The Effect of Tamsulosin on the RestingTone and the ContractileBehaviouroftheFemaleUrethra:AFunctional Urodynamic Study in Healthy Women

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1 European Urology European Urology 46 (24) The Effect of Tamsulosin on the RestingTone and the ContractileBehaviouroftheFemaleUrethra:AFunctional Urodynamic Study in Healthy Women André Reitz a,*, Axel Haferkamp b, Tatiana Kyburz a, Peter A. Knapp a, Björn Wefer a, Brigitte Schurch a a Neuro-Urology, Swiss Paraplegic Center, Balgrist University Hospital, Forchstrasse 34, 88 Zurich, Switzerland b Department of Urology, University of Heidelberg, Germany Accepted 16 April 24 Available online 4 May 24 Abstract Aims: The aim of this functional urodynamic experiment was to study the effect of the selective a1 A -blocker tamsulosin on the urethral pressure in healthy human females and assessed first the resting urethral pressure and second the urethral contractility in response to magnetic stimulation of the sacral roots. Methods: 11 healthy female subjects gave their written informed consent and were included. A microtip pressure transducer catheter was inserted into the bladder and three baseline urethral pressure profiles were obtained. Another three urethral pressure profiles were recorded while magnetic single pulse stimulation of the sacral roots was performed above the motor threshold of the pelvic floor to evoke reproducible urethral contractions. Then the subjects received.4 mg of tamsulosin and the entire protocol was repeated 6 hours after drug administration. Cardiovascular monitoring was obtained during the baseline and follow-up measurements. Mean and maximal urethral pressure values calculated over the entire urethra, mean pressure values calculated over the proximal, middle and distal third of the urethra and the pressure amplitudes to magnetic stimulation at baseline were statistically compared to the follow-up measurements with tamsulosin. Results: The oral administration of tamsulosin did not change the systemic blood pressure, but did significantly reduce the mean and maximal urethral pressure acquired over the entire urethra. When the proximal, middle and distal third of the urethra were analysed separately, there was a significant pressure reduction in all three segments. Amplitudes of the urethral contractions evoked by sacral magnetic stimulation remained unchanged after tamsulosin. Conclusions: These data show a significant relaxing effect of tamsulosin on the resting urethral tone in healthy females in vivo. These results may suggest tamsulosin as a new pharmacological approach to treat urinary retention due to overactive or non-relaxing urethra in women. # 24 Elsevier B.V. All rights reserved. Keywords: Tamsulosin; Urethra; Muscle relaxation 1.Introduction Chronic urinary retention in young women as a part of a syndrome associated with polycystic ovaries has been described in 1988 by Fowler et al. [1]. Women * Corresponding author. Tel. þ ; Fax: þ address: areitz@balgrist.unizh.ch (A. Reitz). affected by chronic urinary retention usually present with impaired detrusor contractility, bladder outflow obstruction or even with a combination of both problems. Since an abnormal electromyographic activity in the external urethral sphincter has been found, a functional bladder outflow obstruction by a non-relaxing or overactive sphincter mechanism is thought to be the underlying reason [2] /$ see front matter # 24 Elsevier B.V. All rights reserved. doi:1.116/j.eururo

2 236 A. Reitz et al. / European Urology 46 (24) In these women treatment modalities basically rely on the intermittent self catheterisation, however the goal in these patients would be to restore voluntary voiding with tolerable amounts of residual urine. Sacral neuromodulation has been tried and was found to be effective to restore the ability to void voluntarily in many patients [3]. Although the injection of botulinum toxin into the external urethral sphincter has been shown to improve the ability to void in some women with urinary retention [4], a study in women with abnormal sphincter electromyography did not show a symptomatic benefit [5]. Only one study tried a-blockers in chronic urinary retention with some success [6], however a pharmacological treatment option to close the gap between catheterisation and invasive procedures would be of value for this patient population. There is now a considerable amount of experimental data from animal and human studies to show that a-blocking agents have the capacity to relax the urethral tone. The aim of this functional urodynamic experiment was to study the effect of the selective a1 A -blocker tamsulosin on the urethral pressure in healthy human females and assessed first the resting urethral pressure and second the urethral contractility in response to magnetic stimulation of the sacral roots. 2.Subjects and methods The experimental protocol was approved by the local ethics committee. 11 healthy female subjects (mean age 24 years, range 2 29 years) gave a written informed consent and were included in the study. None of the subjects had a history of recurrent urinary tract infections, stress or urge urinary incontinence or was taking any medication known to influence the lower urinary tract. Immediately before and two days after the experiment, urine screening tests were done to exclude urinary tract infection. Prior to the study a pregnancy test was obtained which was negative in all participants Urodynamic measurement Prior to the experiment the subjects were asked to empty the bladder. While the subjects laying supine on a fluoroscopy table a microtip pressure transducer catheter was inserted into the bladder. Using a commercially available system the catheter was pulled through the urethra with a standardised velocity of 1 millimetre per second and a 3 o clock transducer orientation. When the pressure transducer left the external urethral ostium, pulling was stopped and the catheter was placed into the bladder again for the next measurement Magnetic stimulation The magnetic impulses were generated by a Dantec 1 MagPro X magnetic stimulator and applied by a liquid cooled magnetic coil Dantec 1 MCF-125. The maximum magnetic field strenght is 1.8 Tesla. For stimulation the coil was positioned under the subject in midline next to the sacrum. urethral pressure (cm H2) s time (sec) Fig. 1. Three baseline urethral pressure profiles at rest reproducibility of the urethral pressure recordings (original data from subject 1). Prior to the experiment the individual motor threshold of the subjects was determined. Single magnetic pulses with low intensities were applied to allow the subjects to get used to the magnetic stimulation. The strenght of the applied magnetic field started at 2% of the maximum stimulator output and was adapted to the individual pain threshold. With special attention to the pain threshold of the subjects the stimulation strength was increased slowly until a clear motor response of the external urethral sphincter (sharp pressure rises) occurred. In all subjects the stimulation at the motor threshold of the pelvic floor was tolerated without any discomfort. The individual motor threshold determined for every subject was then used during the baseline and follow-up measurements to evoke reproducible contractions of the external urethral sphincter Experimental procedure The baseline protocol included six urethral pressure profiles under continuous cardiovascular monitoring. Three urethral pressure profiles were performed without any intervention at rest (Fig. 1). During the remaining three profiles single pulse magnetic stimulation was applied to the sacral roots. Then the subjects received.4 mg tamsulosin while heart rate and blood pressure were monitored continuously for a period of 1 hour. According to pharmacodynamical considerations the follow-up measurements were done identically to the baseline protocol 6 hours after drug administration because the formulation used reaches the maximum plasma level 6 hours after oral intake Data analysis The urethral pressure profiles were recorded with a Hz sampling rate and further analysed using the Soleasy TM -software package (ALEA Solutions, Switzerland). Four steps of further analysis were done. To exclude a systemic effect of tamsulosin on the blood pressure and therefore on the urethral pressure, heart rate and blood pressure values measured at baseline were compared to those measured during the follow-up measurement by analysis of variance for repeated measures (level of significance p < :5). To evaluate tamsulosin induced urethral pressure changes of the entire urethra mean and maximal pressure values calculated of the entire urethral length at baseline were compared to those values after tamsulosin administration by analysis of variance for repeated measures (level of significance p < :5). To evaluate urethral pressure changes in specific urethral segments induced by tamsulosin the functional urethral length was divided into three sections, the proximal, the middle and the distal

3 A. Reitz et al. / European Urology 46 (24) third. Within the single sections the mean urethral pressure values at baseline were compared to those values after tamsulosin administration by analysis of variance for repeated measures (level of significance p < :5). To evaluate the effect of tamsulosin on the urethral contractility the amplitudes of the urethral pressure spikes induced by magnetic stimulation of the sacral root were measured. Then baseline values were compared to those measured with tamsulosin by analysis of variance for repeated measures (level of significance p < :5). 3.Results The experimental procedure was well tolerated by all studied subjects. Each the baseline and the follow-up measurements took around 3 minutes to perform. Urine screening tests were all normal before as well as two days after the experiment. None of the subjects felt any pain or discomfort during single pulse magnetic stimulation. 4 out of the 11 studied subjects reported a light tiredness at the follow-up 6 hours after tamsulosin intake Cardiovascular monitoring In the studied population of healthy female volunteers tamsulosin had no effect on the systemic blood pressure. The mean systolic blood pressure at baseline (12.93 mmhg, S.D. 8.66) did not differ from systolic blood pressure at follow-up ( mmhg, S.D mmhg). There was also no change between the mean diastolic blood pressure at baseline (66.74 mmhg, S.D. 7.53) and follow-up (65.39 mmhg, S.D. 6.49). pressure (cmh2o) p< p mean entire urethra p< p maximal entire urethra p< The effect of tamsulosin on the urethral resting tone (Fig. 2) The mean urethral pressure calculated over the entire urethra length were significantly lower at the follow-up compared to the baseline measurements ( p < :1). The maximal urethral pressures measured with tamsulosin were significantly lower than those at baseline ( p < :1). For details see Fig The effect of tamsulosin on different urethral segments When the mean urethral pressures were analysed for the three thirds of the functional urethral length separately there was a significant difference between the mean pressures measured at baseline and follow-up with tamsulosin (proximal urethral third: p < :5, middle urethral third: p < :1, distal urethral third: p < :32). For details see Fig The effect of tamsulosin on the urethral contractility (Fig. 4) When the amplitudes of the urethral pressure spikes evoked by magnetic stimulation of the sacral roots at baseline were compared to those evoked after tamsulosin there was no significant difference neither in the proximal urethral third ( p < :663), nor in the middle third ( p < :2148) nor in the distal third ( p < :912) p mean proximal third Baseline p< p mean middle third with Tamsulosin p< p mean distal third Fig. 3. Urethral pressures (mean and standard deviation bars) at baseline and 6 hours after.4 mg tamsulosin calculated over the entire urethra (mean and maximal pressure) and the proximal, middle and distal third separately (urethral pressure profiles n ¼ 66) Urethral pressure responses to sacral magnetic stimulation urethral pressure (cm H2O) 5 UPP baseline 1 s UPP tamsulosin time (sec) Fig. 2. Urethral pressure profile (UPP) at baseline and during follow-up 6 hours after.4 mg tamsulosin (original data from subject 2). urethral pressure (cmh2) 5 UPP baseline 1 s UPP tamsulosin time (sec) Fig. 4. Two urethral pressure profiles (UPP) under single pulse magnetic stimulation of the sacral roots for both conditions during baseline and follow-up 6 hours after.4 mg tamsulosin; unchanged amplitudes of the pressure peaks (original data from subject 3).

4 238 A. Reitz et al. / European Urology 46 (24) Discussion To our knowledge this is the first urodynamic controlled study to show that the selective a1 A -antagonist tamsulosin has a significant relaxing effect on the urethral tone in healthy females in vivo. Our data show clearly that the resting tone of the female urethra is lowered significantly while the contractility in response to as sacral magnetic stimulation is not influenced by the drug. The relaxing effect of tamsulosin on the urethra was significant in terms of mean urethral pressure and maximal urethral closure pressure. Additionally, a significant urethral relaxation could be also shown in the proximal, middle and distal urethral third separately. Bladder neck and urethra receive noradrenergic excitatory impulses from the rostral lumbar spinal cord which travel through the sympathetic chain ganglia and then via the hypogastric nerves to the pelvic ganglia [7]. This sympathetic impute is mediated by a1-adrenergic receptors [8]. There is now a considerable amount of experimental data in animals to show that administration of a1-antagonists suppress reflex sympathetic activity in the lower urinary tract [9,1]. Radioligandbindingassaysofa1-adreoceptors in rats, rabbits, dogs and humans revealed that the a1 A -subtype is predominant in the urethra [11]. A study in male and female rabbits compared the gender specific density and affinity of a1-adrenoceptors and found no sex difference for a1-adrenoceptors [12]. Thismay suggest that in both males and females similar a1- adrenergic mechanisms control the urethral tone. In the female animals the a1 A -adrenoceptor subtype was found in the canine [13] andinthepigurethra[14]. Using tamsulosin for blocking the a1 A -adrenoceptors the latter study concluded that the contraction of the female pig urethra is caused by activation of a1 A - adrenoceptors. In vitro studies in human urethral tissue confirmed these findings and provided evidence that the a1 A - adrenoceptor mediates the contraction of the human urethra [15].Takiet al.studiedthefemale humanurethra in organ bath experiments [16]. In this study the entire length of the organ was divided into seven parts from the bladder neck to the external urethral meatus and the contractile response to noradrenaline was measured in all parts separately. Urethral contractions to noradrenalin were observed in all seven sections with peak amplitudes in the middle to proximal urethra. In urodynamic experiments in healthy females prazosin reduced the resting pressure predominantly in the midportion of the urethra while noradrenaline had no effect on the urethral pressure [17]. Both studies are consistent to our findings in vivo because tamsulosin induced a significant urethral relaxation over the entire urethral length with a slightly more extent in the proximal and middle third. Early reports about the use of a-blocking agents for benign prostatic hyperplasia go back to 1976 [18] and now almost 3 years later millions of men with lower urinary tract symptoms rely on these agents. Currently, tamsulosin is the only clinically available a1-adrenoceptor antagonist which is selective for the a1 A -subtype as well as for the a1 B -anda1 D -subtypes but less strong [19,2]. Compared to prazosin, tamsulosin has a 12 times greater affinity to a1-receptores in the prostate than in the aorta, which can be interpreted as a receptor pharmacological uroselectivity [21]. This selectivity to the lower urinary tract may be responsible for less blood pressure related side effects of tamsulosin compared to unselective a1-adrenoceptor antagonists [22,23]. Tamsulosin is widely used in men with benign prostatic hyperplasia and several studies have shown its superiority compared to placebo for treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia [24 26]. Recently tamsulosin was found to be effective in patients with neurogenic lower urinary tract dysfunction due to suprasacral spinal cord injury, the drug decreased the maximal urethral pressure significantly in the long term followup and improved also other cystometric parameters related to bladder storage and emptying [27]. Interestingly, 11% of the randomised subjects were women, however a separate analysis of this group was not given in the paper. A similar study in a 14 males and 1 females with neurogenic bladder elaborated a significant effect of tamsulosin.4 mg on flow rate, residual volume and detrusor pressure in patients with suprasacral lesions while patients with a acontractile bladder did not show a significant improvement. Again a gender specific analysis was not given [28]. To our knowledge, there is only one clinical study to use a-antagonists in women with chronic urinary retention described as functional bladder neck obstruction. However, using prazosin, phenoxybenzamine or terazosin only 5% of the patients improved in symptoms, peak flow and post-void residual urine [6]. Now, our data in healthy females may suggest that the selective a1 A -adrenoceptor antagonist tamsulosin reduces the urethral pressure significantly in the entire urethra. However, this not necessarily imply that tamsulosin lead to a decreased bladder outlet obstruction and improved bladder emptying in females with high urethral resistance. We are aware that in the women with chronic urinary retention according to Fowler s Syndrome the underlying pathology is based on

5 A. Reitz et al. / European Urology 46 (24) abnormalities of the external urethral sphincter which is somatically controlled by a cholinergic transmission from the pudendal nerve. However, a pharmacological treatment option for young women with retention would be of clinical significance. To evaluate the effect of tamsulosin on chronic urinary retention in young women, controlled studies would be of value whereas the post-void residual volume may be used as key parameter. 5.Conclusion These data show a significant relaxing effect of tamsulosin on the resting urethral tone in healthy females in vivo. These results may suggest tamsulosin as a new pharmacological approach to treat urinary retention due to overactive or non-relaxing urethra in women. Acknowledgements The authors are grateful to Ms. Nicole Honegger for excellent technical assistance and Mr. Huub van Hedel for statistical counselling. This study was supported by the Swiss National Foundation (Grant No ), the European Community (Grant REBEC QLG5-CT ) and a research grant from Boehringer Ingelheim. References [1] Fowler CJ, Christmas TJ, Chapple CR, Parkhouse HF, Kirby RS, Jacobs HS. Abnormal electromyographic activity of the urethral sphincter, voiding dysfunction, and polycystic ovaries: a new syndrome? BMJ 1988;297(6661): [2] Fowler CJ, Kirby RS. Electromyography of urethral sphincter in women with urinary retention. Lancet 1986;1(8496): [3] Swinn MJ, Kitchen ND, Goodwin RJ, Fowler CJ. Sacral neuromodulation for women with Fowler s syndrome. Eur Urol 2;38(4): [4] Phelan MW, Franks M, Somogyi GT, Yokoyama T, Fraser MO, Lavelle JP, et al. Botulinum toxin urethral sphincter injection to restore bladder emptying in men and women with voiding dysfunction. J Urol 21;165(4): [5] Fowler CJ, Betts CD, Christmas TJ, Swash M, Fowler CG, Kirby RS. Botulinum toxin in the treatment of chronic urinary retention in women. Br J Urol 1992;7(4): [6] Kumar A, Mandhani A, Gogoi S, Srivastava A. Management of functional bladder neck obstruction in women: use of alpha-blockers and pediatric resectoscope for bladder neck incision. J Urol 1999;162(6): [7] Kihara K, de Groat WC. Sympathetic efferent pathways projecting to the bladder neck and proximal urethra in the rat. J Auton Nerv Syst 1997;62(3): [8] Andersson KE. Pharmacology of the lower urinary tract smooth muscles and penile erectile tissues. Pharmacol Rev 1993;45(3): [9] Danuser H, Bemis K, Thor KB. Pharmacological analysis of the noradrenergic control of central sympathetic and somatic reflexes controlling the lower urinary tract in the anesthetized cat. Inhibition of central sympathetic and somatic outflow to the lower urinary tract of the cat by the alpha 1 adrenergic receptor antagonist prazosin. J Pharmacol Exp Ther 1995;274(2):82 5. [1] Danuser H, Thor KB. Inhibition of central sympathetic and somatic outflow to the lower urinary tract of the cat by the alpha 1 adrenergic receptor antagonist prazosin. J Urol 1995;153(4): [11] Testa R, Guarneri L, Ibba M, Strada G, Poggesi E, Taddei C, et al. Characterization of alpha 1-adrenoceptor subtypes in prostate and prostatic urethra of rat, rabbit, dog and man. Eur J Pharmacol 1993;249(3): [12] Yablonsky F, Riffaud JP, Lacolle JY, Dausse JP. Alpha 1- and alpha 2-adrenoceptors in the smooth muscle of male and female rabbit urethra. Eur J Pharmacol 1986;121(1):1 8. [13] Ahmed H, Moriyama N, Fukasawa R, Nishimatsu H, Tanaka Y, Kitamura T, et al. Contractile properties of urethral smooth muscles of young and aged female dogs: morphological and pharmacological aspects. Int J Urol 2;7(8): [14] Alberts P, Bergstrom PA, Fredrickson MG. Characterisation of the functional alpha-adrenoceptor subtype in the isolated female pig urethra. Eur J Pharmacol 1999;371(1):31 8. [15] Nasu K, Moriyama N, Fukasawa R, Tsujimoto G, Tanaka T, Yano J, et al. Quantification and distribution of alpha1-adrenoceptor subtype mrnas in human proximal urethra. Br J Pharmacol 1998;123(7): [16] Taki N, Taniguchi T, Okada K, Moriyama N, Muramatsu I. Evidence for predominant mediation of alpha1-adrenoceptor in the tonus of entire urethra of women. J Urol 1999;162(5): [17] Thind P, Lose G, Colstrup H, Andersson KE. The effect of alphaadrenoceptor stimulation and blockade on the static urethral sphincter function in healthy females. Scand J Urol Nephrol 1992;26(3): [18] Caine M, Pfau A, Perlberg S. The use of alpha-adrenergic blockers in benign prostatic obstruction. Br J Urol 1976;48(4): [19] Foglar R, Shibata K, Horie K, Hirasawa A, Tsujimoto G. Use of recombinant alpha 1-adrenoceptors to characterize subtype selectivity of drugs for the treatment of prostatic hypertrophy. Eur J Pharmacol 1995;288(2):21 7. [2] Michel MC, Grubbel B, Taguchi K, Verfurth F, Otto T, Kropfl D. Drugs for treatment of benign prostatic hyperplasia: affinity comparison at cloned alpha 1-adrenoceptor subtypes and in human prostate. J Auton Pharmacol 1996;16(1):21 8. [21] Yamada S, Suzuki M, Tanaka C, Mori R, Kimura R, Inagaki O, et al. Comparative study on alpha 1-adrenoceptor antagonist binding in human prostate and aorta. Clin Exp Pharmacol Physiol 1994;21(5): [22] Andersson KE. The concept of uroselectivity. Eur Urol 1998; 33(Suppl 2):7 11. [23] Chapple C, Andersson KE. Tamsulosin: an overview. World J Urol 22;19(6): [24] Abrams P, Schulman CC, Vaage S. Tamsulosin, a selective alpha 1cadrenoceptor antagonist: a randomized, controlled trial in patients with benign prostatic obstruction (symptomatic BPH). The European Tamsulosin Study Group. Br J Urol 1995;76(3):

6 24 A. Reitz et al. / European Urology 46 (24) [25] Abrams P, Speakman M, Stott M, Arkell D, Pocock R. A doseranging study of the efficacy and safety of tamsulosin, the first prostate-selective alpha 1A-adrenoceptor antagonist, in patients with benign prostatic obstruction (symptomatic benign prostatic hyperplasia). Br J Urol 1997;8(4): [26] Lepor H. Long-term evaluation of tamsulosin in benign prostatic hyperplasia: placebo-controlled, double-blind extension of phase III trial. Tamsulosin Investigator Group. Urology 1998;51(6):91 6. [27] Abrams P, Amarenco G, Bakke A, Buczynski A, Castro-Diaz D, Harrison S, et al. Tamsulosin: efficacy and safety in patients with neurogenic lower urinary tract dysfunction due to suprasacral spinal cord injury. J Urol 23;17(4 Pt 1): [28] Kakizaki H, Ameda K, Kobayashi S, Tanaka H, Shibata T, Koyanagi T. Urodynamic effects of alpha1-blocker tamsulosin on voiding dysfunction in patients with neurogenic bladder. Int J Urol 23; 1(11): Editorial Comment C. Chapple, Sheffield, United Kingdom c.r.chapple@sheffield.ac.uk This study has evaluated the effect of tamsulosin on urethral pressure in 11 young asymptomatic females. It is clear that tamsulosin reduced the mean urethral pressure over the entire urethral length. This confirms previous findings reported in the literature where it has been shown that alpha-antagonists reduce urethral closure pressure and have been reported to produce incontinence in females on treatment for hypertension. The use of magnetic stimulation of the sacral roots and the evaluation of the consequences on the urethral pressure is an interesting nuance and it is of note that tamsulosin do not appear to relax the urethra when contracted in this fashion. The disparity between improvement in symptoms and the relatively low improvement in objective outflow measures such as flow-rate has been used in the past to postulate that alpha-antagonistics such as tamsulosin may have sitesof-action at other levels apart from the urethral smooth muscle. The findings documented in this paper certainly don t provide any evidence in support of this view. Whilst tamsulosin appears to reduce urethral tone in the un-contracted urethral in normal volunteers, the supposition put forward here that it maybe useful in chronic urinary retention for example such as that seen in Fowler s syndrome where there is an abnormality of the function of the urethral sphincter does seem rather tenuous. Indeed at an anecdotal level in our experience alpha-antagonists have not proved to be effective in the treatment of the Fowler s syndrome. The finding that contraction of the urethral sphincter due to sacral stimulation is not affected by tamsulosin would in my view rather support the view that an alpha-antagonist such as tamsulosin is unlikely to be effective in patients with a neuro-physiological abnormality. Where there is abnormal sphincter tone as a consequence of altered pathophysiology at the level at the sacral cord and above within the central nervous system.