K.-E. Andersson

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 Prazosin in Patients with Benign Prostatic Obstruction

Prazosin, a selective alpha-1-adrenoceptor blocker, was used in a double-blind crossover study in 20 men with benign prostatic obstruction. Maximum and average flow rates increased, and residual volume and obstructive symptoms were reduced. Voiding pressure parameters, bladder capacity and irritative symptoms did not change significantly. No side effects were noted. We conclude that prazosin seems to be an effective therapeutic alternative in patients with benign prostatic obstruction.

Effects of inhibition of the L-arginine/nitric oxide pathway in the rat lower urinary tract in vivo and in vitro

1 The present study was performed to investigate how blockade of the l‐arginine/nitric oxide (NO) pathway influences the function of the lower urinary tract in vivo, as studied by cystometry in conscious rats and in vitro, in isolated muscle preparations from the rat detrusor and urethra. 2 l‐NG‐nitro arginine methyl ester (l‐NAME), 10 and 20 mg kg−1, administered intra‐arterially, decreased micturition volume and bladder capacity, and increased spontaneous bladder contractions. d‐NAME (20 mg kg−1) had no effect. No changes in the urodynamic parameters were recorded if l‐NAME (20 mg kg−1) was administered in combination with l‐arginine (200 mg kg−1). 3 Cystometries performed after intra‐arterial administration of sodium nitroprusside (SNP) (3 mg kg−1) and 3‐morpholino‐sydnonimin hydrochloride (SIN‐1, 2 mg kg−1) showed a decrease in bladder capacity, micturition volume and threshold pressure. SIN‐1, but not SNP, induced spontaneous bladder contractions. 4 Isolated precontracted urethral preparations responded to electrical stimulation with a frequency‐dependent tetrodotoxin‐sensitive relaxation. l‐NAME (10−4 m), but not d‐NAME, reduced the maximal relaxation to 31 ± 8% (n = 8) of the response prior to drug administration. The inhibition induced by l‐NAME was completely reversed by l‐arginine (10−3 m). SNP (10−8−10−4 m), SIN‐1 (10−6−3 × 10−4 m) and NO (10−5−10−3 m; present in acidified solution of NaNO2), caused relaxation (93–100%) of urethral preparations. l‐NAME did not affect these relaxations. 5 Detrusor strips contracted by carbachol or K+ showed contractions in response to electrical stimulation, even when pretreated with α,β‐methylene ATP and/or atropine. Small relaxations (14–41%) of detrusor strips were evoked by SNP (10−6−10−4 m), SIN‐1 (10−5−3 × 10−4 m) and NO (10−5−10−3 m). Electrically (20 Hz) induced contractions of the detrusor muscle were unaffected by addition of l‐NAME (10−6−10−4 m) or l‐arginine (10−3 m). 6 The present results suggest that the l‐arginine/NO pathway is of functional importance for the bladder outlet region, but that its role in the detrusor is questionable. They also suggest that the site of action of l‐NAME for inducing bladder hyperactivity in the rat is the outlet region rather than the detrusor muscle.

Characterization of inhibitory neurotransmission in the isolated corpus cavernosum from rabbit and man.

1. NG‐nitro‐L‐arginine (L‐NOARG, 10(‐4) M), an inhibitor of nitric oxide (NO) synthesis, had no contractile effect on isolated preparations of rabbit and human corpus cavernosum at baseline tension, but increased tension in preparations contracted by noradrenaline (rabbit 10(‐5) M, man 3 x 10(‐7)‐3 x 10(‐6) M) or K+ (rabbit 60 mM). 2. Electrical field stimulation (supramaximal voltage, 0.8 ms pulses, 5 s train duration, 0.5‐35 Hz) of rabbit and human corpus cavernosum preparations contracted by noradrenaline (rabbit 10(‐5) M, man 3 x 10(‐6) M) or endothelin‐1 (rabbit 10(‐8) M) produced relaxations that were sensitive to tetrodotoxin (10(‐6) M), and dependent on the frequency and number of pulses delivered. L‐NOARG (10(‐6)‐10(‐4) M), but not NG‐nitro‐D‐arginine (D‐NOARG, 10(‐6)‐10(‐4) M), inhibited electrically induced relaxations in a concentration‐dependent manner, and at 10(‐4) M the relaxations were virtually abolished. L‐Arginine (10(‐3) M), but not D‐arginine (10(‐3) M), partly reversed the inhibitory effect of L‐NOARG (10(‐4) M). In rabbit corpus cavernosum preparations, as with Methylene Blue (3 x 10(‐5) M), an inhibitor of the soluble guanylate cyclase, and haemoglobin (10(‐5) M), sequestering NO in the extracellular space, significantly reduced electrically evoked relaxations. Scopolamine (10(‐6) M) had little or no effect on relaxations induced by electrical field stimulation. 3. Preparations of rabbit and human corpus cavernosum contracted by noradrenaline (rabbit 10(‐5) M, man 3 x 10(‐6) M) were relaxed by carbachol (10(‐9)‐10(‐4) M) in a concentration‐dependent manner. Scopolamine (10(‐6) M) and L‐NOARG (10(‐4) M) abolished, and Methylene Blue (3 x 10(‐5) M) and haemoglobin (10(‐5) M) greatly reduced, the carbachol‐induced relaxation, while D‐NOARG (10(‐4) M) had no significant effect. 4. In rabbit corpus cavernosum preparations contracted by noradrenaline (10(‐5) M), L‐NOARG (10(‐4) M) had no significant effect on relaxations induced by vasoactive intestinal polypeptide (10(‐6) M). 5. SIN‐1 (3‐morpholino‐sydnonimin hydrochloride, 10(‐8)‐3 x 10(‐4) M), which spontaneously liberates NO, relaxed preparations of rabbit and human corpus cavernosum contracted by noradrenaline (rabbit 10(‐5) M, man 3 x 10(‐6) M) or endothelin‐1 (rabbit 10(‐8) M, man 3 x 10(‐9) M) in a concentration‐dependent way.(ABSTRACT TRUNCATED AT 400 WORDS)

Nitric oxide synthase and nitric oxide-mediated effects in lower urinary tract smooth muscles

SummaryIn the lower urinary tract smooth muscles, both excitatory and inhibitory non-adrenergic, non-cholinergic (NANC) nerves and neurotransmission can be demonstrated. An inhibitory, relaxation-mediating system may serve not only the detrusor, the trigone, and the bladder neck/urethra, but may also be of importance for their integrated function. Available data suggest that nitric oxide synthase (NOS) is localized in nerve fibres of the lower urinary tract, preferably in the outflow region, and evidence has accumulated that l-arginine-derived nitric oxide (NO) is responsible for the main part of the inhibitory NANC response. Coinciding localization of NOS positive nerves with nerves expressing acetylcholine esterase, vasoactive intestinal peptide, and neuropeptide Y, suggests that NO may have a role both as a directly acting transmitter and as a modulator of efferent neurotransmission. In addition, NO may be involved in afferent neurotransmission. Theoretically, NO released from nerves in the detrusor, could be one factor keeping the bladder relaxed during filling. However, the detrusor has a low sensitivity to NO and agents acting via cyclic GMP, which makes it less likely that NO has a role as a relaxant neurotransmitter. This does not exclude that NO may modulate the effects of other transmitters, or that it has an afferent function. NO effectively relaxes isolated smooth muscle preparations from the outflow region, suggesting that it may be involved in the decrease in intraurethral pressure associated with normal micturition, and with the excessive urethral pressure variations (“unstable urethra”), which may be associated with certain voiding disturbances in women. The l-arginine/NO system may also control afferent activity in the outlet region, where lack of NO may lower the threshold for afferent firing leading to bladder instability. Another possible site where the l-arginine/NO pathway can have a functional role is in the urethral lamina propria. Here, NO-mediated relaxation may influence the “inner urethral softness”, and thereby the sealing function of the urethral mucosa. However, it should be stressed that the functional importance of the l-arginine/NO system in the central and peripheral pathways controlling micturition remains to be established.

Adrenoceptor and Cholinoceptor Mediated Responses of the Isolated Human Urethra

Smooth muscle preparations from various parts of the isolated urethra and the urethrovesical junction were obtained from male and female patients undergoing total cysto-urethrectomy because of bladder malignancy. The preparations were suspended in Krebs solution (37°C) bubbled with carbogen. Isometric tension was recorded. Twenty-nine out of 42 drug-responsive preparations exhibited a spontaneous contractile activity. This was unaffected by tetrodotoxin, atropine, and phenoxybenzamine, suggesting it was of myogenic origin. Noradrenalin contracted preparations from all parts of the urethra, including the urethrovesical junction, in a concentration-related way. No differences in the sensitivity to noradrenalin between different parts of the male or female urethra could be established. The noradrenalin-induced effects were inhibited by phenoxybenzamine, suggesting that they were mediated via α-adrenoceptors. Adrenalin, phenylephrine, ephedrine, and norephedrine had contracting effects that could be blocked b...

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.

The effects of long-term treatment with norephedrine on stress incontinence and urethral closure pressure profile.

Twenty-five women with stress incontinence of urine were given an alpha-adrenoceptor stimulating agent (norephedrine) and a placebo during respective 14-day periods according to a double-blind cross-over schedule. The results were classified as the patients own assessment of therapeutic effect and as change in urethral closure pressure profile measured by a microtransducer catheter. Norephedrine had a significant therapeutic effect on the symptom stress incontinence and produced significant increase in maximum urethral pressure and maximum urethral closure pressure in the lithotomy and the erect position. Reduction of incontinence was associated with increase in maximum urethral closure pressure. The sum therapeutic effect was of moderate degree.

Muscarinic Receptor Stimulation of Phosphoinositide Hydrolysis in the Human Isolated Urinary Bladder

The stimulatory action of carbachol and acetylcholine (ACh) on phosphoinositide turnover, as well as their contractile effects, were investigated in human isolated detrusor muscle. Carbachol, and ACh in combination with 10(-7) M physostigmine, induced increases in phosphoinositide turnover. However, at all the concentrations tested, carbachol was more effective than ACh (plus physostigmine), and at the highest concentration used (10(-4) M), the difference was significant (p less than 0.05). Also in a Ca(2+)-free medium containing the chelator EGTA (10(-4) M), both agonists (10(-4) M) induced small but distinct increases in phosphoinositide breakdown. Carbachol and ACh contracted the detrusor preparations concentration-dependently, and the responses were almost identical when ACh was combined with 10(-7) M physostigmine. In Ca(2+)-free medium the agonists elicited a moderate but concentration-dependent contractile response at high concentrations. The results show that muscarinic receptor agonists stimulate phosphoinositide turnover in the human bladder. Possibly, this effect is coupled to multiple muscarinic receptor subtypes. More studies are required to elucidate to what extent phosphoinositide breakdown participates in the contractile activation of this tissue.