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PubMed1980

Use of bethanechol for the treatment of gastroesophageal reflux.

A double-blind crossover study utilizing bethanechol was performed among 45 pediatric-aged patients with gastroesophageal reflux. Thirty young children (age = less than 1 year) were studied. These infants did significantly better while taking bethanecol than when they were receiving placebo. Fifteen children (age greater than 1 year) were also studied. These patients also had significant clinical improvement while on the drug when compared to the period when they were receiving placebo. Esophageal pH probe testing after the oral administration of bethanecol showed a significant decrease in frequency and duration of episodes of gastroesophageal reflux. This improvement may be secondary to the increases in lower esophageal sphincter pressure and persistaltic activity seen during esophageal manometrics. Bethanechol should be considered for pediatric-aged patients who are not benefited by conventional medical therapeutic regimens.

Adolescent↗
PubMed1983

Results of treatment of gastroesophageal reflux with bethanechol.

Thirty-seven infants and children with gastroesophageal reflux were studied with prolonged esophageal pH monitoring before and during treatment with bethanechol. Total reflux scores improved by 69% (P = 6.47 X 10(-7) during bethanechol therapy. This improvement resulted primarily from decreases in the frequency and the duration of reflux episodes occurring more than two hours after feeding. Our findings indicate that infants and children with gastroesophageal reflux may safely be treated with bethanechol; thus the need for surgery is avoided.

Bethanechol Compounds↗
PubMed1994

Temporal changes in rabbit urinary bladder function and DNA synthesis during chronic treatment with furosemide.

In a preliminary study we showed that 14 days of furosemide infusion in rabbits caused increases in bladder mass and contractile responses of bladder body strips to field stimulation, bethanechol, ATP and KCl. The present study investigated the temporal effects of furosemide-induced diuresis on micturition, bladder mass, bladder wall proliferation activity and DNA synthesis. In addition, contractile responses of bladder body strips were monitored. Furosemide-containing osmotic pumps were implanted in male New Zealand White rabbits. Micturition was monitored for 7 days. Biochemical analyses were done 3, 7 and 14 days after implantation. Contractile responses were measured at 3 and 7 days. Polyuria and polydipsia started within 1 day after implantation of furosemide-containing osmotic pumps and continued at the same level for 7 days. Bladder mass was significantly increased at 3 and 7 days. Diuresis stimulated 3H-thymidine uptake and caused an increase in bladder DNA concentration at 3 days. However, both DNA concentrations and 3H-thymidine levels returned to control levels by 7 days. Contractile responses to field stimulation and agonists were increased at 7 days but unchanged at 3 days. The data confirm that modest increases in bladder mass and the ensuing increases in contractile function are a normal and beneficial physiological response to diuresis.

Adenosine Triphosphate↗
PubMed1994

Comparative studies on the ontogeny and autonomic responses of the fetal calf bladder at different stages of development: involvement of nitric oxide on field stimulated relaxation.

This initial study correlates the passive length-tension relationship, contractile and relaxant responses to field stimulation and contractile responses to specific autonomic agonists and antagonists with gestational age. Fetal bovine bladders were separated into three groups based on the head-rump length (FL): 30 to 45 cm. (early gestation), 50 to 65 cm. (middle gestation) and 70 to 85 cm. (late gestation). Each bladder was separated into upper and lower bladder segments; longitudinal strips of smooth muscle were isolated and placed in individual muscle baths. Passive length-tension studies demonstrated that compliance was greatest in the bladder of late gestation and lowest in the bladder of early gestation period. Field stimulation (FS) elicited frequency-dependent contractile responses in all strips. In the upper bladder, the maximal response and maximal rate of tension generation to FS was lowest in the youngest fetuses and increased in proportion to the gestational age. In the lower bladders, there were no gestational age-related differences in the maximal response or maximal rate of tension generation in response to field stimulation. The maximal response of the upper bladder to bethanechol increased significantly from the youngest gestational age to mid-gestation, with no further changes between mid- and late gestation. The maximal response to field stimulation and bethanechol were equal between upper and lower bladder segments for the youngest gestational bladders, whereas for the oldest gestational ages, the maximal response of the upper bladder to FS and bethanechol were significantly greater than the responses of the lower bladder. In the presence of maximal precontraction with bethanechol, FS induced a rapid and marked decrease in tension. The magnitude of the relaxation was substantially greater for the strips of lower bladder than for the strips of upper bladder at late gestation. In lower bladders, the magnitude of the field stimulated relaxation was greater in the strips from the older fetuses than in the strips from younger fetuses. In all strips, field stimulated relaxations were completely inhibited by pretreatment with L-NAME (an inhibitor of nitric oxide synthesis), indicating that the FS-induced relaxation was due to nitric oxide. In addition to nitric oxide-induced relaxation, beta adrenergic stimulation also induced a significant relaxation of the isolated strips. In summary, these data suggest that, in the tubular shaped fetal bovine bladder, there were distinct differences in the autonomic responses between the upper bladder segment and the lower bladder segment in the late gestation period.

Adenosine Triphosphate↗
PubMed1993

The effect of furosemide-induced diuresis on rabbit micturition and bladder contractile function.

The morphology and contractile function of the urinary bladder can be significantly altered in response to specific forms of physiological and pathophysiological stress placed upon it. For example, partial outlet obstruction results in a marked increase in bladder mass (weight) with associated alterations in the contractile response to specific forms of stimulation. Diabetes and its associated diuresis also induce significant alterations in bladder weight and contractile function. The current study was designed to determine if the increase in bladder weight induced by diuresis is associated with contractile alterations similar to those observed following partial outlet obstruction. Diuresis was induced by continual slow-infusion of furosemide using osmotic pumps. The results can be summarized as follows: 1) After two weeks of furosemide treatment the bladder mass was significantly greater than in the controls. 2) Furosemide-treated rabbits consumed and excreted three times more fluid than did the controls. 3) In vivo cystometric capacity and bladder compliance of the furosemide-treated rabbits were significantly increased. 4) Diuresis induced a significant increase in the contractile response of isolated bladder body strips to field stimulation, ATP, bethanechol, and KCl. 5) Furosemide treatment had no effects on the contractile responses of bladder base strips to any form of stimulation. Diuresis resulted in a significant increase in bladder weight and an associated increase in the contractile state of the bladder body, presumably through an increase in smooth muscle.

Adenosine Triphosphate↗
PubMed1993

Effects of partial outlet obstruction of the rat urinary bladder on micturition characteristics, DNA synthesis and the contractile response to field stimulation and pharmacological agents.

Partial outlet obstruction is one of the major urological complications induced by benign prostatic hypertrophy (BPH). The current study describes the time course of the effect of mild partial outlet obstruction (in rats) on in vivo micturition parameters, DNA synthesis, and on the in vitro response of the bladder to field stimulation, bethanechol, methoxamine, ATP, and KCl. Mild partial outflow obstruction was created by placing a catheter (outside diameter: 1.70 mm.) transabdominally in front of the urethra, tying a ligature (2-zero silk) around both the urethra and catheter, and then removing the catheter. The micturition pattern was monitored for 2 days prior to surgery, and then continuously for 14 days following the surgery. The changes in bladder weight and the in vitro detrusor function of control (sham operated) and obstructed bladders (1, 3, 5, 7, 14 and 28 days after surgery) were examined. Micturition frequency in the dark cycle decreased immediately after the operation, and then increased linearly reaching a maximum at the 5th day, and stabilized at this increased level for the duration of the micturition study. The frequency of the dark cycle was also decreased immediately after the sham surgery and then gradually increased over the period of observation. Bladder weight increased by day 1 following surgery, and remained high throughout the 28 day study. The contractile response of the obstructed bladder base to field stimulation was reduced at days 1 and 3. The response then increased above control for day 5, reached a maximum response at day 7 and remained at this level for days 14 and 28. A similar pattern was observed for the contractile response of the bladder body to bethanechol and KCl, and for the bladder base to methoxamine and KCl. Both obstructed and sham surgeries increased bladder DNA content and 3H-thymidine incorporation, which reached maximal values on days 5 and 3, respectively. DNA content and 3H-thymidine incorporation of obstructed bladders were greater than those of sham operated bladders. In conclusion, partial outlet obstruction in the rat resulted in a progressive increase in bladder mass, an increase in micturition frequency, increases in the in vitro contractile response to field stimulation, bethanechol, methoxamine, and KCl, and increases in bladder DNA content and 3H-thymidine incorporation.

Adenosine Triphosphate↗
PubMed1992

Detubularization-induced contractile response change of the ileum following ileocystoplasty.

We reported previously that following ileocystoplasty the structure and pharmacologic response of the implanted ileum changes towards that of the bladder. Specifically, the relaxation response to alpha adrenergic (methoxamine) and purinergic (ATP) stimulation reverses to a contractile response one month after the ileal segment is surgically made part of the urinary bladder. The present study was designed to investigate possible signals for this change and also to determine whether bladder responses would mimic the ileum if surgically interposed into the ileal stream. Rabbits in group 1 underwent bladder interposition into the functioning terminal ileum, rabbits in group 2 underwent tubularized ileocystoplasty and rabbits in group 3 underwent detubularized ileocystoplasty with urinary diversion. Twelve rabbits survived and were available for evaluation; five in group 1, three in group 2 and four in group 3. Analysis was done six weeks after surgery. In group 1 animals, the interposed bladder showed epithelial changes towards ileum and also a change in its in-vitro contractile responses towards that of ileum. In group 2 animals the tubular cystoplastic ileum showed minimal functional and morphologic changes. In group 3 animals, the defunctionalized, detubular cystoplastic ileum showed alpha adrenergic and purinergic response changes towards bladder. These results indicate that detubularization with interruption in the arrangement of smooth muscle fibers as well as the breach in the integrity of neuronal connections is likely to be the primary signal for the change in the ileum towards bladder induced by cystoplasty. The results can not rule out reinnervation of the intestinal segment by bladder nerves. In addition these data demonstrate that the pharmacologic response of the bladder changes towards the ileum within six weeks after the bladder is surgically made part of the ileum.

Adenosine Triphosphate↗
PubMed1992

The cholinergic and purinergic components of detrusor contractility in a whole rabbit bladder model.

Whole rabbit bladders were suspended in a bath chamber and stimulated with ATP, bethanechol, electrical field stimulation, and bethanechol + ATP. Detrusor pressure and fluid expelled by the bladder were recorded, synchronized, and digitized. Detrusor work and power were calculated with a computer program. Maximum work was 61.4 +/- 28.7, 83.3 +/- 17.0, 85.0 +/- 15.0, 90.8 +/- 13.1 cm. H2O, ml. for ATP, bethanechol, electrical and bethanechol + ATP, respectively. Maximum power generated by ATP was 4.8 +/- 3.0 cm. H2O, ml./sec and was approximately 66% of that generated by bethanechol, and 50% of that generated by electrical stimulation, and bethanechol + ATP. ATP cannot empty the bladder with moderate outlet resistance while bethanechol and electrical stimulation can. Our results suggest that ATP is able to generate detrusor power and achieve work in bladder emptying. However, ATP generated power and work is considerably less than that of electrical stimulation or bethanechol alone. ATP mediated contraction is not inhibited by atropine or tetrodotoxin but is inhibited by P2 purinoceptor desensitization, suggesting a functional role of purine receptors on detrusor smooth muscle. Since ATP generated pressure is more rapid than with bethanechol alone, we support the hypothesis that ATP may be important in the initiation of micturition.

Adenosine Triphosphate↗
PubMed1989

Pharmacological responses of rabbit urinary bladder after subtotal cystectomy.

Partial cystectomy is used clinically in specific circumstances. There have been some reports indicating that the bladder following subtotal cystectomy can regenerate to a certain degree. The present study investigates the physiology and pharmacology of bladder regeneration at eight weeks after resection of a major part of the bladder body in rabbits. The following studies were performed on control and cystectomy bladders: 1) in vivo cystometry (prior to and four weeks after the operation, and before the sacrifice at eight weeks); 2) sequential muscle strip study (the strips were obtained by dividing bladder transversely into upper body, lower body, mid-bladder, upper base and lower base); and 3) in vitro whole bladder studies. The results can be summarized as follows: 1) grossly there was no regeneration of the bladder body; the cystometric capacity was increased slowly after the operation primarily due to increased size and capacity of the bladder base. 2) The contractile response of the subtotal cystectomized bladder body to field stimulation and bethanechol stimulation was less than the response of normal bladder body. 3) The contractile response to epinephrine showed that the ratio of alpha/beta adrenergic response was much greater in the cystectomy bladder than in the normal bladder. 4) In the whole bladder study, the intravesical pressure response to field stimulation was about the same in both groups, the response to bethanechol was less for cystectomized bladder, and the response to methoxamine was greater for the cystectomized bladder. 5) The ability of cystectomy bladder to empty in response to both field stimulation and bethanechol was impaired whereas the control bladder fully emptied to both field stimulation and bethanechol. In conclusion, over the eight week period following subtotal cystectomy the capacity increased via distention (and hypertrophy) of the bladder base area as opposed to regeneration of the bladder body.

Adenosine Triphosphate↗
PubMed1989

Functional and biochemical alterations in the rabbit urinary bladder following ileocystoplasty.

Although the use of ileocystoplasty has increased significantly in recent years, very little is known concerning the smooth muscle properties of the implanted bowel segment. In a previous study, preliminary evidence was presented which indicated that the pharmacological response of the cytoplastic ileal segment to autonomic agonists changed toward that of the bladder. The present study extends and expands these preliminary observations on the physiology and pharmacology of augmentation cystoplasty. Augmentation cystoplasty with detubularized ileum was carried out in 16 rabbits. In vivo and in vitro physiological and pharmacological studies were carried out one and three months after surgery. The results can be summarized as follows: 1) in-vivo CMG at one month was similar to that of the preoperative bladder, but at three months there was a 24% increase in capacity, with the presence of multiple phasic contractions beginning at a volume of approximately 65% of capacity. 2) The frequency and magnitude of spontaneous activity in the cystoplastic ileum did not significantly alter from that of the normal ileum. 3) Cystoplastic ileum responded to muscarinic stimulation differently from the normal ileum. The bladder responded with an increase in the tension whereas the ileum responded with an increase in the frequency and amplitude of phasic contractions. The cystoplastic ileum responded with a pronounced sustained contraction with phasic contractions superimposed. The tonic contraction at three months was of a significantly greater magnitude than that at one month. 4) The qualitative and quantitative response to field stimulation of the cystoplastic ileum was altered from that of the ileum towards that of the bladder. 5) The normal bladder contains greater amount of creatine phosphate and lesser amounts of creatine than the normal ileum. Cystoplasty, after three months induced a change in the ileal segment towards the bladder (increased creatine phosphate and decreased creatine). 6) The normal ileum was found to have greater number of muscarinic receptors than the normal bladder whereas the cystoplastic ileum at three months was intermediate.

Animals↗
PubMed1990

Ontogeny of bladder function in the rabbit.

Although numerous experimental studies have addressed urinary bladder innervation, physiology and pharmacology, little information is available concerning the ontogeny of bladder function. The present study describes the developmental aspects of bladder mass, bladder capacity, pressure development and emptying in white New Zealand rabbits one day of age through maturity (11 to 15 weeks of age). The following studies were performed: Cystometry, pressure generation, rate of pressure generation, and emptying responses to field stimulation, cholinergic and purinergic stimulation using the in vitro whole bladder model. The results of these studies can be summarized as follows: 1) body weight and bladder weight increased in proportion to each other, bladder capacity increase proportionally with development until eight weeks of age, then increased substantially greater than body and bladder weight between eight and 11 to 15 weeks of age; 2) the ability to empty is similar for all ages; 3) pressure responsiveness to field stimulation, bethanechol, and ATP is greater at one day? of age, intermediate at one week of age, and similar for the other age groups; 4) The response to ATP (purinergic transmitter) is of an equal magnitude to the cholinergic response at one day, and reduces rapidly to approximately 45% of the cholinergic response by four weeks. Desensitization of the bladders to ATP reduced the response to field stimulation in the one day bladders to a significantly greater degree than the other age groups. These functional results indicate a marked alteration in cholinergic and purinergic response between the one day and the four week old rabbit bladders, with the response of the one week old bladders in between. The responses of the four, eight, and 11 to 15 week bladders was similar for equal volumes even though the bladder mass increased over threefold. This indicates that the ability of the bladder to generate pressure (during development) is not directly related to bladder mass.

Adenosine Triphosphate↗
PubMed1990

The functional effects of long-term outlet obstruction on the rabbit urinary bladder.

The current study investigated the relationship between duration of outlet obstruction, magnitude of bladder mass, and functional dysfunction on the rabbit urinary bladder. Following the production of obstruction with the "cuff model", bladder wet weight increased to twice control weight within one week, and then slowly to four times control weight by one month, and remained at this level for the six month period. Bladder capacity decreased significantly by one week but returned to control volumes by one month. The in vitro ability of the bladder to empty in response to field stimulation and bethanechol decreased significantly in the one and two week obstructed bladders and remained decreased for six months. One of the major observations of this study was the relatively large variation of bladder weight and histology observed for the one to six month obstructed rabbits. Although the bladders with mild mass increase (less than 3 gm./kg. body weight) had normal distribution of urothelium and muscular elements, the bladders with moderate mass increase (3 to 6 gm./kg.) had thick extrinsic connective tissue deposits and the bladders with severe mass increase (greater than 6 gm./kg.) had thick extrinsic and intrinsic connective tissue deposits and muscular degeneration. The percentage occurrence of mild, moderate and severe mass increase was approximately the same (58%, 30% and 12%, respectively) for the one, three, and six month groups. The bladders with mild mass increase had normal bladder capacities and increased pressure responses to field stimulation and bethanechol. The bladders with moderate-to-severe mass increase showed enlarged bladder capacities and had progressively smaller pressure responses. As the magnitude of bladder mass increased, the ability of the bladder to empty in response to field stimulation and bethanechol decreased proportionally. We conclude that the functional impairment of the bladder is related to the amount of extrinsic and intrinsic connective tissue and the degree of muscle degeneration.

Adenosine Triphosphate↗
PubMed1990

Central actions of bethanechol on the urinary bladder in dogs.

Bethanechol has been used to promote bladder emptying although the clinical efficacy of bethanechol remains uncertain. Both laboratory and clinical observations suggest that the pharmacologic actions of bethanechol are dependent to some extent on intact reflex mechanisms of the bladder. The objective of this study was to determine the effects of central nervous system administration of bethanechol on reflex detrusor contractions. Twelve isolated cross perfusion studies of the central nervous system in dogs were done to determine the cystometric response to central bethanechol administration. Central bethanechol resulted in reflex bladder contractions, decreased cystometric volume, increased maximum intravesical pressure, and increased periurethral EMG activity. This study demonstrated a central nervous system site of pharmacologic activity of bethanechol.

Animals↗
PubMed1990

Comparative physiology and pharmacology of the cat and rabbit urinary bladder.

The cat and the rabbit are two of the most popular models for the study of lower urinary bladder function. The cat has been used extensively for in-vivo studies of spinal and supra-spinal micturition reflexes. In contrast, the rabbit has been used extensively for the in-vitro study of bladder function. In order to determine if the results obtained using one species can be applied to another, we have compared the in-vitro physiology and pharmacology of the cat and rabbit bladder using isolated strips and whole bladder preparations. The results can be summarized as follows: 1) The cat displays significant spontaneous activity during in-vitro cystometry, but the rabbit shows no such activity (whole bladder studies). 2) Although the bladder weights of the cat and rabbit are similar, the rabbit bladder has a capacity three times that of the cat. 3) The maximal response to field stimulation was obtained at one gram of passive tension for the rabbit isolated strips, whereas five grams of passive tension was required for the cat strips. 4) Atropine inhibited the response of isolated strips of cat bladder to field stimulation by approximately 13% whereas the response of rabbit bladder strips was inhibited by approximately 45%. 5) The magnitude of the response of rabbit bladder strips to ATP was similar to the response to field stimulation in the presence of atropine; the response of cat bladder strips to ATP was only 20% of the response of that of the rabbit bladder strips, and approximately 10% of the response of the cat strips to field stimulation in the presence of atropine. 6) Field stimulation produced a 10fold greater rise in intravesical pressure in the cat isolated bladder than in the isolated rabbit bladder; in response to bethanechol, the cat bladder generated a 6-fold greater response than the rabbit bladder. It is clear that the in-vitro pharmacological responses of the cat urinary bladder are qualitatively and quantitatively different from that of the rabbit bladder.

Adenosine Triphosphate↗
PubMed1990

Short term functional effects of bladder outlet obstruction in the cat.

Experimental bladder outlet obstruction in cats was produced by surgical placement of a silastic cuff around the urethra. Two sizes of cuff were used to produce either moderate or severe obstruction. The following is a summary of the short-term effects on bladder function. Obstruction induced a significant increase in the in vivo voiding pressure, in proportion to severity of the obstruction. There were no significant differences between control and obstructed cats in bladder mass, response of the isolated whole bladder to field stimulation or bethanechol, response of isolated bladder strips to field stimulation, bethanechol and ATP, or muscarinic receptor density in the bladder body. Although there were no differences in bladder mass between control and obstructed bladders, the hydroxyproline concentration of the severely obstructed bladders was significantly reduced. Creatine phosphate concentration was also significantly reduced in obstructed bladders. Although all whole cat bladder preparations displayed spontaneous contractile activity during in vitro cystometry, the obstructed bladders had a greater amplitude and frequency of spontaneous contractions with a lower volume threshold. In addition, the obstructed bladders had a greater tetrodotoxin-resistant contractile response to field stimulation. These results suggest that the obstructed cat bladder can compensate for increased outlet resistance without induction of bladder hypertrophy or significant functional changes, as seen in both rat and rabbit.

Adenosine Triphosphate↗