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Keywords:

  • tamsulosin;
  • ureter;
  • adrenoceptor and α-adrenergic blocker

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

OBJECTIVE

To study the effects of tamsulosin on ureteric contractions and its effects on the basal tone of human ureteric specimens, as clinical trials with tamsulosin have shown promising results in the spontaneous expulsion of lower ureteric calculus, but the mechanism of action of tamsulosin in the expulsion of ureteric calculus has not been elucidated in in-vitro studies on human ureters.

MATERIALS AND METHODS

Human mid-ureteric specimens were obtained from live kidney donors. The specimen was transported in Krebs’ solution and the isometric contraction of human ureteric smooth muscle was recorded in the presence of tamsulosin. Ureteric rings from 19 kidney donors were studied.

RESULTS

At 100 µm tamsulosin the frequency of ureteric contraction was blocked completely, or the contraction frequency was reduced in 89% of specimens. There was no change in the frequency or in the amplitude of contraction in the remaining specimens. The basal tone of the ureter was reduced in 16% of the specimens.

CONCLUSION

Our results suggest that peristaltic activity in human ureteric smooth muscle is inhibited by tamsulosin. The effect of tamsulosin on basal tone is marginal.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

Peristalsis in ureteric muscle is myogenic in origin, as evident by the contractility of the denervated renal transplant ureter [1]. The autonomic nervous system has been shown to alter the contractility of the human ureter. The effects of adrenergic compounds in vivo and or in vitro on the ureter have been studied extensively. α-adrenergic agonists increase and their antagonists inhibit ureteric peristalsis [2,3]; β2- and β3-agonists relax the ureter and their effects were blocked by their respective antagonists [4,5]In vitro studies showed the presence of α1-adrenoceptor subtypes in the human ureter [6]. Maximum concentrations of α1-adrenoceptor subtypes are located in the lower ureter [7]. Three types of α1-adrenoceptors have been identified, i.e. α1A, α1B and α1D [8]. The density of α1-adrenoceptor subtypes varies with different tissues in humans; α1A is the predominant receptor subtype in the human prostate [9] and α1D is the predominant receptor subtype in the detrusor [10].

Tamsulosin is a methoxybenzenesulphonamide derivative, is an α-adrenoceptor blocker, and has higher affinity for α1A and α1D receptors [11]. Tamsulosin has been shown to facilitate the spontaneous expulsion of uretric stones in clinical trials [12,13]. To our knowledge, in vitro studies have not been reported of the effects of tamsulosin on human ureter. Thus the purpose of the present study was to test the hypothesis that tamsulosin inhibits ureteric peristalsis and relaxes the ureter, thereby facilitating the spontaneous expulsion of stone.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

The study comprised 27 ureteric specimens obtained from live kidney donors; the excess length of the ureter which was not required for ureteroneocystostomy was used. The specimen was immediately transported in cold, oxygenated Krebs’ solution (composition, mm: 118 NaCl, 4.7 KCl, 25 NaHCO3, 2.5 CaCl2, 1.2 MgSO4, 1.2 KH2PO4, 11.1 glucose) to the laboratory. The peri-ureteric fat was removed and a 5-mm thick cylindrical ring was cut from the specimen. One end of the cylinder was attached to the base of a temperature-controlled bath and the other end to an isometric force transducer. The isolated specimen was mounted in a chamber containing oxygenated Krebs’ solution maintained at 37 °C. The specimen was allowed to stabilize for 90 min. The solution was gassed continuously with 95% oxygen, 5% CO2 mixture. If the tissue failed to develop spontaneous contractions, caesium chloride (100 µm), a blocker of potassium channels (that would lead to depolarization), was used to induce ureteric contractions. The specimens that failed to contract despite adding caesium chloride were discarded. The force transducer was connected to a physiograph. Isometric contractions were recorded on a chart recorder after amplification, with the recording speed maintained at 0.25 mm/s. After the tissue had stabilized and the contractions became regular, the frequency of contraction and amplitude of contraction were calculated.

Donor age and outcome were compared using the Mann–Whitney U-test and the association between gender and outcome using Fisher’s exact test. The frequency of contraction before and after tamsulosin was analysed using a paired t-test.

Pure tamsulosin hydrochloride was a gift from Ranbaxy Pharmaceuticals Research Division, India; prazosin was purchased from Sigma Chemicals Co., St Louis, MO, USA.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

The demographic details of the donors are shown in Table 1; in all, 27 ureteric rings were obtained from 27 donors, but eight of these rings were quiescent even after stimulation with caesium chloride, and were discarded. Thus 19 ureteric specimens were assessed, of which 10 developed spontaneous contractions and nine developed contractions after stimulation with caesium chloride. The mean (sd) amplitude of contraction was 18.5 (7.5) mm and the interval between adjacent contractions was 60.7 (38.7) s. In terms of frequency, the mean frequency of spontaneous contractions before treatment was 0.021 (0.01) Hz. The contractions were blocked completely by tamsulosin (Fig. 1) in 15 specimens. In two specimens the frequency of contraction had decreased by 64% and 50%, respectively. There was no change in the amplitude of the contraction in both these specimens. In two specimens, tamsulosin had no effect on the frequency or on the amplitude of contraction. When all 19 specimens were considered the mean (sd) frequency of contractions after tamsulosin was 0.003 (0.007) Hz. Comparing the frequency of contractions before and after tamsulosin with a paired t-test, there was a significant difference (P < 0.001; Fig. 2).

Table 1.  Comparison of variables between responders and non responders
VariableFrequency of contractionP
RespondersNonresponders
No.172 
Mean (sd) age, years46 (9)45 (4)0.94
Female1321.0
Male40 
image

Figure 1. Tamsulosin-induced inhibition of spontaneous ureteric contractions in an isolated human ureteric specimen.

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image

Figure 2. The mean (sd) inhibition of frequency of spontaneous contractions in human mid-ureteric specimens after tamsulosin was added to the tissue bath (19 samples). *P < 0.001, paired t-test.

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Tamsulosin did not lead to a decrease in baseline tension in 16 of 19 specimens, and in three specimens there was an appreciable decrease in baseline tension (Table 2). The effects of tamsulosin were reversible and spontaneous contractions could be re-induced with caesium chloride after washing the specimens with drug-free perfusate. The effects of tamsulosin were also compared with those of prazosin. Four additional specimens were evaluated with 10 µm prazosin; prazosin blocked the spontaneous contractions in all the specimens and there was no decrease in baseline tension. The effects were reversible and contractions could be re-induced with caesium chloride after washing the tissue with drug free perfusate.

Table 2.  The results with tamsulosin (19 specimens)
VariableComplete/partial responseNo response
Frequency of contraction172
Amplitude of contraction154
Fall in baseline tension316

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

The existence of α1-adrenoceptor subtypes in human ureter has been reported. Tamsulosin has been recommended for the management of lower ureteric calculus and there is considerable evidence confirming the efficacy of tamsulosin in facilitating spontaneous expulsion of calculus [12–14]. It was hypothesized that tamsulosin relaxes the ureteric smooth muscle, thereby facilitating the spontaneous passage of stone [15]. Ureteric relaxation in the region of the stone, and the hydrostatic pressure above the stone, are the factors that are supposed to facilitate stone passage. Tamsulosin has also been shown to decrease the colicky pain and the number of episodes of colic due to calculus. The reduction in pain is probably due to the inhibition of the peristaltic contraction [16]. We found that tamsulosin decreased or completely blocked the peristaltic contractions in 17 of 19 ureteric specimens. However, tamsulosin did not produce a decrease in baseline tension in 16 of 19 specimens. Our results are in agreement with the opinion that the mechanism of action of tamsulosin is the inhibition of peristaltic contractions, and do not support the hypothesis that it causes a relaxation of ureteric smooth muscle. The effect of tamsulosin on the frequency and amplitude of contraction in a pig model was studied by Troxel et al.[17]. They found that tamsulosin reduced the frequency of spontaneous contractions by 27%, whereas it had no significant effect on the amplitude of spontaneous contractions and on stimulus-induced contractions. The difference in outcome with tamsulosin in the present study is probably due to the variation in the density of receptors between the species, and the difference in dose of tamsulosin between the studies. The lack of a decrease in baseline tension is probably due to the predominant selectivity of tamsulosin for α1A receptor subtype than α1D receptor subtype. The α1D receptor subtype is the predominant receptor in the human ureter and the maximum concentration of the receptor is in the lower ureter [7]. Moreover, we used mid-ureteric specimens rather than the lower ureter. Malin et al.[3] reported the existence of α- and β-adrenergic receptors in the distal human ureter; they found that the α-adrenergic receptors were the dominant receptors, over β-receptors, the latter only being detected in the lower third of the ureter. In a porcine model, Nakada et al.[18] reported that doxazocin reduced the frequency of contraction by up to 34% in a dose-dependent fashion. The relaxation effect was better in the presence of adrenaline, due to its relaxation effect on the β-receptors. Davenport et al.[19] used 5-methylurapidil, an α1-blocker, to assess the effects on human ureter; this agent inhibited spontaneous contractions at 10 µm; the median relaxant effect was 55%. The median ureteric relaxation was significantly higher in the distal ureter than in the proximal ureter. Matsushima et al.[20] evaluated the pharmacokinetics of tamsulosin in eight Japanese healthy male volunteers at an oral dose of 0.2 mg. The peak plasma concentration of tamsulosin was 10 ng/mL, equivalent to 0.023 µmol/L. The dose of tamsulosin in the present study was 100 µm; therefore the results of our study cannot be directly compared to in vivo studies. However, clinical trials have shown that 0.4 mg of tamsulosin is effective in the medical management of lower ureteric calculus. Further in vitro studies are required to assess the minimum concentration of tamsulosin required to produce the desired effect.

In conclusion, this in vitro study of tamsulosin on human ureteric tissue showed that peristalsis in human ureter is inhibited by tamsulosin. The outcome with tamsulosin on basal tone might be different if the experiments were done using lower ureteric specimens.

CONFLICT OF INTEREST

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES

None declared. Source of funding: Institutional fund.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. MATERIALS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. REFERENCES
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