Resolution of diurnal incontinence and nocturnal enuresis after adenotonsillectomy in children.

PURPOSE: Adenotonsillar hyperplasia causes upper airway obstruction, leading to obstructive sleep apnea. We reviewed the incidence of nocturnal enuresis in a population of children with adenotonsillar hyperplasia. In addition, we investigated the rate of resolution or improvement in enuresis following surgery for relief of adenotonsillar hyperplasia. MATERIALS AND METHODS: We studied 86 consecutive prepubertal children, 46 boys and 40 girls, who underwent adenotonsillectomy. Severity of adenotonsillar obstruction was graded on a scale of 1 to 4. A questionnaire regarding voiding problems, including nocturnal enuresis, voids per day and daytime enuresis episodes, was filled out preoperatively and postoperatively by the patients and their parents. RESULTS: Among the 86 patients who underwent adenotonsillectomy 36 (42%) had nocturnal enuresis. In patients with nocturnal enuresis the number of episodes was significantly less after adenotonsillectomy. Overall, 12 patients (33%) had complete resolution, 11 (31%) had significant improvement and 13 (36%) showed no change. In addition, we noted a significant decrease in daytime enuresis episodes and voids per day. CONCLUSIONS: Children with upper airway obstruction have a high rate of nocturnal enuresis that improves at twice the anticipated rate after treatment of the airway obstruction. In addition, we observed that daytime voiding dysfunction improves in these patients.

The effect of tamsulosin on the response of the rabbit bladder to partial outlet obstruction.

AIM: To determine if tamsulosin treatment prevents or decreases the incidence and severity of outlet obstruction-induced bladder dysfunction in rabbits. MATERIALS AND METHODS: Male New Zealand White rabbits were treated with tamsulosin or vehicle for 4 weeks with treatments initiated 1 week prior to sham or obstruction surgery. Cystometry was done on anesthetized rabbits 21 days after surgery. The bladders were then removed, weighed, and prepared for in vitro whole bladder studies. Responses to 32 Hz field stimulation (FS), carbachol, phenylephrine, and KCl were measured. RESULTS: Obstruction resulted in a significant increase in bladder weight, which was unchanged by tamsulosin treatment and a significant increase in micturition pressure in the vehicle-treated group but not in the tamsulosin-treated group. Compliance was significantly decreased in both obstructed groups. The vehicle-treated obstructed rabbits had a very sharp increase in intravesical pressure as the bladder reached capacity; this was not seen in the tamsulosin-treated obstructed rabbits. Tamsulosin did not change the pattern of modifications in contractile responses induced by bladder outlet obstruction. CONCLUSIONS: In vitro responses of vehicle and tamsulosin-treated obstructed rabbit groups in this study were similar. A greater micturition pressure was found for the vehicle-treated obstructed group than for the tamsulosin-treated obstructed group, which was probably due to decreased urethral resistance in the latter. On a functional basis, the higher compliance at capacity and decreased micturition pressure in the tamsulosin-treated obstructed group would be considered beneficial for bladder function.

In vivo and in vitro response of corpus cavernosum to phosphodiesterase-5 inhibition in the hypercholesterolaemic rabbit.

OBJECTIVE: To investigate the effects of hypercholesterolaemia (HC) on rabbit corpus cavernosa in vivo and in vitro, and evaluate the efficacy of vardenafil and sildenafil in normal and HC rabbits, as the phosphodiesterase-5 (PDE-5) inhibitors vardenafil and sildenafil are widely used for treating erectile dysfunction (ED) and most organic causes of ED are associated with vascular risk factors like HC. MATERIALS AND METHODS: Male New Zealand White rabbits were randomly divided into two groups; 11 HC rabbits were fed a 2% cholesterol diet, and 12 age-matched control rabbits received a regular diet. After 12-14 weeks, erectile responses to intravenous sodium nitroprusside (SNP) and PDE-5 inhibitors were evaluated for 2 h in conscious rabbits. Penile length was measured and the area under the curve calculated. Relaxant responses of corpus cavernosal strips to electrical-field stimulation (EFS) were measured before and after exposure to PDE-5 inhibitors and the nitric oxide synthase inhibitor N'-nitro-L-arginine methyl ester. RESULTS: HC rabbits had a lower erectile response to SNP than controls; in both control and HC rabbits there was a greater erectile response after simultaneous exposure to SNP and vardenafil, or SNP and sildenafil. However, the responses of the HC rabbits were still significantly less than those of the controls. Corpora from control rabbits responded to EFS with greater relaxations at all frequencies, except 1 Hz. Corpora from both HC and control rabbits had greater responses to EFS after exposure to vardenafil and sildenafil; N'-nitro-L-arginine methyl ester diminished the response to EFS. CONCLUSIONS: There was a significantly lower in vivo and in vitro erectile response in HC rabbits than in controls; erectile function measured in conscious rabbits can be used to assess quantitatively the efficacy of different agents, e.g. sildenafil and vardenafil, in pathological animals. In addition, both agents improve in vitro responses of erectile tissue from HC rabbits to EFS.

Regional differences in responses of rabbit detrusor to electrical and adrenergic stimulation: influence of outlet obstruction.

OBJECTIVE: To examine regional responses of control and obstructed rabbit detrusor strips to electrical and adrenergic stimulation, and determine whether outlet obstruction causes regional variations in blood flow throughout the detrusor, as the detrusor smooth muscle of the bladder body has previously been considered homogeneous in its pharmacological properties. MATERIALS AND METHODS: Fourteen male rabbits had the bladder outlet surgically obstructed for 2 weeks and were compared with 10 unoperated control rabbits. Blood flow was measured with the bladder empty and at capacity, using fluorescent microspheres. Paired dorsal and ventral strips were harvested from the midline equatorial detrusor and electrically and adrenergically stimulated. RESULTS: Obstructed rabbits had significantly higher bladder capacities and bladder weights than control rabbits. Dorsal strips from both control and obstructed rabbits contracted in response to noradrenaline, whereas ventral strips relaxed. The addition of prazosin, a nonselective alpha1-adrenergic-receptor blocker, completely blocked the contraction in dorsal strips, but had no effect on responses of ventral strips. There was also a regional difference in response to electrical stimulation, with ventral strips generating significantly more tension than dorsal strips in both control and obstructed rabbits. There were no regional differences in detrusor blood flow. Obstruction resulted in significantly lower responses to all forms of stimulation, and significantly less blood flow throughout the detrusor. CONCLUSION: There are regional differences in adrenergic receptor function and response to electrical-field stimulation throughout control and obstructed rabbit detrusor, a region that was previously thought to be functionally homogeneous. These differences must be recognized and acknowledged to obtain accurate and reproducible data from in vitro studies of the bladder.

Activation of mu opioid receptors in the ventrolateral periaqueductal gray inhibits reflex micturition in anesthetized rats.

This study tested the hypothesis that morphine and other opiates cause urinary retention by activating mu opioid receptors in the midbrain periaqueductal gray (PAG) region. Selective mu, delta and kappa receptor agonists were microinjected into the PAG of urethane-anesthetized rats and the amplitude and incidence of bladder contractions were recorded during continuous saline infusion. Arterial pressure was monitored through a femoral artery catheter. Microinjection of the mu receptor agonist DAMGO into the ventrolateral PAG (vlPAG) suppressed volume-evoked bladder contractions completely. Bladder contractions ceased within 5 min of DAMGO injection and remained essentially undetectable for the rest of the 20 min recording period. Microinjection of the delta receptor agonist DPDPE into the vlPAG did not significantly affect either the amplitude of bladder contractions or the time interval separating contractions. The kappa receptor agonist U-69593 caused no discernible change in amplitude but increased the interval between bladder contractions significantly. Microinjection of DAMGO, DPDPE or U-69593 into the lateral or dorsolateral PAG columns was ineffective. DAMGO injection into the vlPAG increased arterial pressure whereas DPDPE and U-69593 produced a small but significant depressor response. These data support the hypothesis that mu and kappa receptors in the vlPAG participate in the micturition reflex.

Diabetes mellitus increases the rate of development of decompensation in rats with outlet obstruction.

PURPOSE: We investigated the effects of the combination of bladder outlet obstruction and diabetes mellitus on in vitro rat bladder body strip function. MATERIALS AND METHODS: Longitudinal strips were removed from ventral and dorsal detrusor of age matched control, 2-week diabetic, 2-week obstructed and 2-week obstructed diabetic rats. Contractile responses to electrical field stimulation, carbachol, adenosine triphosphate, KCl and phenylephrine, and relaxations in response to norepinephrine and isoproterenol were measured. RESULTS: Bladders from diabetic, obstructed and obstructed diabetic rats were 1.6-fold, 2.6-fold and 3.6-fold heavier than those from controls. Responses of bladder strips from diabetics to all stimuli were similar to those of controls. Strips from obstructed rats were significantly less responsive to norepinephrine than those from controls or diabetics and strips from obstructed diabetics were significantly less responsive to norepinephrine and isoproterenol than those from all other groups. Strips from obstructed diabetics had significantly decreased responses to field stimulation, while responses to carbachol were decreased to a lesser extent. Responses of strips from obstructed rats to field stimulation were also decreased compared with controls but were significantly greater than those of the obstructed diabetic group. Responses to adenosine triphosphate, KCl and phenylephrine were similar in all groups. CONCLUSIONS: The combination of outlet obstruction and diabetes mellitus causes significant increases in bladder mass compared with either diabetes or obstruction alone. Bladder strips from obstructed diabetics show characteristics of denervation accompanied by alterations in beta-adrenergic function, suggesting that the coexistence of outlet obstruction and diabetes increases the rate of development of bladder decompensation.

Excitatory alpha1-adrenergic receptors predominate over inhibitory beta-receptors in rabbit dorsal detrusor.

PURPOSE: We mapped the regional distribution of alpha1 and beta-adrenergic receptors (ARs) in rabbit ventral and dorsal bladder, and characterized the alpha1-AR subtypes responsible for norepinephrine induced contraction of rabbit dorsal detrusor smooth muscle. MATERIALS AND METHODS: Responses to norepinephrine in the absence and presence of adrenergic antagonists were measured in strips taken from clearly defined regions of male rabbit ventral and dorsal bladder. RESULTS: In the absence of antagonists ventral strips from the bladder body relaxed in response to norepinephrine, while those from the ventral base contracted. Dorsal strips from the bladder dome also relaxed in response to norepinephrine but dorsal strips from the mid and lower body, and the base contracted. All contractile responses were antagonized by incubation with prazosin. Characterization of the alpha-AR subtypes present in dorsal strips from the mid and lower bladder body using BMY 7378 (8-[2-[4 to 2(-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro [4,5] decane-7,9-dione dihydrochloride), chloroethylclonidine, 5-methylurapidil and WB 4101 (2-(2,6-dimethoxyphenoxyethyl)-aminomethyl-1,4-benzodioxane) suggested that the alpha1-AR subtype responsible for the contraction is the alpha1A or alpha1L-AR. CONCLUSIONS: The male rabbit bladder contains at least 4 heterogeneous regions with differing functional responses to adrenergic stimulation, that is 1) the dorsal and ventral dome, where beta-ARs predominate, 2) the ventral detrusor, where beta-ARs predominate, 3) the dorsal detrusor, where alpha1-ARs predominate, and 4) the dorsal and ventral bladder neck, where alpha1-ARs predominate.

Functional response of bladder strips from streptozotocin diabetic rats depends on bladder mass.

PURPOSE: We investigated the relationship of bladder mass to responses to electrical field stimulation and adrenergic agonists in diabetic rat bladders. MATERIALS AND METHODS: Longitudinal strips were removed from the ventral and dorsal detrusor of age matched control, 2-month diabetic and sucrose drinking rats. Contractile responses to electrical field stimulation, KCl and phenylephrine, and relaxation in response to norepinephrine and isoproterenol were measured. RESULTS: Bladders from sucrose drinking and diabetic rats weighed significantly more than those of controls. Diabetic rats were divided into 2 groups with the bladder weighing less than or greater than 265 mg. Strips from small diabetic bladders were generally more responsive to field stimulation and norepinephrine than those from control or sucrose drinking rats. Conversely decreased function was especially apparent in dorsal strips from large diabetic bladders. Ventral strips were significantly more sensitive to the relaxant actions of norepinephrine and isoproterenol than dorsal strips. CONCLUSIONS: Our results suggest that the responsiveness of diabetic rat bladder to electrical field stimulation and adrenergic agonists is related to bladder mass, analogous to observations after partial outlet obstruction. Decreased function was particularly apparent in dorsal strips from diabetic rats with a large bladder.

Functional development of the rat urinary bladder after pre- or postpubertal castration.

Experiments were done to evaluate the role of sex hormones in the functional development of the rat urinary bladder. Rats were orchiectomized or ovariectomized at 30 (prepubertal) or 70 (postpubertal) days of age and bladders were removed 1 month later. An additional group of immature male and female rats was used in which the bladders were removed at 30 days of age. There were only minor differences in contractile responses of bladder strips from any group to electrical field stimulation, ATP, carbachol, or KCl compared to age-matched controls. There were no differences in responses of bladder strips from immature females or males to the adrenergic agonists, isoproterenol, norepinephrine, or methoxamine. Bladders from the pre- and postpubertally castrated rats and their controls relaxed fully in response to isoproterenol, but strips from prepubertally castrated rats relaxed significantly less in response to norepinephrine than those from other groups. Approximately one half of the bladder strips from prepubertally castrated rats failed to relax by at least 50% in response to norepinephrine; these same strips responded to methoxamine with exaggerated contractions. Our data indicate that the normal development of rat bladder alpha-adrenergic responsiveness is adversely altered by prepubertal castration. We postulate that this may result from an alteration in the relative expression of alpha(1)-adrenergic receptor subtypes.

Downregulation of CYP2D16 by ACTH in the guinea pig adrenal cortex: time course, reversibility, and mechanism of action.

Studies were done to investigate the actions of ACTH on the expression of CYP2D16 in the guinea pig adrenal cortex. Guinea pigs were treated with ACTH for 1, 3, or 7 days. In addition, some animals received ACTH for 7 days and were then untreated for an additional 3 or 7 days to test for reversibility of ACTH actions. ACTH treatment caused a time-dependent decrease in the rates of adrenal microsomal bufuralol metabolism, a CYP2D-catalyzed reaction; hepatic bufuralol metabolism was unaffected by ACTH. Adrenal enzyme activity was significantly reduced by ACTH within 1 day and decreased by 80% after 7 days. Western blotting and in situ hybridization analyses revealed corresponding declines in adrenal CYP2D16 protein and mRNA concentrations. Nuclear runoff assays indicated that ACTH treatment inhibited CYP2D16 expression at the transcriptional level. Adrenal 17 alpha-hydroxylase activities were increased by ACTH treatment, but CYP17 protein concentrations were not affected. Following cessation of ACTH administration, the rates of adrenal bufuralol metabolism and CYP2D16 protein and mRNA concentrations returned to control levels within 7 days. The results demonstrate that ACTH has a relatively rapid and reversible effect to inhibit adrenal CYP2D16 transcription, thereby decreasing adrenal xenobiotic metabolism. Thus, the actions of ACTH on CYP2D16 expression are opposite to those on other adrenal p450 isozymes, indicating unique regulatory mechanisms.

In vitro rat bladder function after neonatal estrogenization.

PURPOSE: Experiments were done to evaluate the functional effects of neonatal diethylstilbestrol (DES) treatment on bladder function in male and female Noble rats. MATERIALS AND METHODS: At 5 months after neonatal DES bladders were removed and weighed. Ventral and dorsal bladder strips were prepared to evaluate the effects of neonatal DES on contractile responses to electrical field stimulation, carbachol, adenosine triphosphate, phenylephrine and KCl. Relaxant responses to the catecholamines arterenol (norepinephrine), epinephrine and isoproterenol were also monitored. RESULTS: Neonatal DES resulted in significant increases in bladder mass in males and females. Contractile and relaxant responses were largely unchanged by neonatal DES treatment and the only change observed was a decreased response of ventral strips from male neonatal DES rats to 4 and 8 Hz. stimulation. Ventral strips from male control and neonatal DES rats responded to field stimulation and carbachol with significantly greater responses than dorsal strips and were more sensitive to the relaxant actions of norepinephrine and epinephrine. CONCLUSIONS: The data confirm that neonatal DES causes infravesical obstruction. However, in contrast to published reports of the effects of surgically induced mild outlet obstruction, neonatal DES treatment has little effect on in vitro bladder strip contractile or relaxant function. Thus, the neonatal DES treated rat does not seem to be a useful model in which to study the in vitro effects of partial outlet obstruction on the bladder.

Relationship of mass of obstructed rat bladders and responsiveness to adrenergic stimulation.

PURPOSE: The effects of experimental partial bladder outlet obstruction on the bladder response to nerve stimulation and contractile agonists have been well characterized. Mildly obstructed bladders have small increases in mass and increased contractile responses to electrical field stimulation. More severely obstructed bladders become decompensated with large increases in mass and decreased functional responses. Little is known about relaxant mechanisms after obstruction. We investigated the relationship of the increase in rat bladder mass induced by outlet obstruction and responses to alpha and beta-adrenergic stimulation. MATERIALS AND METHODS: Male Sprague-Dawley rats were divided into 3 groups, namely control, sham operated and obstructed. Surgical obstruction was done by tying a 2-zero silk ligature around the urethra. The ligature was placed around the urethra and removed in sham operated rats. At 2 and 6 weeks bladders from all groups were harvested, weighed and cut into strips. Contractile responses to electrical field stimulation and norepinephrine in the presence of propranolol were measured. Relaxant responses to norepinephrine and isoproterenol were measured after pre-contraction with KCl. RESULTS: All strips from control and sham operated rats relaxed completely in response to norepinephrine. Obstructed bladders that weighed 2 to 3-fold more than control or sham operated bladders also relaxed. In contrast, bladders that were 5 to 10-fold heavier failed to relax by at least 50% in response to norepinephrine, independent of duration of bladder outlet obstruction. These were called nonresponders. Two week nonresponders relaxed completely in response to isoproterenol, but 6-week nonresponders did not, suggesting that the duration of decompensation is important. All nonresponders relaxed in response to pinacidil (Sigma-Aldrich Corp., St. Louis, Missouri). Nonresponders tended to contract in response to norepinephrine in the presence of propranolol. Strips from the other rats were less responsive, suggesting an increase in alpha1-receptors with decompensation. Contractile responses to field stimulation were increased in obstructed strips that relaxed to norepinephrine, while responses of nonresponders were decreased compared with controls and sham operated rats. CONCLUSIONS: Severely obstructed bladders had an increase in mass and a decreased response to field stimulation, indicative of decompensation. This response was accompanied by decreased ability to relax to beta-agonists and an increased response to alpha-agonists. These changes were not seen in smaller, compensated bladders. Our findings suggest a change in detrusor alpha1 and beta-adrenergic receptor density. An increase in detrusor alpha-receptors may explain the clinical efficacy of alpha-blockers in alleviating irritative voiding symptoms in men with benign prostatic hyperplasia.

Regional differences in bladder enlargement and in vitro contractility after outlet obstruction in the rabbit.

PURPOSE: Bladder outlet obstruction leads to bladder enlargement and subsequent decreases in contractile function in vivo and in vitro. We determined whether there were regional differences in bladder wall properties and in vitro contractile responses after 2 weeks of bladder outlet obstruction. MATERIALS AND METHODS: Male rabbits underwent cystometry. The bladder was then filled to 40 ml. and the surface was marked with 2-zero silk knots placed approximately 1 cm. apart. The distance between the knots was measured at 20, 40 and 80 ml. The animals then underwent the creation of surgical obstruction. After 2 weeks the obstruction was removed. Cystometry and measurements were repeated and strips were obtained from defined dorsal and ventral areas. Contractile responses to electrical field stimulation, adenosine triphosphate, carbachol and KCl were determined and compared with strips from unobstructed controls. RESULTS: In vivo expansion during bladder filling occurred evenly throughout the bladder wall in controls and the contractile response to all stimuli was similar in ventral and dorsal strips. After 2 weeks of bladder outlet obstruction the upper dome expanded to a significantly higher degree than the lower bladder body. The response to all stimuli was significantly reduced after bladder outlet obstruction and there was a significantly decreased response to all stimuli in dorsal compared with ventral strips. Strips from the dorsal midline showed a relaxation response to electrical field stimulation at low frequencies, whereas all ventral strips contracted. CONCLUSIONS: Functional remodeling after bladder outlet obstruction is a process that does not occur to the same extent throughout the bladder. The obstructed bladder is an inhomogeneous organ with significant regional differences in mechanical and pharmacological properties.