The effects of α1A-adrenoceptor antagonists on the urethral perfusion pressure of the female rat

Authors


Jeong-Gu Lee, Department of Urology, Korea University Hospital, 126–1, 5-ka, Anam-dong, Sungbuk-ku, Seoul 136–705, Korea.
e-mail: urobae@genetherapy.or.kr

Abstract

OBJECTIVE

To assess the effects of α1A-adrenoceptor antagonists on urethral perfusion pressure (UPP) in the female rate and their therapeutic potential for treating female bladder outlet obstruction (BOO).

MATERIALS AND METHODS

A cannula was inserted into the femoral arteries of female rats to administer tamsulosin (group I), doxazosin (group II) or phentolamine (group III) and to monitor systemic blood pressure. Tamsulosin was also administered to male rats (group IV). UPP and vesical pressures (Pves) were monitored using a triple-lumen catheter.

RESULTS

After administration of tamsulosin to group I the frequency of bladder contractions decreased significantly and the duration of minimal urethral relaxation with high-frequency oscillations (HFOs) was significantly prolonged. Except for mean arterial blood pressure (MAP), none of the variables in group I differed significantly from those in group II and group III. The change in MAP after tamsulosin treatment was significantly lower than after doxazosin or phentolamine. Except for the maximum Pves, which was significantly higher in males (group IV) than in females of group I, the UPP and Pves curves of male rats were similar to those of females before giving tamsulosin. The prolonged frequency and duration of HFO in group IV (with tamsulosin) were significantly different from those of females.

CONCLUSIONS

The α1A-adrenergic receptor may be a functional subtype in the female rat urethra. α1A-adrenoceptor antagonists prolonged the duration of HFOs and decreased the frequency of involuntary bladder contraction. It is possible that treatment with α1A-adrenoceptor antagonists would not only improve obstructive symptoms, but also ameliorate irritative symptoms by prolonging HFOs and the frequency of involuntary bladder contractions.

Abbreviations
UPP(min)

urethral perfusion pressure (minimum)

HFO

high-frequency oscillation

MAP

mean arterial pressure

Pves

intravesical pressure.

INTRODUCTION

α-Adrenergic antagonists have long been used to treat LUTS associated with BPH. Proximal urethral tone in the human is largely maintained by activation of postsynaptic α-adrenoceptors [1,2]. Therefore, α-adrenergic antagonists decrease proximal urethral tone and improve LUTS. However, they can have adverse cardiovascular effects, such as orthostatic hypotension [3]. Two subtypes of the α-adrenoceptor (α1 and α2) have been described, and molecular cloning studies have identified three subtypes of the α1-adrenoceptor. It was reported that mRNA that encodes the α1A-adrenoceptor is predominant in the human prostate. Tamsulosin is an α1-adrenergic antagonist that is usually administered once daily; it has greater selectivity for the α1A- than the α1B-adrenoceptor, but distinguishes between the α1A- and α1D-adrenoceptors [4–6], a feature unique to tamsulosin.

The causes of female voiding dysfunction, including urinary retention, are various. LUTS in women remains a poorly understood and improperly diagnosed clinical entity. Kumar et al.[7] reported that female patients with LUTS had an improvement in their symptoms after taking an α-adrenergic antagonist. However, the efficacy and mechanism of α-adrenergic antagonists in such female patients has not been established. In this study we tried to identify the effects of α-adrenoceptor antagonists, including α1A subtypes, on urethral perfusion pressure (UPP) and to assess their therapeutic potential for female LUTS.

MATERIALS AND METHODS

Thirty mature female Sprague-Dawley white rats (200–250 g) were randomized into three equal groups, each of which was treated with tamsulosin (group I), doxazosin (group II) or phentolamine (group III). Tamsulosin was also administered to 10 male rats (group IV). Polyethylene catheters (PE-10) for infusion of drugs and monitoring of systemic blood pressure were inserted into the femoral arteries and advanced to the bifurcation of the aorta, with the rats under general anaesthesia by i.p. 20% (w/v) urethane. A tracheotomy was performed to facilitate respiration.

To monitor the UPP and intravesical pressure (Pves), the rats were prepared using a modification of the method of Jung et al.[8]. After exposing the bladder and proximal urethra via a midline abdominal incision, the UPP was monitored using a custom-designed triple-lumen catheter, which consisted of an outer catheter (8 F cut-down tube) containing two polyethylene catheters of different sizes (PE-160 and PE-50) connected to a pipette tip (Fig. 1). This was introduced transvesically through an incision in the bladder dome, and the pipette tip placed securely in the bladder neck. The outer lumen was connected to a polygraph (Model 7E, Grass Instruments, Quincy, MA, USA) to monitor Pves. The middle lumen (PE-160) was connected to an infusion pump for continuous saline infusion. The inner lumen (PE-50) was connected to the polygraph through a pressure transducer and used to monitor urethral pressure. After a 30-min stabilization period after surgery, the bladder was filled with 0.7–1.0 mL of normal saline via the outer lumen of the catheter, and isovolumetric pressure recorded throughout the experiment. The urethra was continuously infused with warm saline (37 °C, 0.075 mL/min) in an antegrade manner using an infusion pump. The infused saline was allowed to drain freely through the urethral meatus. Thus, isovolumetric Pves and UPP were recorded independently and simultaneously. Changes of Pves and UPP were monitored after giving each experimental drug.

Figure 1.


A triple-lumen catheter is seated securely in the bladder neck for the functional separation of bladder and urethral activity.

All data are reported as the mean (sd) with the means compared using a paired t-test or one-way anova, with P < 0.05 deemed to indicate a significant difference.

RESULTS

Before drug administration the urinary bladders showed periodic contractions with a pressure of 54.4 (12.2) cmH2O and a frequency of 0.44 (0.23)/min. The UPP varied according to vesical contractions; the baseline UPP was 28.4 (4.0) cmH2O, which decreased to 8.2 (3.2) cmH2O before intravesical contractions and oscillated periodically (Fig. 2).

Figure 2.


Urethral and bladder pressure are monitored by the triple-lumen catheter in a normal female rat. HFOs of urethral pressure were recorded simultaneously during isovolumetric reflex bladder contractions. UPPbasal, baseline urethral perfusion pressure during contraction.

The minimum concentration required to evoke the maximum change in UPP after 0.1 mL of tamsulosin (group I) was 10−7m, which decreased the baseline UPP by 1.3 (1.0) cmH2O, but this change was not statistically significant (Fig. 3, Table 1; P > 0.05). The frequency of bladder contraction was decreased significantly from 0.44 (0.23) to 0.32 (0.18)/min (P < 0.01) and the duration of urethral relaxation with high-frequency oscillations (HFOs) was prolonged significantly from 33 (6) to 44 (8) s by tamsulosin (P < 0.01). The UPP during urethral relaxation (UPPmin) was not decreased (P > 0.05). The mean arterial pressure (MAP) was not significantly different before and after tamsulosin (P > 0.05).

Figure 3.


Effect of tamsulosin on bladder and urethral pressure in the female rat. After tamsulosin treatment the frequency was significantly lower and the duration of bladder contraction and urethral relaxation with HFOs significantly prolonged. Also, in urethral pressure, the time to return to baseline pressure was prolonged.

Table 1. 
Changes in the variables before and after tamsulosin administration in female rats
Mean (sd) variableBeforeAfterDifference, %
  • *

    P < 0.01;

  • †difference between peak and baseline pressure.

Frequency, /min 0.44 (0.23) 0.32 (0.18)−29.5*
UPP, cmH2O
 baseline28.4 (4.0)27.1 (4.7)−4.5
 minimum 8.2 (3.2) 8.0 (2.5)−2.5
Duration of HFO, s33 (6)44 (8)−34*
Δ Pves, cmH2O54.4 (12.2)51.9 (13.5)−5.8
MAP, mmHg97.8 (7.5)95.6 (8.5)−2.3

The minimum concentrations (in 0.1 mL injection volumes) required to induce the maximum change in UPP were 0.5 × 10−6m–for doxazosin (group II) and 10−5m for phentolamine (group III). Changes in Pves and UPP after giving these drugs were similar to those after giving tamsulosin. Baseline UPP and UPPmin were not significantly changed. The frequency of bladder contraction was significantly lower and the duration of HFOs significantly prolonged in both groups. The changes after doxazosin or phentolamine were not significantly different from those after tamsulosin, but the magnitude of the MAP decrease was significantly greater in group II, at 9.6 (3.9) mmHg, and group III, at 13.5 (4.9) mmHg, than in group I (Table 2, P < 0.05).

Table 2. 
Changes in the variables before and after administration of various α-adrenoceptor antagonists in female rats, and in male rats treated with tamsulosin
Mean (sd) change in:Tamsulosin (group I)Doxazosin (group II)Phentolamine (group III)Male rats (group IV)
  • *

    P < 0.05.

Frequency, /min−0.12 (0.03)−0.10 (0.05)−0.14 (0.04)−0.18 (0.07)*
UPP, cmH2O−1.1 (0.3)−1.3 (0.5)−1.3 (0.6)−1.0 (0.5)
Duration HFO, s 11 (6)12 (5) 11 (6)16 (4)*
Pves, cmH2O 2.5 (0.5) 3.9 (1.1) 2.9 (0.9) 3.1 (1.0)
MAP, mmHg−1.5 (0.4)*−9.6 (3.9)*−13.5 (4.9)*−1.0 (0.7)

The baseline UPP and Pves curves of male rats (group IV) were similar to those of female rats (Fig. 4). However, maximum Pves, baseline UPP and UPPmin, at 80 (6.7), 32.3 (5.3) and 13.7 (6.2) cmH2O, respectively, were significantly higher than those of group I (P < 0.05). The contraction frequency, at 0.67 (0.31)/min, was also significantly higher than that of group I (P < 0.05). Frequency and the duration of HFO were significantly prolonged by tamsulosin in group IV, and these changes were more significant than those in group I (Table 2). The MAP was 100.8 (6.5) mmHg and was unchanged after tamsulosin.

Figure 4.


Effect of tamsulosin on bladder and urethral pressure in the male rat. UPP and Pves changes were similar to that in the female rat except for a significantly higher maximal Pves. After tamsulosin treatment the frequency was significantly lower and the duration of bladder contraction and urethral relaxation with HFOs significantly prolonged.

DISCUSSION

The micturition process can be visualized as a complex of neural circuits in the brain and spinal cord, which coordinate the activity of smooth muscle in the bladder and urethra. These circuits act as on/off switches that alternate the state of the LUT between one of storage and one of elimination [9]. Sympathetic outflow from the rostral lumbar spinal cord provides a noradrenergic excitatory and inhibitory input to the bladder and urethra. Activation of sympathetic nerves induces relaxation of the bladder body and contraction of the bladder outlet and urethra, which results in the storage of urine in the bladder [10].

α-Adrenoreceptor antagonists relax the bladder outlet to improve urinary flow in patients with BPH, by reducing prostatic smooth muscle tone through the blockade of sympathetic adrenergic receptors. However, the effect of α-adrenoreceptor antagonists on women with LUTS and with BOO is not well established.

Since Gallagher et al.[11] described the female urethral syndrome, recently also termed LUTS, female LUTS has been only vaguely defined, resulting in much controversy. However, female LUTS still draws the attention of many clinicians because there are significantly many patients who report this problem. Because there is no definition of this syndrome, and a clear mechanism has not yet been elucidated, there are no objective data and no agreement on treatment. These patients are treated according to the individual doctor's personal experience [12,13]. Various treatments, e.g. urethral dilatation, electrocauterization, electrical stimulation, acupuncture and numerous medical therapies, are applied, but the mechanisms and effects of these treatments have not been established [12–14]. One treatment entails the use of α-adrenoreceptor antagonists, but it is also the subject of debate.

Durant et al.[15] reported that α-adrenoreceptor antagonists had an insignificant effect on the female urethra, but Yoon et al.[16] reported that functional bladder volume was increased by an α-adrenoreceptor antagonist in female rats, and that the frequency of involuntary bladder contraction induced by partial bladder-neck obstruction was significantly less. Kim et al.[17] reported that electrically induced contraction of the detrusor muscle was decreased by doxazosin in female rats, but not by tamsulosin. Jeong et al.[18] reported that α-adrenoceptor antagonists, including tamsulosin, decreased detrusor pressure and frequency of involuntary bladder contraction in vitro using tissue from female rats. In the present study, the frequency of involuntary bladder contraction was also decreased by α-adrenoceptor antagonists, including tamsulosin.

Recent RNase protection and in situ hybridization studies showed that there are three α-adrenoceptor subtypes [19]. Several in vitro studies have used tissue from beagle dogs or rabbits to elucidate the function of these subtypes, and indicate that α1A-adrenoceptors may be the functional subtype in the urethra [20–23], but there is a paucity of in vivo studies.

On the basis of previous in vitro data, the present in vivo study showed that while α-adrenoceptor antagonists did not decrease the minimum urethral pressure, they prolonged the duration of HFOs. Although the prolongation was not prominent in the male rat, the pattern was very similar to that of the female rat. The findings were the same after using selective α1A-adrenoceptor antagonists with a minimum effect on systemic blood pressure. These results suggest that the α1A-adrenoceptor may be the functional subtype in female rat urethra and possibly effective in female patients with LUTS. Also, the α1A-adrenoceptor antagonist prolonged the duration of HFO and decreased the frequency of involuntary bladder contraction. Possibly, an α1A-adrenoceptor antagonist might improve not only obstructive symptoms but also bladder irritative symptoms, by prolonging the duration of HFOs and decreasing the frequency of involuntary bladder contraction.

CONFLICT OF INTEREST

None declared.

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