A. Malmgren

Cystometrical Evaluation of Bladder Instability in Rats with Infravesical Outflow Obstruction

Cystometries were performed in normal rats and in rats with bladder hypertrophy due to infravesical outflow obstruction. Investigations were performed in the presence and absence of anesthesia. pentobarbital anesthesia depressed spontaneous contractile activity in the bladder and the micturition reflex, thereby making measurements of other variables, such as bladder capacity and residual volume, impossible. In conscious animals infravesical outflow obstruction led to development of increased bladder capacity, marked residual volume, and unstable detrusor contractions. The model seems to be well suited for further evaluation of the mechanisms involved in the development of detrusor instability and the responses to pharmacological treatment.

Effects of Pinacidil and Cromakalim (BRL 34915) On Bladder Function in Rats with Detrusor Instability

Normal rats as well as rats with bladder hypertrophy secondary to outflow obstruction were investigated cystometrically before and after administration of the potassium channel openers pinacidil or cromakalim one mg./kg. orally. In normal rats cromakalim decreased micturition pressure by 15 +/- 6%. A diminished micturition pressure was also seen after pinacidil (by 18 +/- 8%) but this did not achieve statistical significance. Further, no clear-cut effects on bladder capacity, residual volume, basal bladder pressure, threshold pressure, bladder compliance or on bladder wall tension were seen in this group of rats neither in the presence of pinacidil nor cromakalim. Rats with bladder hypertrophy exhibited a significant bladder instability during cystometrical investigations. The mean amplitude of the spontaneous bladder contraction exceeded 20 cm. H2O prior to micturition. Administration of pinacidil and cromakalin decreased the spontaneous contractions to 26 +/- 12% and 22 +/- 7%, respectively, of that seen in the absence of the drugs. Furthermore, pinacidil decreased micturition pressure by 61 +/- 12%. Also cromakalim decreased micturition pressure (by 27 +/- 13%) but this effect did not achieve statistical significance. After both pinacidil and cromakalim these rats tended to develop residual urine. In accordance with the results in normal rats pinacidil and cromakalim showed no effects on bladder capacity, basal bladder pressure, threshold pressure, bladder compliance or on bladder wall tension in rats with bladder hypertrophy. The findings of an almost complete disappearance of spontaneous bladder contractions in rats with bladder instability and a remaining voiding ability after administration of pinacidil or cromakalim suggest that potassium channel openers may be a therapeutic alternative in the treatment of bladder instability associated with outflow obstruction.

On the Reversibility of Functional Bladder Changes Induced by Infra Vesical Outflow Obstruction in the Rat

Rats were subjected to infravesical outflow obstruction for six weeks. The bladder function was followed by cytometrical and in vitro investigations and by recordings of micturition pattern before and after removal of the obstruction. Cytometrical investigations showed that outflow obstruction for six weeks induced a bladder instability. Further, in the presence of obstruction the micturition pressure was large as was the bladder capacity and the rats had residual urine. After removal of the obstruction the bladder function rapidly normalized. The bladder instability disappeared within one week, bladder capacity decreased as did the micturition pressure. Moreover, only a minor amount of residual urine was present post-obstruction. In vitro investigation showed that the response to carbachol and to electrical stimulation was similar in normal and obstructed bladders. However, after removal of the obstruction a supersensitivity to carbachol as well as to electrical stimulation had developed. Obstructed bladders showed a markedly decreased response to substance P. The sensitivity to substance P was rapidly enhanced post-obstruction and after four days the response was restored to the control level. The present study shows that the bladder function in rats with infravesical outflow obstruction rapidly normalized after removal of the obstruction. The disappearance of the bladder instability despite the developed supersensitivity to muscarinic receptor stimulation supports the opinion that the bladder instability is not of muscarinic origin.

Cystometrical and in vitro evaluation of urinary bladder function in rats with streptozotocin-induced diabetes

Micturition pattern and cystometric characteristics were determined in control rats, and in rats with streptozotocin-induced diabetes (six weeks duration). The diabetic rats had an increased frequency of micturition, an increased micturition volume, and an increased 24 hr. urinary output. The cystometry showed that the diabetic bladders had an increased compliance and a higher threshold volume for initiating a micturition reflex. No spontaneous rhythmic contractions were seen during the filling phase, and no residual urine could be detected. While micturition pressure increased, the micturition time was virtually unaltered. In vitro a right-ward shift for passive and active length-tension relations was noted. The observed changes in cystometric characteristics and length-tension relations might probably be explained on the basis of adaptive changes to the increased diuresis involving both sensory and motor control of the urinary bladder.

Bladder function in rats with short- and long-term diabetes; effects of age and muscarinic blockade

The development of alterations in urinary bladder function was studied in rats during six months of streptozotocin-induced diabetes. The results were compared with those obtained in age-matched controls. The bladders from the control rats developed with increasing age an increased micturition volume, a decreased micturition interval, and increased bladder compliance and capacity despite an unaltered bladder weight and unaltered passive and active length-tension relations. The effects of muscarinic blockade were somewhat more pronounced in the older control rats. Following streptozotocin 24 hour diuresis increased rapidly to stabilize within two weeks at a level 15 times higher than the original. This was accomplished initially by an increase in the micturition frequency and then gradually by an increased micturition volume. After six weeks bladder weight had increased more than twofold and did not increase further with time. Despite this both micturition volume and bladder capacity increased from six weeks to six months of diabetes. The diabetic bladders had at low frequencies of stimulation a higher resistance to scopolamine than their age-matched controls. At higher frequencies the resistance to muscarinic blockade showed a similar decrease with age as for the controls. The more pronounced decrease in micturition pressure following atropine treatment in six weeks diabetic rats thus suggests an increased excitation frequency during micturition. No supersensitivity to carbachol was found even after six months of diabetes.

Effects of Cromakalim (BRL 34915) and Pinacidil on Normal and Hypertrophied Rat Detrusor in Vitro

Normal and hypertrophied rat detrusor were investigated in vitro with regard to effects of the K(+)-channel openers pinacidil and cromakalim. Both drugs abolished spontaneous contractile activity and induced a relaxation of normal and hypertrophied detrusor preparations. In both types of preparation, contractions elicited by K+, carbachol or electrical field stimulation were depressed in the presence of the K(+)-channel openers. Responses induced by K+ or electrical stimulation were more reduced in the hypertrophied than in the normal detrusor. Both K(+)-channel openers increased the efflux of 86Rb+ in a concentration-dependent way and this increase was similar in normal and hypertrophied detrusor. If applicable to man, this data suggest that K(+)-channel openers may be effective in the treatment of bladder instability secondary to outflow obstruction.

Urinary Bladder Function in Rats with Hereditary Diabetes Insipidus; A Cystometrical and in Vitro Evaluation

Bladder function was investigated in female rats with hereditary diabetes insipidus (DI) and in healthy controls, in vivo by means of recordings of micturition pattern and cystometry, and in vitro in organ bath experiments. Rats with DI exhibited bladder hypertrophy, the weight of the bladder in these rats being two times that of controls. Recordings of micturition pattern showed that DI-rats had an increased 24 hour diuresis and micturition volume, and decreased micturition interval in comparison with controls. Cystometry recordings revealed increased bladder capacity and micturition volume in DI-rats. However, in these rats basal bladder pressure and threshold pressure were lower than in controls. No significant changes in micturition pressure or bladder compliance were observed, and none of the rats had residual urine. In organ bath studies, a lower maximal response to electrical field stimulation was obtained in bladder strips from DI-rats, than in the control strips, when expressed relative to the response elicited by K(+)-solution. When activated by field stimulation, the DI-bladder strips and the control strips had similar sensitivity to muscarinic receptor blockade with scopolamine at all stimulation frequencies. The sensitivity to carbachol was similar in the two groups. The results suggest that the increased functional demands of DI on the detrusor do not result in major changes pre- or postjunctionally. Further, several of the previously reported urinary bladder changes observed in rats with diabetes mellitus (DM) are similar to those now reported in rats with DI, emphasizing the importance of an increased diuresis per se for the development of alterations in bladder function. However, in contrast to the findings in DM rats, the sensitivity to electrical stimulation of nerves during blockade of muscarinic receptors was similar in DI-rats and their controls. This supports our previous suggestion that the increased resistance to muscarinic receptor blockade of the bladder in DM-rats at low stimulation frequencies is induced by the disease (diabetes mellitus) as such and not by the increased diuresis.

Effects of pinacidil on bladder muscle.

SummaryInfravesical outflow obstruction and bladder hypertrophy are often associated with bladder hyperactivity causing frequency, urge and urinary incontinence. This hyperactivity may be due to a supersensitivity to depolarising stimuli. Drugs that inhibit smooth muscle activity by opening K+channels, resulting in hyperpolarisation, would therefore seem to be an attractive therapeutic principle. Pinacidil is an effective vasodilator classified as a K+channel opener. The drug has been shown to effectively depress spontaneous contractile activity, the contractions induced by low (< 40 mmol/L) concentrations of K+, carbachol and by electrical stimulation of nerves in isolated normal human bladder tissue and also in normal and hypertrophied rat bladder. The effect was more pronounced in hypertrophied detrusor. Pinacidil in concentrations inhibiting muscle activity also increased the efflux of86Rb in bladder tissue. In vivo pinacidil suppressed spontaneous contractile activity in rats with infravesical bladder obstruction and detrusor hypertrophy. The findings make K+channel openers an interesting, potentially useful therapeutic principle in hyperactivity associated with bladder hypertrophy.

Effects of Variations in Extracellular pH on Spontaneous Contractile Activity and Response to Nerve Stimulation in Smooth Muscle from Rat Urinary Bladder

The effects of variations in extracellular pH have been studied on rat detrusor muscle in vitro. At pH 7.4 a continuous low amplitude spontaneous contractile activity was found. At pH 6.75 the contractions became more regular with periods of relaxation between the contractions which had increased in amplitude. At pH 7.85 the reverse was found. The results are interpreted as a membrane effect of pH. No effect of pH on amplitudes of high-K(+)-induced contractures was found. Carbachol dose-response relations and maximal contraction amplitude to carbachol was similar at pH 7.4 and 6.75. A significant depression in response to nerve stimulation was, however, noted at pH 6.75. We suggest that, while the force output of the activated detrusor smooth muscle cell is unaffected by changes in extracellular pH, a prejunctional inhibition of nerve induced contraction might occur at low pH.