Anurag K. Das

RABBIT URINARY BLADDER BLOOD FLOW CHANGES DURING THE INITIAL STAGE OF PARTIAL OUTLET OBSTRUCTION

PURPOSE The rabbit urinary bladders early response to partial outlet obstruction includes bladder wall remodeling with marked urothelial and fibroblast hyperplasia (1 day) and smooth muscle hypertrophy (3-5 days) resulting in a 4-5 fold increase in bladder mass within 7 days. In this study, we examined the effect of partial outlet obstruction on bladder blood flow during the initial period of rapid growth (1-7 days). MATERIALS AND METHODS Each New Zealand White rabbit was partially obstructed by tying a 2-0 silk ligature loosely around the vesical outlet. After 0 (unoperated), 4 hours, 1, 3, or 7 days of obstruction, 5 rabbits per group were anesthetized and the carotid and femoral arteries cannulated with polyethylene tubing. Additional rabbits receiving sham surgeries were treated like obstructed animals at 4 hours and 1 day post-obstruction (5/group). Using standard methods, fluorescent microspheres were infused through the right carotid artery. Bladder and right kidney were rapidly removed upon completion of sphere infusion; bladder mucosa and muscle were separated. Sphere densities in detrusor, mucosa, and kidney were measured by Interactive Medical Technologies, Ltd. A section of each detrusor tissue was fixed in formalin and immunostained for smooth muscle alpha-actin. RESULTS Mucosal blood flow (0.20 +/- 0.03 ml./min./gm.) was approximately 4-fold greater than that of detrusor (0.05 +/- 0.01 ml./min./gm.). Sham surgery caused a significant increase in bladder blood flow at 4 hours post-obstruction that returned to control levels by 1 day. Both mucosal and muscle blood flows were slightly higher in rabbit bladders obstructed for 4 hours than in sham-operated rabbits, and substantially greater in those obstructed for 1 day: 0.68 +/- 0.13 ml./min./gm. (mucosa) and 0.26 +/- 0.04 ml./min./gm. (muscle). Blood flows returned to control values by 3 days post-obstruction and remained constant through 7 days. Kidney blood flow was unchanged. Although bladder weight increased 4-fold after 7 days of obstruction, the volume fraction of smooth muscle (transverse section) remained constant at approximately 40%. CONCLUSIONS Blood flow was approximately 4-fold greater in bladder mucosa than in muscle, which may relate to the significantly higher metabolic rate and lower high energy phosphate concentration of mucosa than muscle. Partial outlet obstruction resulted in a significant increase in blood flow at 1 day post-obstruction, which coincides temporally with the early cellular hyperplasia and hypertrophy of obstructed rabbit bladder. This increase in blood flow may be an essential factor for the initial increase in bladder mass. By three days, the blood flow per gram of tissue returned to control levels. The mechanisms relating to the changes in blood flow induced by partial outlet obstruction are currently under investigation.

Biochemical evaluation of obstructive bladder dysfunction in men secondary to BPH: a preliminary report☆

Abstract Objectives. In the rabbit, two of the major cellular alterations that mediate bladder dysfunction secondary to partial outlet obstruction are a decreased ability of the sarcoplasmic reticulum (SR) to store and release Ca 2+ , and mitochondrial dysfunction. The objective of the current study was to determine whether SR and mitochondrial dysfunctions are associated with symptomatic benign prostatic hyperplasia (BPH) in men. Methods. Bladder biopsies were obtained from men with symptomatic BPH and from age-matched men with no urologic dysfunction. Each biopsy was analyzed for the following enzyme activities: malate dehydrogenase and citrate synthase (mitochondrial markers) and the sarcoplasmic reticular enzyme Ca 2+ -dependent adenosine triphosphatase (ATPase). These values were compared with the enzyme activities of control rabbit bladder smooth muscle and bladder smooth muscle obtained from rabbits subjected to 2 weeks of partial outlet obstruction. Results. The enzymatic activities of all three enzymes are significantly lower in human bladder smooth muscle than in rabbit bladder smooth muscle. The maximal activities of all three enzymes are significantly lower in human bladder samples obtained from men with diagnosed obstructive uropathy than in men of equal age with no urologic dysfunction. Conclusions. These studies demonstrate that similar to the response of the rabbit to partial outlet obstruction, obstructive dysfunction secondary to BPH is characterized by mitochondrial and SR dysfunction.

Absorption of oxybutynin from vaginal inserts: drug blood levels and the response of the rabbit bladder☆

OBJECTIVES Oxybutynin has been used for treatment of urge urinary incontinence for more than 20 years. However, one of the major problems with its use is uncomfortable anticholinergic side effects that can lead to discontinuation of treatment. Alternative forms of drug administration may reduce side effects and thus improve patient compliance. METHODS A cylinder-shaped, curved silicone elastomer insert containing oxybutynin was anchored in the vagina of female rabbits. The inserts were designed to release oxybutynin at rates of 0.5, 1.0, and 5.0 mg/day, respectively. Blood drug and metabolite levels were monitored for 1 to 7 days and cystometry was carried out after 7 days of treatment. RESULTS There was a consistent dose-dependent absorption of the oxybutynin resulting in stable plasma concentrations by 3 days. Levels of N-desethyloxybutynin, the active metabolite that is thought to be responsible for side effects, were less than 1.0 ng/mL in all groups. The cystometrograms showed a decrease in the detrusor pressures for the higher oxybutynin groups and a dose-dependent decrease in micturition pressure. The vaginal wall in contact with the insert showed no irritation. CONCLUSIONS The inserts produced stable blood levels and released sufficient amounts of oxybutynin to have measurable effects on the bladder. There was no irritating effect of the insert on the vaginal wall after a 1-week treatment. Vaginal inserts containing oxybutynin may be an interesting alternative method for the chronic delivery of oxybutynin.

Beneficial effects of Tadenan therapy after two weeks of partial obstruction in the rabbit

Tadenan® (Debat Laboratories, France) is a plant extract used in Europe for the treatment of micturition disorders associated with benign prostatic hypertrophy (BPH). Prior studies demonstrated that pretreatment of rabbits with Tadenan significantly reduced the contractile dysfunction observed after 2 weeks of partial outlet obstruction. The specific aim of the present study was to determine the effect of Tadenan therapy following the creation of partial outlet obstruction.

The effect of urine volume and nitric oxide on basal bladder blood flow: response to catheterization and drainage.

Preliminary studies demonstrated that catheterization and drainage of the urinary bladder resulted in a significant increase in blood flow to the bladder. The objectives of this study were to determine 1) the relationship between urine volume and basal blood flow to the bladder smooth muscle and mucosa, 2) the effect of acute catheterization and drainage on bladder mucosal and smooth muscle blood flow, and 3) whether nitric oxide was involved in regulation of basal blood flow or the increase in blood flow observed after catheterization and bladder drainage. Twenty‐four rabbits were separated into two groups: group 1(14 rabbits) and group 2 (10 rabbits) treated with L‐NAME (NOS inhibitor) 30 minutes before blood flow measurement. Blood flow was measured in all animals using a fluorescent microsphere technique before and immediately after catheterization and drainage of the bladder. The results demonstrated that 1) blood flow to the muscle and mucosa were independent of urine volume at the time of catheterization and drainage; 2) catheterization and drainage significantly increased blood flow to both the bladder smooth muscle and bladder mucosa, but not to the kidney; 3) L‐NAME significantly reduced basal blood flow to the kidney, but not to the bladder smooth muscle or mucosa; and 4) L‐NAME completely prevented the catheterization‐ and drainage‐induced increases in blood flow to the bladder body mucosa and muscle. This study demonstrates that basal blood flow to the bladder smooth muscle and mucosa during filling is independent of NO control; although bladder blood flow may be increased significantly by NO synthesis and release during bladder emptying, and thus may be an important regulator of blood flow during and immediately following micturition. Neurourol. Urodynam. 20:115–124, 2001.

Urethral erosion of tension-free vaginal tape

We report a case of urinary retention and urethral erosion after placement of tension-free vaginal tape. This procedure is gaining wide popularity in both Europe and the United States. Careful attention is necessary to assure tension-free placement of the sling.

Endoscopic Management of Milk of Calcium-Filled Ureterocele Stump

A 38-year-old woman with a duplicated right collecting system and a history of right upper-pole heminephrectomy was referred for persistent dysuria and right lower-quadrant abdominal discomfort. Imaging identified a remnant ureter and a ureterocele filled with what appeared to be a large homogenous stone. At cystoscopy, the ureterocele was incised with a holmium:YAG laser, releasing a large quantity of white milky fluid (milk of calcium). There was no evidence of any solid material. Endoscopic evaluation should be the first step in patients with stones in a ureteral stump because milk of calcium may be the etiology of what appears to be a large stone burden in an obstructed system.

Electrical and mechanical office-based neuromodulation.

Overactive bladder (OAB) is commonly encountered in urologic practice. Treatment algorithms begin with conservative therapy and pharmacotherapy with antimuscarinics. Some patients do not receive adequate relief from these methods or they do not tolerate side effects from pharmacotherapy. A test stimulation for sacral neuromodulation and percutaneous tibial nerve stimulation are office-based techniques that are commonly used as the next step in the algorithm of care in patients with OAB. These techniques are efficacious and approved by the Food and Drug Administration for treatment of overactive bladder and its associated symptoms.

Biochemical Evaluation of Obstructive Bladder Dysfunction in Men Secondary to BPH

OBJECTIVES In the rabbit, two of the major cellular alterations that mediate bladder dysfunction secondary to partial outlet obstruction are a decreased ability of the sarcoplasmic reticulum (SR) to store and release Ca2+, and mitochondrial dysfunction. The objective of the current study was to determine whether SR and mitochondrial dysfunctions are associated with symptomatic benign prostatic hyperplasia (BPH) in men. METHODS Bladder biopsies were obtained from men with symptomatic BPH and from age-matched men with no urologic dysfunction. Each biopsy was analyzed for the following enzyme activities: malate dehydrogenase and citrate synthase (mitochondrial markers) and the sarcoplasmic reticular enzyme Ca2+ -dependent adenosine triphosphatase (ATPase). These values were compared with the enzyme activities of control rabbit bladder smooth muscle and bladder smooth muscle obtained from rabbits subjected to 2 weeks of partial outlet obstruction. RESULTS The enzymatic activities of all three enzymes are significantly lower in human bladder smooth muscle than in rabbit bladder smooth muscle. The maximal activities of all three enzymes are significantly lower in human bladder samples obtained from men with diagnosed obstructive uropathy than in men of equal age with no urologic dysfunction. CONCLUSIONS These studies demonstrate that similar to the response of the rabbit to partial outlet obstruction, obstructive dysfunction secondary to BPH is characterized by mitochondrial and SR dysfunction.

Selection of Ideal Candidates for Neuromodulation in Refractory Overactive Bladder

Sacral neuromodulation is a minimally invasive, reversible treatment option that has been approved by the US Food and Drug Administration for patients with urgency/frequency and urge incontinence. While long-term success rates are high, the high treatment cost and the need for operative revision or explantation in cases of failure make the selection of ideal candidates particularly important. Because predictive factors for success and the exact mechanism of action are not known, physicians must rely on a preimplantation test procedure, either in the office or in the operating room, to select patients for implantation of a pulse generator. In this paper, we review the recent literature on performing a test procedure with both temporary and permanent leads and the selection of optimal candidates for sacral neuromodulation therapy.