Effect of stimulation of anterior hypothalamic area on urinary bladder function of the anesthetized rat

Abstract. The hypothalamus is a key area for the integration of the autonomic features of affective behavior. Hypothalamic defence area (HDA) stimulation evokes major cardiorespiratory changes as well as modifications of general autonomic activity both in the anesthetized and conscious animal. Micturition is due to an increase in pelvic parasympathetic activity and, in the cat, the anterior hypothalamus has been implicated in urinary bladder control with the demonstration of a dorsolateral vesicoconstrictor pathway and a ventromedial inhibitory pathway. In this study we have investigated the effect of electrical and chemical stimulation of the HDA on bladder pressure and contractions in rat. Female rats (n = 15) were anesthetized, paralyzed and ventilated artificially. Arterial blood pressure, heart rate, urinary bladder pressure and pelvic nerve activity were recorded. HDA was electrically (1 ms, 100 Hz, 5–10 s train at intensities up to 150 µA) and chemically (sodium glutamate, 50nl, 2mM) stimulated. For statistical analysis the t–test was used, data were expressed as mean ± SEM. Values of t were taken as significant when p < 0.05.HDA stimulation at 100–150 µA evoked changes of both mean blood pressure (mBP) and bladder pressure (BlP). However, stimulation at < 30µA allowed a distinction within HDA of two different regions, at the same antero–posterior and lateral level, but separated 100–150µm in depth, which evoked differential effects on blood pressure and urinary bladder pressure. Results show that low intensity stimulation at ventral sites evoked a significant increase of mBP (from 102 ± 5.9 to 127 ± 8.6mmHg, n = 10, p < 0.0001) with little changes of BlP (from 12 ± 2.2 to 16 ± 2.9cmH₂O, n = 10, p < 0.0005), whilst at more dorsal sites significant increases of BlP were elicited (from 12 ± 8.3 to 38 ± 4.6cmH₂O,n = 10, p < 0.0001) with only a small rise of mBP (from 102 ± 6.2 to 111 ± 9.8mmHg, n = 10, p < 0.005). Glutamate injections at dorsal sites evoked a rise of BlP (from 11 ± 2.2 to 30 ± 3.0cmH₂O (n = 5; p < 0.0001) with small changes in BP, whilst at ventral sites (n = 4) glutamate microinjections evoked changes in BP but not of BlP. In conclusion stimulation at different sites within HDA can elicit separate changes in BP and BlP.     

Role of the forebrain in bladder overactivity following cerebral infarction in the rat

This study was undertaken to investigate the contribution of the forebrain to bladder overactivity induced by cerebral infarction (CI). CI was induced by left middle cerebral artery (MCA) occlusion in female SD rat. Two and a half hours after CI or a sham operation (SO) decerebration was performed in some animals to eliminate forebrain influences on voiding function. Then bladder activity was monitored during continuous infusion cystometrograms in awake rats for 2.5 h. The effects of cumulative intravenous doses of MK-801 (0.1-1.4 mg/kg), an NMDA (N-methyl-D-aspartate) glutamatergic receptor antagonist, or sulpiride (0.1-41.1 mg/kg), D(2) selective dopaminergic receptor antagonists were studied over a 1.5-h period beginning 5 h after MCA occlusion. Bladder capacity was reduced by 57.5% after CI. In CI rats decerebration increased bladder capacity by 62.5% of predecerebration capacity. In SO rats bladder capacity was reduced by 25% after decerebration. MK-801 (0.4 and 1.4 mg/kg) increased bladder capacity in CI and CI-decerebrate rats, but did not change bladder capacity in SO-decerebrate rats. MK-801 decreased (60.7%) bladder capacity in SO-nondecerebrate rats. Sulpiride (11.1 and 41.1 mg/kg) significantly increased bladder capacity in CI, CI-decerebrate, and SO-decerebrate rats, but had no effect in SO-nondecerebrate rats. These results indicate that CI-induced decrease in bladder capacity is mediated by two mechanisms: (1) upregulation of an excitatory pathway from the forebrain, an effect blocked by decerebration and (2) downregulation of a tonic inhibitory pathway from the forebrain. The latter effect which can be induced by decerebration as well as CI unmasks a D(2) dopaminergic excitatory mechanism. An NMDA excitatory mechanism also contributes to the bladder overactivity after CI, but not after decerebration.     

人工反射弧建立后大鼠膀胱胆碱能神经的形态学变化(英文)

目的观察体神经—内脏神经人工反射弧建立后,大鼠膀胱肌间神经丛分布的改变以及神经肌肉接头处的变化。方法Sprague-Dawley大鼠随机分为三组:对照组、脊髓横断组和手术重建组。手术重建组大鼠术后饲养3个月,与脊髓横断组大鼠一起进行脊髓横断,再继续饲养3个月,对照组不做任何处理。DiI进行逆行神经追踪;免疫荧光的方法显示DiI阳性标记细胞中的胆碱乙酰转移酶(choline acetyltransferase,ChAT);改良的Karnovsky-Roots法检测膀胱铺片中神经纤维的分布。结果DiI阳性标记细胞主要分布于脊髓L3尾部至L5头侧前角,ChAT阳性细胞和DiI阳性标记细胞部分重叠。手术重建组和对照组相比,膀胱肌间神经纤维的数量较少,染色浓度也较浅(P<0.05);而手术重建组神经纤维密度较脊髓横断组增大,染色浓度增强(P<0.05),且出现明显的神经再分布。结论人工体内脏神经反射弧建立后,新的传出支为体神经,可以长入副交感神经纤维,传出神经元的递质仍为乙酰胆碱,膀胱内胆碱能神经纤维再生和乙酰胆碱活性增强且出现神经再分布,这可能在膀胱的控制性排尿中起作用。     

人工反射弧建立后大鼠膀胱胆碱能神经的形态学变化

目的观察体神经一内脏神经人工反射弧建立后,大鼠膀胱肌间神经丛分布的改变以及神经肌肉接头处的变化。方法Sprague—Dawley大鼠随机分为三组：对照组、脊髓横断组和手术重建组。手术重建组大鼠术后饲养3个月,与脊髓横断组大鼠一起进行脊髓横断,再继续饲养3个月,对照组不做任何处理。DiI进行逆行神经追踪;免疫荧光的方法显示DiI阳性标记细胞中的胆碱乙酰转移酶（cholineacetyltransferase,CHAT）;改良的Kamovsky—Roots法检测膀胱铺片中神经纤维的分布。结果DiI阳性标记细胞主要分布于脊髓L3尾部至L5头侧前角,ChAT阳性细胞和DiI阳性标记细胞部分重叠。手术重建组和对照组相比,膀胱肌间神经纤维的数量较少,染色浓度也较浅护〈0．05）;而手术重建组神经纤维密度较脊髓横断组增大,染色浓度增强妒〈0．05）,且出现明显的神经再分布。结论人工体内脏神经反射弧建立后,新的传出支为体神经,可以长入副交感神经纤维,传出神经元的递质仍为乙酰胆碱,膀胱内胆碱能神经纤维再生和乙酰胆碱活性增强且出现神经再分布,这可能在膀胱的控制性排尿中起作用。     

Effects of acupuncture to the sacral segment on the bladder activity and electroencephalogram

Using urethane-anaesthetized rats, the effects of acupunctural stimulation to the sacral segment on the urinary bladder activity and cortical electroencephalogram (EEG) were examined. The acupuncture suppressed urinary bladder activity in 36 of 68 trials. On many occasions (22/36 trials), suppression was accompanied by an increase in EEG amplitude. In such cases, the EEG power increased in all frequency bands after stimulation. The same EEG changes could be induced when the bladder was empty with no contraction. The results suggest that acupuncture stimulation affects both the bladder activity and sleep-arousal system.     

Are micturition systems influenced by sleep‐arousal system?

To clarify a relation between contractile condition of the urinary bladder and vigilance condition, bladder pressure was monitored simultaneously with cortical electroencephalogram (EEG) in urethane-anesthetized rats. Slow waves of large amplitude and those of lower amplitude appeared in EEG alternately. The bladder showed no contractile activity in the former EEG condition, while it contracted intermittently or continuously to urinate in the latter EEG condition. The relative power of EEG delta waves was significantly different in these two conditions. These results suggest that activity of the micturition system changes according to vigilance conditions, which may serve to prevent enuresis during sleep.     

Evidence that naloxonazine produces prolonged antagonism of central delta opioid receptor activity in vivo

Intracerebroventricular (i.c.v.) administrations of the postulated μ₁ opioid receptor antagonist naloxonazine produced an increase in the frequency of urinary bladder contractions recorded isometrically in the anesthetized rat. This substance also antagonized the inhibition of spontaneous bladder contractions produced by submaximal i.c.v. doses of the highly selective μ opioid agonist [D-Ala²-MePhe⁴,Gly-(ol)⁵]enkephalin (DAGO) and the δ opioid agonist [D-Pen²,D-Pen⁵]enkephalin (DPDPE). The antagonism of DAGO was reversible but that of DPDPE lasted up to 30 h. These data suggest that endogenous opioids are involved in the central control of bladder motility and that naloxonazine is a long-lasting δ opioid receptor antagonist.     

Changes in dopaminergic and glutamatergic excitatory mechanisms of micturition reflex after middle cerebral artery occlusion in conscious rats

Previous reports have shown that N-methyl-d-aspartate (NMDA) glutamatergic and D2 dopaminergic mechanisms have independent excitatory effects on bladder activity in normal and cerebral infarcted (CI) rats under urethane anesthesia. The study presented here was undertaken to investigate the interaction between these two mechanisms on bladder activity in conscious Sprague-Dawley female rats with or without cerebral infarction. Occlusion of the left middle cerebral artery or a sham operation (SO) was performed under halothane anesthesia. After recovery from the anesthesia, bladder activity was monitored continuously by means of infusion cystometrography in awake rats. The effects of cumulative intravenous doses of quinpirole (0.001-1 mg/kg), a D2 dopamine receptor agonist, were studied in awake SO and CI rats with or without dizocilpine (10 mg/kg) pretreatment. The effects of dizocilpine (1 or 10 mg/kg) were also examined in other SO or CI rats pretreated with 1 mg/kg of quinpirole. Bladder capacity in CI rats was significantly smaller (0.18 ml) than that in SO rats (0.48 ml). Quinpirole (0.1 and 1 mg/kg) further reduced bladder capacity in both types of rats, an effect blocked by sulpiride (20 mg/kg), a D2 dopamine receptor antagonist. The effect of quinpirole was also antagonized by dizocilpine (1 mg/kg) to a significantly (P < 0.01) greater degree in CI than in SO rats. In SO rats pretreated with 1 mg/kg of quinpirole, dizocilpine significantly increased bladder capacity in a dose-dependent manner. After the maximum dose (10 mg/kg) of dizocilpine, sulpiride did not produce any changes in bladder activity. In CI rats pretreated with 1 mg/kg of quinpirole, 1 mg/kg of dizocilpine increased bladder capacity. After administration of the maximum dose of dizocilpine (10 mg/kg), which did not produce an additional effect, sulpiride (20 mg/kg) increased bladder capacity by 58.3%. These results indicate that in awake rats D2 dopaminergic excitatory effects on the urinary bladder are mediated in part by NMDA glutamatergic mechanisms and in part by non-NMDA mechanisms. The latter type was more prominent in CI rats, indicating that the bladder hyperactivity induced by cerebral infarction may be mediated by an alteration in dopaminergic-glutamatergic interactions in the brain.     

The distribution and morphology of parasympathetic preganglionic neurons in the cat sacral spinal cord as revealed by horseradish peroxidase applied to the sacral ventral roots

Parasympathetic preganglionic neurons in the sacral parasympathetic nucleus (SPN) of the cat were studied by applying horseradish peroxidase (HRP) to the sacral ventral roots. The results were compared to data from earlier experiments in which these same neurons were labelled by HRP applied to the pelvic nerve at a point much further from the spinal cord. The present experiments have shown. The total number of neurons in the SPN determined by ventral root labelling is equal to the number obtained by pelvic nerve labelling. This indicates that virtually all SPN neurons send their axons into the pelvic nerve. More extensive dendritic projections from SPN neurons were revealed than in the pelvic nerve experiments. In particular, a strong dendritic projection extended within the lateral marginal zone of the dorsal horn close to Lissauer's tract and horizontal dendrites projected well into the contralateral gray matter, some reaching the contralateral sacral parasympathetic nucleus. The neurons labelled via any one ventral root were all contained within a region equal in length to one spinal segment but shifted rostrally by a small amount. Thus, no evidence was obtained for a long intraspinal pathway in which axons of spinal cord neurons entered ventral roots many segments away from their somata.     

Efficacy of desmopressin in patients with multiple sclerosis suffering from bladder dysfunction: a meta-analysis

OBJECTIVES: The current review evaluates the safety and efficacy of desmopressin in patients with multiple sclerosis (MS) who suffer from both daytime and nocturnal voiding frequency and from incontinence. MATERIALS AND METHODS: A literature search was carried out looking for studies published between 1990 and 2003 which evaluated desmopressin in MS patients with bladder dysfunction. RESULTS: The grand total mean effect sizes show the following estimates of clinical relevant differences: desmopressin has a moderate effect on the number of voids during the day or during the night over a period of 6 h after taking the drug. A large effect associated with the use of desmopressin was detected by the mean difference in urine volume (ml) in 6 h. A small effect was detected in the mean 24-h urine volume. Serum sodium levels were combined with plasma osmolality in some studies and were found to be not significantly affected by desmopressin treatment.     

Management of lower urinary tract symptoms in Parkinson's disease in the neurology clinic

This clinical review aims to evaluate lower urinary tract symptoms (LUTS) in Parkinson's disease (PD) patients and the current treatment options available for these symptoms in a neurology setting. The review also addresses when referral to urology is appropriate.

A literature search was conducted using the keywords ‘LUTS’, ‘non-motor symptoms’, ‘overactive bladder’, ‘Parkinson's disease’ and ‘urinary symptoms’ using the Medline/Pubmed search engine. Data collected ranged from 2000 to present with emphasis on recent publications.

This review was conducted because LUTS in PD has a major impact on quality of life and is associated with early institutionalization. Emphasis is placed on treating overactive bladder with conservative strategies and medical management in the neurology setting.

Quality of life can be improved and institutionalization can be delayed with a multimodal approach to bladder care.     

Increased spinal cord phosphorylation of extracellular signal-regulated kinases mediates micturition overactivity in rats with chronic bladder inflammation

Spinal processing of somatosensory and viscerosensory information is greatly facilitated in some persistent pain states. Growing evidence suggests that the so-called central sensitization depends in part on intracellular activation and signalling via specific MAP kinases. Here we studied the expression of phosphorylated extracellular signal-regulated kinases 1 and 2 (phosphoERK), the active form of these kinases, in spinal neurons following innocuous and noxious distension of non-inflamed and cyclophosphamide (CYP)-inflamed rat urinary bladders. Additionally, we investigated the nature of bladder primary afferents responsible for spinal ERK activation. Finally, we used a specific inhibitor of ERK phosphorylation to study the influence of these kinases on the bladder reflex activity of normal and inflamed bladders. Results indicated that, in non-inflamed rats, noxious but not innocuous bladder distension significantly increased spinal phosphoERK immunoreactivity from its normal very low level. However, in CYP-inflamed rats, innocuous and noxious bladder distension significantly increased the number of spinal neurons immunoreactive to phosphoERK. ERK activation was rapid (within minutes) and transient. Desensitization of vanilloid-sensitive afferents by intravesical resiniferatoxin, a capsaicin analogue, did not decrease phosphoERK immunoreactivity in normal or CYP-inflamed rats. ERK inhibition by intrathecal PD 98059 had no effect on bladder reflex contractions of non-inflamed bladders but significantly decreased its frequency in inflamed animals. Our results suggest that spinal ERK intervene in acute and chronic inflammatory pain perception and mediate bladder reflex overactivity accompanying chronic bladder inflammation. In addition, bladder noxious input conveyed in vanilloid-resistant primary afferents is important to spinal ERK phosphorylation in both noninflamed and CYP-inflamed animals.     

Bladder dysfunction in a transgenic mouse model of multiple system atrophy

Multiple system atrophy (MSA) is an adult‐onset neurodegenerative disorder presenting with motor impairment and autonomic dysfunction. Urological function is altered in the majority of MSA patients, and urological symptoms often precede the motor syndrome. To date, bladder function and structure have never been investigated in MSA models. We aimed to test bladder function in a transgenic MSA mouse featuring oligodendroglial α‐synucleinopathy and define its applicability as a preclinical model to study urological failure in MSA. Experiments were performed in proteolipid protein (PLP)–human α‐synuclein (hαSyn) transgenic and control wild‐type mice. Diuresis, urodynamics, and detrusor strip contractility were assessed to characterize the urological phenotype. Bladder morphology and neuropathology of the lumbosacral intermediolateral column and the pontine micturition center (PMC) were analyzed in young and aged mice. Urodynamic analysis revealed a less efficient and unstable bladder in MSA mice with increased voiding contraction amplitude, higher frequency of nonvoiding contractions, and increased postvoid residual volume. MSA mice bladder walls showed early detrusor hypertrophy and age‐related urothelium hypertrophy. Transgenic hαSyn expression was detected in Schwann cells ensheathing the local nerve fibers in the lamina propria and muscularis of MSA bladders. Early loss of parasympathetic outflow neurons and delayed degeneration of the PMC accompanied the urological deficits in MSA mice. PLP‐hαSyn mice recapitulate major urological symptoms of human MSA that may be linked to αSyn‐related central and peripheral neuropathology and can be further used as a preclinical model to decipher pathomechanisms of MSA. © 2013 Movement Disorder Society     

Supraspinal control of external anal sphincter motility: effects of vesical distension in humans and cats

A pontine centre located near the micturition centre controlling external anal sphincter (EAS) motility via noradrenergic neurones has been described in cats. The aim of this study was to determine (i) whether a similar centre controls EAS motility in humans and (ii) whether this centre is involved in vesico-sphincteric reflexes in cats and humans. The effects of an alpha-1-adrenoceptor antagonist (nicergoline) and those of vesical distension on the electrical activity of the EAS were studied in paraplegic and non-paraplegic volunteers. The effects of vesical distension by injecting saline at physiological levels on the responses of the EAS to pudendal nerve stimulation were investigated in intact cats and cats with nerve sections. In non-paraplegic subjects, nicergoline and vesical distension abolished the activity of the EAS. These effects were no longer observed in paraplegic patients. In cats, vesical distension inhibited the reflex response of the EAS to pudendal nerve stimulation. This vesico-sphincteric reflex, which was no longer observed in spinal animals, persisted after nicergoline injection. These findings indicate that in humans, there exists a supra-spinal centre facilitating the tonic activity of the EAS via noradrenergic neurones not involved in the inhibitory vesico-sphincteric reflex.     

Evaluation of the urinary tract in children with myelomeningocele

Of 43 children suffering from myelomeningocele, 2 died of obstructive nephropathy; 30 survived for more than 6 years and 12 of these developed upper urinary tract dilatation. A bladder compliance above 20 was only found in 4 patients, while in 11 with detrusor hyperreflexia, a low pressure amplitude was generally observed. Detrusor-sphincter dyssynergia accompanied by large residual volumes was found in 4 patients. Surveillance of the urological condition is discussed.     

A risk prediction model of urinary tract infections for patients with neurogenic bladder

Abstract

Objectives: To develop a nomogram to evaluate the risk of urinary tract infections (UTI) in patients with neurogenic bladder (NGB)

Methods: A retrospective analysis was conducted on 337 patients with NGB admitted to three hospitals. Collected data included clinical symptoms, patients’ general characteristics, laboratory examinations and imaging findings. Multivariate logistic regression analysis was conducted to develop the risk prediction nomogram of UTIs for NGB patients. C index was used for the internal and external validation of that model.

Results: The occurrence of UTIs was 45.7% (154 of 337), 52.6% (102 of 194), and 36.4% (52 of 143) in the overall, training and validation data sets, respectively. The prediction nomogram was developed with 5 prognostic factors which included white blood cell (WBC) in blood, Leukocyte (LEU) in urine, Urinary pH, length of stay and urination mode. The nomogram presented good discrimination with a C-index value of 0.921 (95% confidence interval: 0.87396???0.96804) and good calibration. The C-index values of the interval validation and external validation were 0.8905541 and 0.817, respectively. The results of decision curve analysis (DCA) demonstrated that the model was clinically useful.

Conclusions: The prediction nomogram we developed is a simple and accurate tool for early prediction of UTIs in patients with NGB. This tool can assess risk of UTIs early, allowing for timely initiation of appropriate preventive measures.     

Somatostatin receptor subtypes 2 and 5 mediate inhibition of egg yolk‐induced gall bladder emptying in mice

Background Somatostatin inhibits gall bladder contraction. Impaired gall bladder emptying is associated with gall bladder stone formation. The incidence of cholecystolithiasis is high in patients treated with a somatostatin agonist octreotide, which predominantly interacts with somatostatin receptor subtype 2 (SSTR2). Therefore, it is believed that SSTR2 regulates gall bladder contraction; however, evidence has not been provided. Here, we evaluate the effects of SSTR1‐SSTR5‐selective agonists on egg yolk‐induced gall bladder contraction in mice. Methods Homozygous deletion of SSTR2 and SSTR5 was generated by cross‐mating of SSTR2^?/? with SSTR5^?/? mice. Mice of different genotypes were injected with SSTR1‐5‐selective agonists or octreotide 15 min before induction of gall bladder emptying by egg yolk. One hour later, gall bladders were removed and weighed. Key Results Egg yolk‐reduced gall bladder weights in all mice, irrespective of their genotype. Octreotide was the most potent inhibitor of gall bladder emptying in wild‐type mice. In contrast, agonists with high selectivity for SSTR2 or SSTR5 inhibited gall bladder emptying by approximately 50–60%, whereas SSTR1‐, SSTR3‐ and SSTR4‐selective agonists failed to influence gall bladder contraction. In SSTR2^?/? mice, octreotide and an SSTR5‐selective agonist inhibited gall bladder emptying by approximately 50%, whereas SSTR2‐selective agonists were inactive. Octreotide inhibited gall bladder emptying in SSTR5^?/? mice by approximately 50%, without any effect in SSTR2^?/?/SSTR5^?/? mice. Conclusions & Inferences Our study provides evidence for the role of SSTR2 and SSTR5 in regulating gall bladder emptying in mice.     

Findings with Bilateral Sacral Neurostimulation: Sixty‐two PNE‐Tests in Patients with Neurogenic and Idiopathic Bladder Dysfunctions

We performed bilateral PNE (peripheral nerve evaluation) tests to identify which diagnostic groups are the most likely to profit from bilateral sacral neuromodulation since the results published so far have been obtained exclusively on the basis of unilateral sacral root stimulation. In contrast to the original unilateral technique, we performed bilateral PNE test stimulation in 62 patients (36 with urinary retention symptoms and 26 with overactive detrusor; 21 with idiopathic and 41 with neurogenic bladder dysfunction) over 3–4 days. We used an advanced electrode, model #3057 (Medtronic, Inc. Minneapolis, MN). The stimulation amplitudes were adjusted individually for each side. Retrospectively, we analyzed our data according to diagnostic characteristics (retention vs. overactive bladder and neurogenic vs. idiopathic) of those patients who had positive PNE test results. The PNE test was successful in 32 patients (51.6%). Of these, 27 suffered from neurogenic bladder dysfunction; in five cases the cause was idiopathic. We conclude that bilateral PNE test stimulation with side‐specific amplitude adjustment and the use of advanced PNE electrodes led to a positive PNE result in 51.6% of the patients, which is a substantially increased response rate compared to previous studies. Of the diagnostics groups, the group with neurogenic bladder dysfunctions showed the highest response rate.