we characterized the alpha and beta-adrenergic receptors in the base and body of the rabbit urinary bladder. The density of alpha receptors (in femtomoles per milligram of protein) was significantly greater in the bladder base (78 ± 10) than in the body (18±4), whereas the density of beta receptors was significantly more concentrated in the body (96±10) than in the base (42±6). This uneven receptor distribution correlated well with the physiological response of isolated bladder strips to various adrenergic agonists. Methoxamine (an alpha agonist) stimulated contractility to a significantly greater degree in the musculature of the bladder base than in that of the body. Isoproterenol (a beta agonist) more effectively relaxed the bladder body than the bladder base. Epinephrine (alpha and beta agonist) produced a dose-dependent relaxation in the bladder body, whereas the bladder base responded to the same concentrations with a dose-dependent increase in contractility. The authors conclude from these studies that the greater response of bladder base to alpha-adrenergic agonists results from the predominance of alpha receptors in the bladder base and of beta receptors in the bladder body.
A double-blind study of the effects of placebo and oral bethanechol chloride (25, 50 and 100 mg.) on the carbon dioxide cystometrogram of the normal male adult was done. Statistical analysis of the data showed no significant dose-response relationship for any of the parameters measured.
Twenty-five women with stress incontinence of urine were given an alpha-adrenoceptor stimulating agent (norephedrine) and a placebo during respective 14-day periods according to a double-blind cross-over schedule. The results were classified as the patient's own assessment of therapeutic effect and as change in urethral closure pressure profile measured by a microtransducer catheter. Norephedrine had a significant therapeutic effect on the symptom stress incontinence and produced significant increase in maximum urethral pressure and maximum urethral closure pressure in the lithotomy and the erect position. Reduction of incontinence was associated with increase in maximum urethral closure pressure. The sum therapeutic effect was of moderate degree.
The sensitivity of alpha-adrenoceptors to phenylephrine as indicated by the ED50 of the rabbit bladder and urethra was compared for segments in vitro from control (estrous), ovariectomized, ovariectomized-estrogen-treated, and pregnant animals. In control animals there was a trend for urethral segments to be more sensitive to phenylephrine (lower ED50) than bladder segments. This difference was abolished by castration, which decreased the sensitivity of the anular urethral segment, and by pregnancy, which tended to enhance the sensitivity of the bladder. The tension generated by bladder segments was enhanced by pregnancy and tended to be decreased by castration. The effects of castration tended to be reversed by treatment with estrogen (1 microgram per kg of body weight per day for 14 days). These data indicate that estrogen can influence the response of the urethra and urinary bladder to alpha adrenergic stimulation.
A review of the management of neurogenic bladder dysfunction in the adult is presented. The various modes of therapy are classified according to their effects on bladder contractility and outlet resistance, providing a logical framework for discussion.
A modified approach of the glyoxylic acid (GA) condensation reaction for the visualization of biogenic amines in tissue is described.
Cryostat sections are used from brain or extracerebral tissue in dog, monkey, rat and mouse and exposed for 3 s to a room temperature solution containing sucrose-potassium phosphate-glyoxylic acid (SPG). The tissues are air dried and heated in an oven for 5 min. The complete processing time from fresh tissue to microscopic examination takes 18 min. Morphologically sharp and brightly fluorescent monoamine-containing neurons, pre-and terminal axons are seen against a dark parenchymal background without drug pre-treatment. The SPG method retains the high specific sensitivity for monoamines previously described in the original technique but is, in addition, more rapid and simple and is easily accessible as a research tool to investigators inexperienced in histofluorescence techniques.
Estrogene has a tonicising effect upon urethra musculature. There is also the same demonstrable influence of alpha-receptor stimulating drugs upon the urethra pressure profile. After preliminary treatment with estrogene, there is a considerably stronger tonicising effect of alpha-stimulating drugs than without such a treatment. So the combination of estrogene and alpha-stimulating drugs seems a useful addition to the conservative treatment of stress incontinence.
PIP
Estrogenic sensitivity of alpha-receptors in the urethra musculature was investigated. The main object of this study was to determine if est rogene could cause the alpha-receptors to be more sensitive to the alpha -receptor stimulating drugs, so that by using an equal dosage of alpha-r eceptor stimulating drugs in a preliminary estrogenic treatment, a stronger tonic effect would be achieved in the urethra musculature than by using the alpha-receptor stimulating drugs alone. 5 healthy continen t females and 3 females suffering from 1st-degree stress incontinence were studied. There was a demonstrable influence of estrogene upon the urethra musculature. And there was also the same demonstrable influence of alpha-receptor stimulating drugs upon the urethra pressure profile. Following preliminary treatment with estrogene, there was a considerally stronger tonicising effect of alpha-stimulating drugs than without such a treatment. Therefore, it appears that the combination of estrogene and alpha-stimulating drugs is a useful addition to the conservative treatment of stress incontinuence.
Immature Dutch rabbits were treated as follows: group 1, 70 µg estradiol-17ß every other day for 4 days; group 2, 70 µg estradiol-17ß every other day for 4 days, then 5 mg progesterone daily for 5 days; group 3, untreated controls. Uterine muscles with their hypogastric nerves attached were isolated, and the responses of the uterus to hypogastric nerve stimulation were recorded. Nerve stimulation (5–50 pulses/sec) contracted uteri from untreated and estrogen-treated rabbits. Nerve stimulation inhibited the spontaneous contractions of estrogen + progesterone-treated animals. These effects were unchanged by atropine or hexamethonium but were abolished by the adrenergic blocking agents phentolamine (estrogen-treated uteri) and propranolol (estrogen + progesterone-treated uteri). Uterine catecholamine content was unaltered by hormonal treatment. Pretreatment with reserpine greatly diminished uterine catecholamine content as well as the response to nerve stimulation in all animals. The hypogastric nerves therefore contain predominantly postganglionic adrenergic fibers, and the effects of their stimulation on uterine activity depend on the hormonal status of the myometrium.
In this study, we have characterized the response of five sequential segments of urinary bladder to cholinergic, adrenergic, and purinergic agonists. The results indicate that an abrupt alteration in pharmacological response between bladder body and base occurs at the level of the ureteral orifices. The bladder body responds preferentially to urecholine (muscarinic cholinergic), isoproterenol (beta adrenergic) and ATP (purinergic), whereas the bladder base responds perferentially to methoxamine alpha adrenergic). In parallel studies, the density of both muscarinic cholinergic receptors ([3H]quinuclidinyl benzilate binding sites) and beta adrenergic receptors were significantly higher in the body than in the base, whereas the concentration of alpha adrenergic receptors was greater in the bladder base than in the body. From these studies, we conclude that the differences in the response of the bladder base and body to cholinergic and adrenergic agents are primarily due to differences in the densities of the specific autonomic receptors. In addition, the response of the bladder to ATP (which is a putative neurotransmitter in the urinary bladder) can also be separated between body and base. The distribution is similar to that observed for urecholine.
A 5 mg. subcutaneous dose of bethanechol chloride was given to 12 women with residual urine volumes equal to or greater than 20 per cent of bladder capacity but no evidence of neurologic disease, or anatomic or functional outlet obstruction and to 27 normal women wtih approximately the same mean age. The cystometric and some profilometric parameters did change, indicating that the drug was pharmacologically active. No improvement in voiding function was noted, as judged by residual urine volume and flow rate measurements. These results raise significant questions regarding the contemporary use of this drug, especially in the currently recommended oral dosages.
The effect of estrogen administration on the autonomic innervation of the rabbit urinary bladder was studied. Immature female white rabbits were injected twice daily with estrogen (150 microgram/kg) for 4 consecutive days. Control animals received injections of vehicle. The response of bladder strips to the following agonists were determined for control and estrogen-treated animals: methoxamine (alpha adrenergic); isoproterenol (beta adrenergic); bethanechol (muscarinic cholinergic); ATP (purinergic); and potassium chloride (nonreceptor mediated). Additionally, the adrenergic and cholinergic receptor densities were determined by standard radioligand binding techniques. Estrogen induced a marked increase in the response to alpha adrenergic, muscarinic cholinergic and purinergic agonists in the bladder body and midbladder. No significant alterations were noted in the bladder base. In addition, no alterations were noted for isoproterenol or potassium chloride. The receptor densities paralleled closely the physiological responses. Estrogen induced a significant increase in alpha adrenergic and muscarinic receptors in the bladder body and midsection, whereas no change was noted in the receptor density of the bladder base. Estrogen did not alter the beta receptor density. These findings indicate that the urinary bladder responds as a target organ for estrogen-induced alterations in autonomic innervation.
The urinary bladder: physiology and biophysics
- Ruch
The use of estrogen in the treatment of dysuria and incontinence in post-menopausal women.
- Salmon U.J.
- Walter R.I.
- Geist S.H.
The role of female hormones in stress incontinence
- Caine
Alpha-adrenergic agents in urinary disorders of the proximal urethra. Part 1. Stress incontinence
- Awad
Cholinergic muscarinic receptor density in the human urinary bladder compared to that of the dog and rabbit
- A J Wein
- R M Levin