Elsevier

European Urology

Volume 52, Issue 2, August 2007, Pages 582-589
European Urology

From Lab to Clinic
Effects of Botulinum Toxin A on the Contractile Function of Dog Prostate

https://doi.org/10.1016/j.eururo.2007.03.002Get rights and content

Abstract

Objectives

To study effects of botulinum toxin A (BoNT/A) on prostate contractile function in dogs.

Methods

One hundred units (N = 6) or 200 units (N = 5) BoNT/A was injected into dog prostate. Sham control group (N = 7) received normal saline injections. Before and 1 mo after injection, prostate urethral pressure response to electrostimulation and intravenous (IV) norepinephrine was measured. Contractile responses of prostate strips were tested in tissue bath. Structural changes were evaluated with conventional histology and smoothelin immunohistochemistry.

Results

Injection of normal saline and 100 units BoNT/A did not significantly change prostate urethral pressure response to IV norepinephrine and electrostimulation. However, injection of 200 units BoNT/A significantly reduced prostate urethral pressure response to IV norepinephrine and electrostimulation. Contractile responses of prostate strips to potassium chloride, electrostimulation, and phenylephrine did not differ between sham control and 100U groups. In the 200U group, however, all responses were less than those of sham controls. Control and BoNT/A groups exhibited nitric oxide-related relaxation in prostate strips precontracted by phenylephrine. Injection of 100 units BoNT/A induced mild atrophy of prostate gland; injection of 200 units BoNT/A induced more pronounced atrophic changes in prostate gland and vacuoles formation in smooth muscle cells of stromal tissue.

Conclusions

Injecting BoNT/A into dog prostate reduces contractile function while maintaining relaxation response of the prostate. These effects make BoNT/A a viable option in managing prostate-related symptoms. However, large, randomized clinical studies to determine long-term effects and safety of BoNT/A application in human prostates are required.

Introduction

Although prostatectomy is effective in treating lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH), its potential complications preclude acceptance by many patients. Less invasive therapy, like botulinum toxin A (BoNT/A) injection, is therefore desirable. BoNT/A inhibits cleavage of the cytosolic translocation protein synaptosomal-associated membrane protein (SNAP-25) and prevents fusion of neurotransmitter-containing vesicles with plasma membrane, resulting in inhibited release of neurotransmitters. BoNT/A inhibited acetylcholine release from presynaptic nerve terminals, which resulted in decreasing muscle tone in skeletal and smooth muscles. BoNT/A has been used to reduce spasticity of skeletal muscles, improve symptoms of strabismus [1], and reduce facial wrinkles [2]. Recent papers also demonstrated the therapeutic effects of intravesical injection of BoNT/A for detrusor overactivity [3], [4].

Growth and secretion of some exocrine glands, including sweat glands and salivary glands, are also modulated by cholinergic nerves, which are subjected to blockade by BoNT/A. Clinical studies showed that BoNT/A injection might decrease sweating and improved symptoms of hyperhydrosis [5], [6]. Several papers have already reported good results in treating sialorrhoea by BoNT/A injection into salivary glands [7], [8].

Studies have indicated that the prostatic gland is richly innervated by cholinergic nerves [9], [10]. Theoretically, prostatic glandular secretion should also be depressed by BoNT/A. One study did show atrophic effects of BoNT/A on rat prostate. One and 2 wk after prostate BoNT/A injection, a significant atrophy of prostate glands was found, with an abundance of apoptosis [11]. Kuo [12] and also Chuang et al [13] demonstrated that BoNT/A was effective in reducing prostate size and symptoms of BPH. These laboratory and clinical studies clearly show that BoNT/A could induce an atrophic change in the prostate gland. Nevertheless, the effect of BoNT/A on prostate contractile function is still unknown.

Contractile function of the prostate comes from smooth muscle cells in the stroma component, which are adrenergically innervated [14]. Upon stimulation with alpha-adrenergic agonists, smooth muscle fibers of the prostate contract, resulting in increased bladder outlet resistance. This dynamic occlusive force may account for 40% of obstruction caused by BPH [15], suggesting that contractile function of the prostate plays an important role in pathophysiology of bladder outlet obstruction secondary to BPH. In this study, we used an animal model to research effects of BoNT/A on prostrate contractile function.

Section snippets

Animals

Mature male mongrel dogs, body weight 10–15 kg, were used in this study. The study was approved by the Institutional Review Board (IRB) for Animal Research in our institution.

In vivo prostate urethral pressure response to intravenous norepinephrine

We have used this method previously, and it has been described in our published paper [16]. An 8F catheter specifically designed for measuring urethral closure pressure (Life-tech, Texas, USA) was inserted into the bladder through the urethra. Through a three-way stopcock, the catheter was connected to an infusion pump (1.4 

Effects of BoNT/A on prostate urethral pressure response to IV norepinephrine

Before injection, there were no statistically significant differences in the size of the prostate between the groups with 24.0 ± 4.5, 22.3 ± 3.4, and 28.1 ± 4.1 ml for control, 100U, and 200U group, respectively. One month after injection there was no significant change in the prostate size in control and 100U groups. The size of the prostate in 200U group had a mean of 24% reduction.

Before injection, there was no statistically significant difference in basal prostate urethral pressure between the

Discussion

The present study confirms that BoNT/A induces atrophy of glandular component of dog prostate as shown by Chuang el at [17]. The present study further demonstrated that, with an adequate dose, BoNT/A also reduced contractile activity of the prostate. In vivo and in vitro contractile responses of the prostate to stimulations were reduced by injecting 200 units BoNT/A. The impaired contractility may come from two factors: (1) impaired release of contractile neurotransmitters; (2) impaired

Conclusions

The present study confirms that BoNT/A may induce atrophy of the prostate gland and reduce contractile activity of prostate tissue in dogs. These properties make BoNT/A a viable option in managing prostate-related LUTS. However, large, randomized clinical studies to determine long-term effects and safety of BoNT/A application in human prostates are required.

Conflicts of interest

The authors have nothing to disclose.

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