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PubMed1999

The spontaneously hypertensive rat: insight into the pathogenesis of irritative symptoms in benign prostatic hyperplasia and young anxious males.

Recent epidemiological studies have shown that hypertensive men are more likely to undergo surgical intervention for irritative voiding symptoms from BPH than age-matched controls. Indeed, noradrenergic nerves which regulate vascular tone also participate in the functional component of bladder outlet obstruction due to BPH. Newer, less invasive therapies for BPH such as thermal therapy can relieve symptoms yet do not eliminate obstruction based on urodynamic studies. Coincidentally, drugs such as alpha-adrenoceptor antagonists, which have been thought to relieve obstruction due to a peripheral effect, can be given intrathecally in animals to relieve urinary frequency due to obstruction. Taken together these observations implicate both peripheral and central sympathetic pathways in the motor control of the urinary bladder especially with disease states. We have used the hypertensive and behaviourally hyperactive spontaneously hypertensive rat (SHR), to investigate the roles sympathetic pathways or micturition. Elevated nerve growth factor (NGF) derived from vascular and bladder smooth muscle cells of the SHR appears to direct morphological, biochemical, and functional changes. The increase in NGF can apparently be explained by stabilization of its mRNA leading to increased synthesis in NGF. Bladders from SHRs develop a profuse noradrenergic hyperinnervation compared with the control WKY strain. Since afferents supplying the SHR bladder are hypertrophied, changes in afferent pathways are also likely. These differences in innervation and NGF in the SHR may explain changes in function. SHRs void 3 times as frequently as their genetic controls. Urinary frequency can be reduced by alpha-adrenoceptor antagonists. Cystometrograms performed in SHRs reveal lower bladder capacities and micturition volumes and the presence of unstable contractions compared with the WKY rat. Intrathecal, rather than intra-arterial administration of the alpha-adrenoceptor antagonist doxazosin reduces unstable contractions in the SHR. In vitro muscle bath studies have shown enhanced responses of SHR bladder smooth muscle to alpha-adrenoceptor agonists. It is likely that upregulation of NGF production causes sensory and possibly noradrenergic pathways to elicit hyperactive voiding. Increase in NGF in the adult bladder due to pathological conditions yields similar, yet distinct, consequences for voiding behaviour and innervation. Likewise, increased NGF in adult bladders following obstruction or inflammation triggers neuronal hypertrophy, enhanced reflex activity and urinary frequency. In contrast to the SHR, hyper-innervation is not observed. Moreover, peripheral or spinal alpha-adrenoceptor blockade eliminates urinary frequency following obstruction. These observations support the role for sympathetic pathways in the motor function of the bladder, especially in congenital or adult disease states. A similar process may underlie the neuroplasticity involved in alterations after obstruction or inflammation of the lower urinary tract in humans. The SHR strain raises the possibility that a common genetic defect exists capable of predisposing to both hypertension and overactivity of the urinary bladder. Whether a genetic predisposition to sustained bladder overactivity in response to inflammatory stimuli in obstruction exists in humans is an intriguing prospect.

Animals↗
PubMed2004

KW-7158 [(2S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide] enhances A-type K+ currents in neurons of the dorsal root ganglion of the adult rat.

Recent studies revealed that a new compound, KW-7158 [(2S)-(+)-3,3,3-trifluoro-2-hydroxy-2-methyl-N-(5,5,10-trioxo-4,10-dihydrothieno[3,2-c][1]benzothiepin-9-yl)propanamide], can depress the excitability of afferent pathways from the urinary bladder and reduce bladder overactivity induced by chemical irritation of the urinary tract with xylene, an agent that sensitizes capsaicin-sensitive, C-fiber afferent nerves. In the present experiments, we examined the mechanisms that might underlie the depressant effect of KW-7158 on primary afferent neurons by studying the actions of the compound on ion channels and firing in dissociated dorsal root ganglion (DRG) cells from adult rats using whole cell patch-clamp techniques. KW-7158 increased transient, A-type K+ currents at concentrations ranging from 50 nM to 1 microM (20-50% increases). Similar effects were seen in fast blue identified bladder afferent neurons. Low concentrations of KW-7158 shortened the action potential duration, produced a 5- to 10-mV hyperpolarization, and inhibited repetitive firing induced by either 4-AP (50 microM) or substance P (0.5 microM) in phasic firing DRG neurons. Above 1 microM, KW-7158 elicited a smaller enhancement of A-type K+currents and in high concentrations inhibited the currents. Tetraethylammonium (5-60 mM) and verapamil (50 microM), which block noninactivating K+ currents, did not prevent the facilitatory effects of KW-7158. High concentrations of 4-AP (5 mM) inhibited A-type K+ currents and prevented the facilitatory effect of KW-7158 on the remaining currents. These data suggest that KW-7158 enhances A-type K+ currents in DRG neurons. Because A-type K+ channels regulate afferent neuron excitability and firing properties, KW-7158 is a promising new compound for treatment of hyper-reflexic bladder conditions.

4-Aminopyridine↗
PubMed2005

How do urinary diaries of women with an overactive bladder differ from those of asymptomatic controls?

OBJECTIVE: To quantify clinically important differences in common diary variables between asymptomatic controls and women with symptoms of overactive bladder (OAB), controlling for the effects of age and race. PATIENTS, SUBJECTS AND METHODS: The 24-h urinary diaries of 49 women with symptoms of OAB were compared to those of age- and race-matched asymptomatic controls. Control subjects did not have a physical examination. RESULTS: The 49 patients with OAB symptoms had a median (range) age of 51 (20-85) years, a body mass index of 25 (17-46) kg/m(2) and a parity of 2 (0-5). The median number of voids was significantly greater in women with OAB than asymptomatic controls (P < 0.001). The median value for mean voided volume was significantly lower in women with OAB than asymptomatic controls (P = 0.014). There was no difference in the maximum voided volume, total voided volume, daytime or night-time diuresis rates, voids per litre intake, or total fluid intake. CONCLUSIONS: This preliminary study suggests that a median reduction of three voids/24 h and an increase of 70 mL in the mean voided volume might be clinically important goals in therapeutic trials for treating OAB symptoms. This remains to be confirmed by further studies linking improvements in quality of life and the overall impression of bladder health with these quantitative diary variable changes.

Adult↗
PubMed2005

The role of urodynamics in the treatment of lower urinary tract symptoms in women.

PURPOSE OF REVIEW: Urodynamic investigation was developed as an extension of patient history and physical examination in order to reveal the pathology of a patient's complaints. Much progress in standardizing definitions and procedures has been made in recent years. In particular, stress urinary incontinence and overactive bladder can be differentiated with urodynamics. The developed parameters, however, cannot distinguish the various types of stress urinary incontinence. Moreover the definition and diagnosis of voiding dysfunction is not clear. Finally our understanding of bladder sensations and the impact on voiding behaviour has only started to emerge. This review is about last year's publications that focus on urodynamics and lower urinary tract symptoms in women. RECENT FINDINGS: Defining bladder outlet obstruction is based on voiding pressure, urinary flow speed and residual urine but standardization is lacking. Urodynamics to reveal occult stress urinary incontinence in patients with pelvic organ prolapse needs standardization of the reducing manoeuvres. The quest for urodynamic tools for distinguishing intrinsic sphincter deficiency from urethral hypermobility continues. Urodynamics are still not good enough to discriminate between treatment options for stress urinary incontinence. The use of urodynamics in overactive bladder is developing and has elicited new findings. Voiding habit seems to be independent from bladder sensations. Also bladder sensations appear to be imperfectly correlated with bladder filling. Even bladder volumes do not predict entirely bladder fullness sensations. SUMMARY: In order to use urodynamics as a proper clinical tool, defining subtypes of stress urinary incontinence and standardization of urodynamics in pelvic organ prolapse and bladder outlet obstruction in women is needed.

Female↗
PubMedDate not supplied

The impact of urinary urgency and frequency on health-related quality of life in overactive bladder: results from a national community survey.

OBJECTIVES: Overactive bladder (OAB) is described as urinary urgency, with and without urge incontinence and usually with frequency and nocturia. Most attention to OAB's impact on health-related quality of life (HRQL), however, has focused on urge incontinence. The objective of this study was to evaluate the burden of OAB, specifically urinary urgency and frequency on HRQL. METHODS: In the National Overactive Bladder Evaluation Program (NOBLE), a computer-assisted telephone interview survey was conducted to assess the prevalence of OAB in the United States. Based on interview responses, respondents were classified into three groups: continent OAB, incontinent OAB, and controls. To evaluate the HRQL impact of OAB, HRQL questionnaires were mailed to all respondents with OAB and age- and sex-matched controls as a performed nested case-control study. Continuous data were compared using Student's t tests and analysis of variance with post hoc pairwise comparisons; results were adjusted for age, sex, and comorbid conditions. Multivariable regressions were performed to assess the impact of each urinary variable on symptom bother and HRQL. RESULTS: A total of 919 participants responded to the questionnaires (52% response rate) with a mean age of 54.2 years (SD 16.4 years); 70.4% were female and 85% were white. Continent OAB participants comprised 24.8% of the sample, incontinent OAB 18.3%, and controls 56.9%. In each regression analysis, urinary urge intensity accounted for the greatest variance for increases in symptom bother and decreases in HRQL. CONCLUSIONS: The experience of urinary urgency has a significant negative effect on HRQL and increases symptom bother, an effect that, in this community sample, is greater than that of incontinence, frequency, or nocturia.

Aged↗
PubMed2006

Selective beta-adrenoceptor agonists, calcium antagonists and potassium channel openers as a possible medical treatment of the overactive bladder and urge incontinence.

Urinary incontinence affects millions of people worldwide and also represents a social problem. People of all ages suffer from urinary incontinence. The disease is found in about 30% of women aged 30 to 60 years. There are different types of incontinence. Urge incontinence is the most often pharmacologically treated type. The mainly used substances belong to the class of antimuscarinic drugs. Their use is limited by several side effects. Furthermore, in some patients anticholinergic medication is ineffective and antimuscarinics used as single medication do not lead to a sufficient therapeutic effect. Other possible pharmacological substances for treatment of overactive bladder (detrusor instability) associated with urge and urge incontinence are the selective beta-adrenoceptor-agonists which are mainly responsible for the adrenergic mediated relaxation. It depends on the species, which beta-adrenoceptor-subtype (the beta2- and/or beta3-adrenoceptor) mainly mediates the relaxation. Non selective beta-adrenoceptor-agonists exhibit serious cardiovascular side effects like tachycardia or decrease of blood pressure by stimulating beta1- and beta2-adrenoceptors. These side effects should be decreased when using selective agonists. Additionally, substances whose targets are membrane channels of muscle cells could be interesting for treatment of overactive bladder. This group includes L-type calcium antagonists and potassium channel openers of ATP-sensitive potassium channels or BK channels. Especially the local use of the pharmacologically very potent calcium antagonists could be an interesting therapeutic approach, since systemic cardiovascular side effects were avoided. After chronic oral treatment with different calcium antagonists effects on the detrusor muscle were reduced or could not be detected, possibly due to an upregulation of 1,4-dihydropyridine-sensitive potassium channels. A very interesting approach is the use of potassium channel openers said to be selective for the urinary bladder. If there is a selectivity for the detrusor muscle, cardiovascular side effects were reduced. Possibly, the local use is a useful application form. Selective beta-adrenoceptor agonists, calcium antagonists and potassium channel openers are pharmacological approaches, which are not yet available for clinical use.

Adrenergic beta-Agonists↗
PubMed1993

Subtypes of overactive bladder in old age.

The prevalence of urinary incontinence increases dramatically with age and is mainly related to urge incontinence and bladder overactivity. It is a reasonable hypothesis that bladder overactivity primarily results from a disturbed central neuronal control of the lower urinary tract. Different sites and extents of neurogenic lesions or dysfunctions should result in different functional and urodynamic characteristics. We have recently identified three distinct urodynamic subtypes of bladder overactivity, and we report a retrospective study of the distribution of these subtypes in elderly patients. Eight hundred and fourteen patients aged 65 years or older with symptoms of urgency and/or urge incontinence underwent cystometry and the ice-water test. Two hundred and sixty-seven of them (33%) presented an overactive bladder. The prevalence of overactive bladder was constant up to the age of 65. A marked increase above this age was almost entirely ascribed to an increase of the so-called uninhibited overactive bladder subtype. This dysfunction occurred in 70% of the older patients. Patients with this condition have a coordinated reflex micturition at normal bladder volumes, but an abnormal perception of bladder fullness and lack of voluntary inhibitory control. This constellation of symptoms and signs indicates a suprapontine dysfunction.

Aged↗