Aspirin treatment improves bladder function after outlet obstruction in rabbits.

OBJECTIVES: To examine whether bladder smooth muscle dysfunction after outlet obstruction could be altered by treatment with aspirin. Long-term outlet obstruction causes contractile and metabolic dysfunction of the bladder in vivo and in vitro. The evidence is growing that a decrease in bladder perfusion is an important cause of this phenomenon. The platelet aggregation inhibitor, acetylsalicylic acid (aspirin), has been used to improve perfusion of the heart for decades. METHODS: Ten male New Zealand white rabbits were obstructed for 4 weeks. Five rabbits received no further treatment (Obs), and 5 rabbits received 2 mg/kg/day aspirin (Obs+aspirin), administered by an osmotic pump implanted subcutaneously 1 week before the surgical obstruction. The bleeding time was measured to confirm the effectiveness of the aspirin treatment. Three different control groups were created: sham-operated rabbits, unobstructed rabbits with pumps containing DMSO (vehicle), and unobstructed rabbits with pumps containing aspirin. The contractile responses of bladder strips to field stimulation, adenosine triphosphate, carbachol, and KCl were determined. A section of each detrusor tissue was fixed in formalin and used to determine the smooth muscle and collagen (connective tissue) volume fraction. RESULTS: No differences were found in the bladder weights or responses to stimuli in the different control groups, which were therefore combined. Partial bladder outlet obstruction caused significant increases in the bladder weight of the obstructed animals (Obs+aspirin, 10.15 +/- 0.87 g; Obs, 10.17 +/- 0.88 g; and controls, 2.87 +/- 0.21 g). The aspirin treatment increased the bleeding time from 1.7 +/- 0.3 minutes to 3.3 +/- 0.1 minutes. The responses to field stimulation were significantly reduced in all of the obstructed rabbits. However, the responses of the bladder strips from the Obs rabbits to field stimulation were impaired to a significantly greater degree than were those from the Obs+aspirin rabbits. The response to 32-Hz stimulation was reduced by 86% in the Obs group but by only 64% in the Obs+aspirin group. The responses to carbachol were significantly reduced by 62% in the strips from the Obs rabbits, but the responses of the strips from the Obs+aspirin rabbits were similar to the responses of the strips from the controls. The responses to KCl and adenosine triphosphate were reduced, although they just failed to achieve statistical significance using Bonferroni's analysis. The ratio of smooth muscle and connective tissue shifted slightly toward smooth muscle after 4 weeks of obstruction, but no difference was found with or without aspirin treatment. CONCLUSIONS: Low-dose aspirin has a small but significant protective effect on the contractile dysfunction induced by bladder outlet obstruction in rabbits, although the increase in bladder mass was not altered. Bladders of the same weight showed improved responses to all forms of stimulation after pretreatment with aspirin. Already used by millions of patients with heart diseases, aspirin could be a useful protection against contractile dysfunction of the obstructed bladder.

Bufuralol metabolism by guinea pig adrenal and hepatic microsomes.

Previous investigations demonstrated that CYP2D16 was expressed at high levels in guinea pig adrenal microsomes. The studies presented here were done to determine whether adrenal metabolism of bufuralol (BUF), a model CYP2D substrate, was similar to that in the liver. Guinea pig adrenal microsomes converted BUF to 1'-hydroxybufuralol (1'-OH-BUF) as the major metabolite and smaller amounts of a compound identified as 6-hydroxybufuralol (6-OH-BUF). In contrast, 6-OH-BUF was the major product formed by hepatic microsomal preparations. The apparent Km values were similar for 1'-OH-BUF and 6-OH-BUF production in each tissue. Quinidine, a selective CYP2D inhibitor, decreased the production of both BUF metabolites equally in liver and adrenal microsomes. Cortisol also caused equivalent decreases in the rates of 1'-OH-BUF and 6-OH-BUF formation by adrenal microsomes, but had no effect on hepatic BUF metabolism. Although both BUF metabolites may be produced by CYP2D16, unknown factors appear to effect some differences in the catalytic characteristics of BUF metabolism in adrenal and liver. The large amount of 6-OH-BUF produced distinguishes BUF metabolism in guinea pigs from that in other species previously studied.

Changes in mitochondrial and microsomal lipid peroxidation and fatty acid profiles in adrenal glands, testes, and livers from alpha-tocopherol-deficient rats.

Studies were done to evaluate the effects of alpha-tocopherol deficiency in rats on the fatty acid composition and sensitivity to lipid peroxidation (LP) of mitochondria and microsomes from adrenal glands, testes, and livers. In control (alpha-tocopherol-sufficient) animals, adrenal concentrations of alpha-tocopherol were approximately 10 times greater than those in livers and testes. Dietary deficiency of alpha-tocopherol for 8 weeks decreased adrenal and hepatic concentrations by 80-90% and testicular concentrations by approximately 60-70%. Incubation of testicular or hepatic mitochondria and microsomes from control rats with FeSO(4) (1.0 mM) caused a time-dependent stimulation of LP as indicated by the formation of thiobarbituric acid reactive substances (TBARS); the rate of TBARS production increased in preparations from alpha-tocopherol-deficient animals. TBARS formation was not demonstrable in adrenal mitochondria or microsomes from alpha-tocopherol sufficient rats, but reached high levels in alpha-tocopherol-deficient preparations. The fatty acid composition of mitochondria and microsomes was tissue-dependent. In particular, arachidonic acid comprised approximately 40% of the total fatty acids in adrenal membranes, but only 20-25% in testes and livers. alpha-Tocopherol deficiency increased oleic acid concentrations in adrenal and hepatic mitochondria and microsomes but not in testes. In all three tissues, linoleic acid concentrations decreased by approximately 50%, but arachidonic acid levels were unaffected by alpha-tocopherol deficiency. The results indicate a close relationship between tissue sensitivity to LP in vitro and alpha-tocopherol concentrations. Nonetheless, any oxidative stress in vivo caused by alpha-tocopherol deficiency seems to spare arachidonic acid in mitochondria and microsomes but decreases linoleic acid concentrations. It is possible that because of the important physiological functions of arachidonic acid, metabolic adaptations serve to maintain membrane content during periods of oxidative stress.

Suppression of lipid peroxidation in adrenal microsomes following ACTH administration to guinea pigs.

Previous studies demonstrated high levels of lipid peroxidation (LP) in the guinea pig adrenal cortex. The present studies were done to determine if adrenal LP activity was influenced by ACTH, the major hormonal regulator of the gland. Guinea pigs were treated with ACTH for 1, 3 or 7 days. In addition, some guinea pigs received ACTH for 7 days and were killed 3 or 7 days later. After treatment, adrenal microsomal fractions were prepared and incubated in vitro with 1 mM ferrous sulfate to initiate LP. ACTH treatment caused a progressive decrease in adrenal LP; activity was almost totally inhibited within 3 days. The inhibitory effects of ACTH on LP were dose-dependent. Following cessation of ACTH treatment, adrenal LP gradually returned toward control levels. Microsomal concentrations of linoleic acid, a major substrate for adrenal LP, were increased by ACTH administration and then also returned to control levels after cessation of treatment. There were no significant changes in adrenal alpha-tocopherol or beta-carotene concentrations resulting from ACTH treatment. The results indicate that ACTH has a role in the regulation of adrenal LP. The actions of ACTH cannot be attributed to an increase in adrenal content of the antioxidants, alpha-tocopherol and beta-carotene, or to a decrease in LP substrate. The actions of ACTH to inhibit LP may contribute to an increase in adrenal hormone production by protecting steroidogenic enzymes from peroxidative degradation.

Effect of chronic bladder outlet obstruction on blood flow of the rabbit bladder.

PURPOSE: Previous studies have shown that the initial reaction of the rabbit bladder to partial bladder outlet obstruction is increased blood flow at day 1 and a return to baseline blood flow at 1 week. Mucosal and muscle blood flow followed this pattern but mucosal blood flow was always 4 to 5-fold greater. In this study we examined the effect of 4 weeks of outlet obstruction on bladder blood flow and correlated it with the severity of bladder contractile dysfunction. MATERIALS AND METHODS: A total of 14 male New Zealand White rabbits underwent partial outlet obstruction creation by standard methods. After 4 weeks the rabbits were anesthetized, and blood flow to the muscle and mucosa was determined by standard fluorescent microsphere technique. A section of each detrusor was used for in vitro contractility studies. Contractile responses to field stimulation, carbachol and potassium chloride were determined. A section of each detrusor tissue was fixed in formalin and used to determine the smooth muscle volume fraction. RESULTS: Four weeks of partial bladder outlet obstruction caused a significant and variable increase in bladder weight and a decrease in blood flow to bladder muscle without changes in the blood flow to mucosa. There was a clear correlation between the severity of contractile dysfunction, bladder weight and the magnitude of the decrease in blood flow in muscle. The smooth muscle volume fraction remained stable at approximately 40%. CONCLUSIONS: Bladder decompensation was associated with decreased blood flow to bladder smooth muscle. Because compensated obstructed bladders with relatively normal contractile function are also hypertrophied but have normal blood flow, decreased blood flow in decompensated bladders is not simply a response to bladder hypertrophy. From this study we hypothesize that decreased blood flow to bladder smooth muscle is an etiological factor in bladder contractile dysfunction (bladder decompensation) secondary to partial outlet obstruction.

Influence of gender and the oestrous cycle on in vitro contractile responses of the rat urinary bladder to cholinergic stimulation.

1. Experiments were done to determine the influence of gender and the oestrous cycle on rat urinary bladder contractility in response to cholinergic stimulation. 2. Bladder strips from female rats responded to high frequency stimulation with smaller contractile responses than did strips from males, and to low concentrations of carbachol with greater responses. The decreased responsiveness of bladder strips from female rats to electrical field stimulation can be primarily attributed to the rats in the oestrous stage of the oestrous cycle. 3. Bladder strips from female rats in all stages of the oestrous cycle were more sensitive to carbachol than those from males, but there were no differences in sensitivity to electrical field stimulation. 4. The contractile responses of strips from both male and female rats to carbachol were antagonized by muscarinic antagonists with the following rank order of affinity (pA(2)) estimates: 4-DAMP>>pirenzepine>methoctramine, suggesting that the receptor mediating contraction was the M3 subtype. There were no differences in pA(2) values between bladder strips from male and female rats. 5. The data indicate that responsiveness of bladder strips to electrical field stimulation and carbachol is altered in female rats in the oestrous stage of the oestrous cycle. Furthermore, gender influences the sensitivity of rat bladder to muscarinic stimulation.

Sacral nerve stimulation for the management of voiding dysfunction.

Voiding dysfunction is common, and patients with urge incontinence, frequency/urgency syndromes, and chronic urinary retention are challenging to treat once conservative therapies (such as pharmacologic agents, pelvic floor rehabilitation, and intermittent catheterization) have been exhausted. Sacral nerve stimulation (SNS) is a new, minimally invasive, reversible therapy for the management of refractory voiding dysfunction and provides an attractive therapeutic alternative for patients with this condition. In this review, the role of SNS in the management of voiding dysfunction is examined critically, and the efficacy, risks, and benefits of this new modality are evaluated.

Filling mechanics of obstructed and de-obstructed rat urinary bladders.

Chronic bladder distension occurs after partial outlet obstruction and can lead to decompensation and impaired function. To quantify the degree of chronic bladder distension, we previously defined the zero pressure volume (ZPV), the largest contained volume at zero transmural pressure. In the current study, we investigated the short- and long-term effects of outlet obstruction and de-obstruction on chronic distension and passive bladder filling mechanics. Voiding patterns were measured 10 days (short term) or 6 weeks (long term) after partial bladder outlet obstruction and the bladders were tested in vitro at that time. De-obstructed bladders were obstructed for 6 weeks, and voiding patterns were measured 10 days or 6 weeks after de-obstruction, followed by in vitro testing. Mean voided volume was increased in de-obstructed bladders but not obstructed bladders. The volume of urine in the bladder at euthanasia was greater than mean voided volume in obstructed bladders and less than mean voided volume in de-obstructed bladders, indicating large residual urine in the obstructed bladders. ZPV was significantly increased only after long-term obstruction or de-obstruction. Similarly, intravesical pressure and mean bladder wall stress were increased only after long-term obstruction or de-obstruction. We conclude that tissue remodeling occurs in the bladder wall after long-term obstruction, possibly both as a result of and leading to chronic overdistension and high residual urine. Tissue remodeling occurs in the bladder wall after long-term de-obstruction, possibly due to large voided volumes. Neurourol. Urodynam. 18:659-671, 1999.

Pharmacological characterization of beta-adrenoceptors mediating relaxation of the rat urinary bladder in vitro.

1. Isoproterenol relaxed KCl-precontracted rat bladder strips with a pD2 of 7.21 leaving a residual contractile response of 3.2% after 30 microM. The selective beta1-agonist, T-0509 (pD2 : 6.24, 10.1% residual contraction after 100 microM), beta2-agonist, terbutaline (pD2 : 5.43, 13.7% residual contraction after 100 microM), and beta3-agonists, BRL 37344A (pD2 : 6.60, 17.3% residual contraction after 100 microM), and SR 58611A (pD2 : 5.15, 34.0% residual contraction after 100 microM), also relaxed bladder strips. 2. The relaxant response to isoproterenol was weakly but significantly antagonized by 1 microM propranolol which produced a 3 fold shift of the concentration-response curve to the right, and significantly antagonized by the beta1-selective antagonist, metoprolol (10 microM, 3 fold shift), and the beta2-selective antagonist, butoxamine (100 microM, 6 fold shift). A combination of 10 microM metoprolol and 100 microM butoxamine caused a 15 fold shift of the concentration-response curve for isoproterenol to the right. Incubation with the beta3-antagonist, SR 59230A (1 microM), caused a 6 fold shift of the concentration response curve for isoproterenol to the right. 3. The non-conventional partial agonist, CGP 12177A, weakly relaxed KCl-precontracted bladder strips (pD2 : 3.31, 51.3% residual contraction after 300 microM); the relaxation was resistant to blockade by 1 or 10 microM propranolol. 4. In the presence of 200 microM propranolol, CGP 12177A (20 microM) or SR 59230A (10 microM) antagonized surmountably the relaxant effects of BRL 37344A. 5. The data suggest that rat urinary bladder body contains beta1, beta2, and beta3-adrenoceptors, all of which mediate relaxation.

Species differences in adrenal lipid peroxidation: role of alpha-tocopherol.

Previous reports have noted high levels of lipid peroxidation (LP) in vitro in a variety of adrenocortical preparations. However, we have observed that susceptibility to adrenal LP seems to vary considerably from species to species. The current study was done to confirm these apparent species differences in adrenal LP in vitro and to determine if they were attributable to differences in alpha-tocopherol content. Incubation of mitochondrial or microsomal preparations from guinea pig or rabbit adrenal glands with ferrous ion (Fe2+) caused a time-dependent increase in the formation of thiobarbituric acid reactive substances (TBARS) accompanied by depletion of alpha-tocopherol. By contrast, incubation of adrenal mitochondria or microsomes from rats or monkeys with Fe2+ had little or no detectable effect on TBARS and basal adrenal alpha-tocopherol levels were five to ten-fold greater than those in guinea pigs or rabbits. In addition, there was little change in alpha-tocopherol concentrations during incubation of rat or monkey adrenal tissue. Dietary alpha-tocopherol deficiency in rats reduced adrenal alpha-tocopherol to concentrations approximating those in guinea pigs. Incubation with Fe2+ induced high levels of TBARS in adrenal mitochondria and microsomes from the alpha-tocopherol deficient rats. Conversely, dietary alpha-tocopherol supplementation in rabbits increased adrenal alpha-tocopherol levels and prevented Fe2+ induced TBARS formation in mitochondria and microsomes. The results indicate that there are large species differences in adrenal susceptibility to LP in vitro and that these differences are at least partly attributable to species differences in adrenal alpha-tocopherol concentrations.

Effects of adrenocorticotropic hormone and dexamethasone on adrenal and hepatic alpha-tocopherol concentrations.

Studies were done to determine the effects of ACTH treatment on adrenal alpha-tocopherol (alpha-T) concentrations in female rats. Administration of dexamethasone (DEX) to inhibit endogenous ACTH secretion increased whole adrenal alpha-T levels as well as the fractional amount in adrenal cytosol. Adrenal ascorbic acid (AA) concentrations were unaffected by DEX. DEX treatment also had no effect on hepatic AA content but decreased alpha-T concentrations in the liver. The subcellular distribution of alpha-T in the liver was not altered by DEX. Administration of ACTH to DEX-treated animals decreased adrenal alpha-T content and restored the pattern of subcellular distribution to that seen in controls. ACTH had no effect on hepatic alpha-T concentrations or subcellular distribution. ACTH treatment also had no effect on AA concentrations in adrenals or livers. The results demonstrate that ACTH has a role in the regulation of adrenal alpha-T but the mechanism(s) involved remain to be determined. The data also indicate that glucocorticoids such as DEX directly influence hepatic alpha-T levels independent of their effects on ACTH secretion.

Identification of components of Prunus africana extract that inhibit lipid peroxidation.

Extractive and chromatographic separations were performed on V-1326, a chloroform extract from the bark of Prunus africana (also referred to as Pygeum africanum), which is used to treat the symptoms associated with benign prostate hyperplasia (BPH). The relative amounts of eleven identified constituents in crude V-1326 and in separated fractions were determined using gas chromatographic analysis. The ability of V-1326 and its separated fractions to inhibit ferrous ion-induced stimulation of lipid peroxidation in microsomal preparations from rabbit livers was evaluated. The extract, V-1326, and fractions containing high levels of myristic acid potently inhibited lipid peroxidation.

Effect of age and outlet resistance on rabbit urinary bladder emptying.

PURPOSE: To investigate the influence of age and effect of increased outlet resistance on the ability of rabbit bladders to empty in response to various methods of stimulation. MATERIALS AND METHODS: Bladders from six-month-old (young) and three-year-old rabbits (aged) were mounted in an in vitro whole organ bath system and filled with 15 ml. saline. The ability of the bladders to empty against low outlet resistance (LOR) and high outlet resistance (HOR) in response to field stimulation, bethanechol, and KCl was measured. The following parameters were measured: intravesical pressure and volume emptied. From these, flow rate, power, and external mechanical work were calculated. RESULTS: Maximum isometric pressure did not change with age. All bladders emptied with increased pressure and decreased flow rate at HOR. The young bladders generated a greater maximum power in response to bethanechol and KCl than the aged bladders at both outlet resistances, and maximum power did not change with increased resistance. The aged bladders did less work and emptied significantly less than the young bladders at the HOR. CONCLUSIONS: The aged rabbit bladders were unable to maintain the bladder contraction long enough to empty completely through an increased outlet resistance. Because maximum power remained constant when the outlet resistance was increased, it might be useful clinically to determine the emptying ability of the urinary bladder, independent of changes in outlet resistance. In addition, bladder work could be used to evaluate bladder function if the volume emptied is also taken into consideration.

The role of cyclic nucleotides in guinea-pig bladder contractility.

1. The effects of phosphodiesterase (PDE) inhibition and forskolin pretreatment on the contractile responses of guinea-pig urinary bladder strips to electrical field stimulation, carbachol, ATP and KCl were studied. 2. Inhibition of cyclic AMP-specific PDE4 isozymes by rolipram significantly reduced the contractile response of bladder strips to field stimulation. Rolipram also suppressed the contractile response to low concentrations of carbachol, but potentiated the response to high concentrations. The contractile response to ATP was significantly reduced by rolipram treatment, but that to KCl was unaltered. 3. Inhibition of cyclic GMP-specific PDE5 isozymes by zaprinast had no effects on the contractile response of bladder strips to field stimulation, ATP or KCl. Zaprinast suppressed the contractile responses to 1 microM carbachol and potentiated the response to high concentrations. 4. Contractile responses to field stimulation and to carbachol after pretreatment with the adenylyl cyclase activator, forskolin, were qualitatively similar to those caused by rolipram treatment. beta-Adrenoceptor blockade with propranolol partially reversed the inhibitory effects of rolipram on the response to field stimulation. 5. Rolipram significantly reduced the contractile response of bladder strips from sensitized guinea-pigs to ovalbumin challenge, but zaprinast was ineffective. PDE inhibition had similar effects on the responsiveness of control and of sensitized guinea-pig bladder strips to field stimulation, carbachol, ATP and KCl. 6. The data suggest that the contractile response of guinea-pig bladder strips can be modified by increases in cyclic AMP levels.

Calcium regulation of urinary bladder function.

PURPOSE: To investigate the effect of independently inhibiting calcium influx from extracellular sources and calcium release from intracellular stores on the ability of the urinary bladder to generate pressure and empty. MATERIALS AND METHODS: Rabbit bladders were mounted in an in vitro whole organ bath and filled with 15 ml. saline. Each bladder was incubated separately in Tyrode's solution, with diltiazem (10 microM), to block extracellular calcium influx, or with thapsigargin (40 microM) and ryanodine (80 microM), to block the uptake and release of calcium from the sarcoplasmic reticulum. The bladder was then stimulated isometrically with field stimulation (32 Hz), and to empty with field stimulation and with bethanechol (250 microM), independently. During stimulation, transmural pressure and volume emptied were measured. From these, flow rate, power, and external mechanical work were calculated. RESULTS: In the presence of diltiazem, the time to maximal pressure decreased while the rate of pressure generation increased. This results from increased participation of intracellular calcium release, which occurs rapidly and near the smooth muscle filaments, decreasing the diffusion time. In the presence of thapsigargin and ryanodine the maximal rate of pressure generation was decreased, due to the increased diffusion time required for calcium to move to the muscle filaments from extracellular sites. CONCLUSIONS: The current study demonstrates that bladder pressure generation and emptying are dependent upon both an influx of calcium through L-type calcium channels (inhibited by diltiazem) and the stimulated release of calcium from the SR (inhibited by thapsigargin and ryanodine).

Etiology of bladder dysfunction secondary to partial outlet obstruction. Calcium disregulation in bladder power generation and the ability to perform work.

Similar to all smooth muscle, contraction of urinary bladder smooth muscle depends upon a rise in intracellular free calcium, which results from both calcium influx from extracellular spaces and calcium release from intracellular stores (calcium-induced calcium release [CICR]). Recent studies from our laboratory demonstrate that one of the major dysfunctions induced by partial outlet obstruction is a marked reduction in the participation of CICR (from IP3-sensitive and IP3-insensitive sites on the sarcoplasmic reticulum [SR]) during stimulation by both field stimulation (neurotransmitter release) and by direct muscarinic stimulation (bethanechol). Experimentally, rabbit urinary bladder function can be evaluated using an isolated whole bladder model. The current study utilizes the isolated whole bladder model to compare the effects of partial outlet obstruction on the responses to field stimulation and bethanechol with the responses of normal bladders following inhibition of CICR with the combination of thapsigargin+ryanodine. The parameters measured include the magnitude of pressure generation, rate of pressure generation, time to maximal pressure generation, percent volume emptied, rate of emptying, power generation, and work performed (both total work and work per ml emptied). Partial outlet obstruction resulted in virtually identical alterations in the responses of the bladder to stimulation (field stimulation and bethanechol) to that of inhibition of CICR by thapsigargin+ryanodine. Thus, these studies provide strong support for our hypothesis that the contractile dysfunctions secondary to partial outlet obstruction are directly related to a marked inhibition of the CICR component of the response to both field stimulation and bethanechol.

Effect of partial outlet obstruction on 14C-adenine incorporation in the rabbit urinary bladder.

Bladder outlet obstruction induces severe changes in urinary bladder function and metabolism. These changes are characterized by significant reductions in the ability of the in vitro whole bladder to generate pressure and to empty. Metabolically, partial outlet obstruction induces a shift from oxidative to anaerobic metabolism. The decreased oxidative metabolism is mediated in part by significant decreases in mitochondrial substrate metabolism, which in turn is correlated with decreased activity of 2 important mitochondrial enzymes: citrate synthase and malate dehydrogenase. The present study was designed to evaluate mitochondrial function by studying the incorporation of 14C-adenine into high-energy phosphates (ATP, AMP, and ADP). Mild partial outlet obstructions were created by surgically placing silk ligatures loosely around the bladder neck. The results of these studies demonstrate that after 60 min incubation in oxygenated medium containing glucose + 1uCi14C-adenine, 1) There was no significant differences in the total AMP, ADP, and ATP concentrations measured in bladders taken from controls, 7- and 14-day obstructed rabbits; 2) there was no effect of obstruction on either the concentration of 14C-AMP in the tissue or in the ratio of hot to cold AMP; and 3) there was a 50% decrease in the concentration of 14C-ADP and a 70% decrease in the concentration of 14C-ATP in the bladder smooth muscle obtained from obstructed tissue (from both 7- and 14-day obstructions) compared to concentration in the control bladder smooth muscle. These results confirm the previous finding that obstruction did not reduce the rate of incorporation of adenine to AMP within the obstructed bladder smooth muscle and extends these studies to identify a significant reduction in the synthesis of both ADP and ATP. These results support the hypothesis that partial outlet obstruction induce a major dysfunction in mitochondrial function, both in the ability to oxidize substrates and in the ability to generate ATP.

Ability of obstructed bladders to empty is dependent on method of stimulation.

PURPOSE: To correlate pharmacologic changes that occur in the bladder after a partial outlet obstruction with the bladder's ability to perform work and empty. METHODS: After 2 weeks of partial outlet obstruction, rabbit bladders were stimulated in vitro both isovolumetrically [field stimulation (FS)] and to empty (FS, bethanechol, and KCl). RESULTS: The obstructed bladders were separated into two groups according to their ability to empty when stimulated with FS. Compensated bladders were those that could empty as much as controls. Decompensated bladders emptied significantly less than controls. With FS and bethanechol, the compensated obstructed bladders showed no difference from the control bladders in their ability to empty. In contrast, with KCl, the compensated bladders generated significantly less pressure, performed less work, and emptied less than controls. When the decompensated bladders were stimulated with all three types of stimulation, all parameters, including emptying ability, were significantly decreased. CONCLUSIONS: The reduction in the response of compensated bladders to KCl stimulation suggested that the initial defects to the bladder after an outlet obstruction involved the interaction of smooth muscle proteins with calcium and ATP. In contrast, the response of decompensated bladders to all three forms of stimulation was equally reduced, suggesting that the degenerative processes were directly related to significant cellular damage to metabolic processes involved in energy synthesis, storage, and utilization.