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Archivos Españoles de Urología ISSN: 0004-0614 [email protected] Editorial Iniestares S.A. España Pérez Martínez, Francisco Carlos; Vela Navarrete, Remigio; Castilla Reparaz, Carlos COMPARATIVE EFFECTS OF CLOMIPRAMINE AND DULOXETINE ON DETRUSOR AND STRIATED SPHINCTER FUNCTION IN MALE AND FEMALE RABBITS. Archivos Españoles de Urología, vol. 59, núm. 8, octubre, 2006, pp. 839-848 Editorial Iniestares S.A. Madrid, España Available in: http://www.redalyc.org/articulo.oa?id=181013929019 How to cite Complete issue Scientific Information System More information about this article Network of Scientific Journals from Latin America, the Caribbean, Spain and Portugal Journal's homepage in redalyc.org Non-profit academic project, developed under the open access initiative International Section Arch. Esp. Urol., 59, 8 (839-848), 2006 COMPARATIVE EFFECTS OF CLOMIPRAMINE AND DULOXETINE ON DETRUSOR AND STRIATED SPHINCTER FUNCTION IN MALE AND FEMALE RABBITS. Francisco Carlos Pérez Martínez1, Remigio Vela Navarrete1 and Carlos Castilla Reparaz2. 1Departamento de Urología, Universidad Autónoma de Madrid. Fundación Jiménez Díaz. Madrid. 2Departamento de Cirugía Experimental y Experimentación Animal. Fundación Jiménez Díaz. Madrid. Spain. Summary.- OBJECTIVE: Serotonin and norepinephri- cystometrogram. Simultaneously, SAS-EMG was recor- ne systems are involved in the neural control of lower ded through electromyography electrodes placed in the urinary tract function. The aim of this study was to com- perianal striated muscle. pare the response on striated anal sphincter electromyo- RESULTS: Cystometric parameters: Under irritative condi- graphic (SAS-EMG) activity and cystometric parameters, tions, 2 mg./Kg. clomipramine in male rabbits and 1 or when duloxetine and clomipramine were intravenously 2 mg./Kg. in female rabbits, depending on the dose, administrated. increased bladder capacity (BC), contraction duration METHODS: The effects of intravenous 1 and 2 mg./Kg. (CD) and intercontraction interval (ICI), and decreased duloxetine or clomipramine on lower urinary tract func- baseline pressure (BP). In male and female rabbits, du- tion were studied in a total of 32 male and 32 female loxetine dose-dependently increased BC, CD and ICI. rabbits, under nonirritative conditions (intravesical infu- Under nonirritative conditions, clomipramine at 2 mg./ sion of saline) and in a model of bladder irritation (i.e., Kg. and duloxetine dose-dependently solely increased transvesical infusion of 0.5% acetic acid). A transurethral BC in female rabbits. Electromyographic activity: A double-lumen catheter in male rabbits, and a subcuta- marked effect on SAS-EMG activity of duloxetine under neous cystostomy in female rabbits, were used for liquid irritative conditions was revealed in male and female infusion and recording of intravesical pressure during a rabbits. Under these conditions, clomipramine increased SAS-EMG activity only in female rabbits. Under nonirri- tative conditions, 2 mg./Kg. duloxetine increased SAS- EMG activity only in female rabbits. CONCLUSIONS: The stronger effects on the SAS-EMG activity were produced by duloxetine in female rabbits under irritated bladder conditions. Clomipramine, under irritative conditions, had a relaxing effect on intravesical pressure, which is not the case with duloxetine. Keywords: Urinary incontinence. Clomipramine. Duloxetine. Lower urinary tract. e to: R. Vela Navarrete Resumen.- OBJETIVO: Neurotransmisores como la Catedrático de Urología serotonina y la norepinefrina están involucrados en el Fundación Jiménez Díaz control neural del tracto urinario inferior. El objetivo de Avda. de los Reyes Católicos, 2 este trabajo consistió en comparar los efectos de du- loxetina y clomipramina sobre parámetros cistométricos 28040 Madrid. (España) y la actividad electromiográfica del esfínter anal estria- Correspondenc [email protected] do (SAS-EMG). 840 F. C. Pérez Martínez, R. Vela Navarrete and C. Castilla Reparaz. MÉTODOS: Los efectos de dosis progresivas (1 y 2 ventions and surgery. Currently, there is no globally- mg./Kg.) de duloxetina o clomipramina, administra- approved pharmaceutical treatment. dos intravenosamente, sobre el tracto urinario inferior se estudiaron en un total de 32 conejos machos y 32 Pharmacological studies have implicated hembras, en condiciones normales (infundiendo conti- serotonin (5-hydroxytryptamine [5HT]) and norepi- nuamente suero salino en la vejiga) y mediante un mo- nephrine (NE) systems in the neural control of lower delo de irritación vesical (infusión continua de ácido urinary tract (LUT) function (2). In addition, bladder acético al 0,5% en la vejiga). Un catéter transuretral de contraction occurs from acetylcholine stimulation of doble lumen en machos, y una cistostomía subcutánea detrusor muscarinic receptors (3). Thus, the treatment en hembras, se utilizaron para la infusión de líquido y of urinary incontinence could be done by drugs like para recoger la presión intravesical durante el cistome- antimuscarinic compounds, tricyclic antidepressants trograma. Simultaneamente, SAS-EMG fué registrada a (TCAs) and combined 5HT and NE reuptake inhibi- través de dos electrodes situados en el músculo estriado tors (SNRIs), depending on the type of urinary incon- perianal. tinence. RESULTADOS: Parámetros cistométricos: En condiciones Clomipramine belongs to the TCA family and irritativas, clomipramina tras 2 mg./Kg. en los machos is used to treat depression and obsessive-compulsive y de forma dosis-dependiente en las hembras, incremen- disorders, as it produces slight sedation in healthy tó la capacidad vesical (CV), la duracion de la con- and sick patients (4). The primary action mechanism tracción (DC) y el intervalo entre contracciones (IC), y of TCAs is to block 5HT and NE presynaptic neuro- redujo la presión vesical (PB). Por otro lado, duloxetina transmitter reuptake in the brain, reducing turnover incrementó la CV, la DC y el IC, de forma dosis-de- and thus effectively increasing the action of these neu- pendiente, tanto en conejos machos como en hembras, rotransmitters. TCAs also have anticholinergic effects cuando fueron estudiados en condiciones irritativas. that traditionally account for several of their most com- En condiciones normales, duloxetina, de forma dosis- mon side effects. Clomipramine is distinguished from dependiente, y clomipramina, tras la administración the other TCAs by its potent 5HT reuptake-inhibiting de 2 mg./Kg., sólo aumentaron la CV en los conejos properties, which resemble those of the selective 5HT hembra. Electromigrafía: Un potente efecto de duloxeti- reuptake inhibitors such as fluoxetine (4,5). na sobre la SAS-EMG, en condiciones de irritabilidad vesical, se vio tanto en machos como en hembras. En The class of SNRIs now comprises three me- estas condiciones, la clomipramina incrementó, de for- dications: venlafaxine, milnacipran, and duloxetine. ma dosis-dependiente, la SAS-EMG sólo en hembras. These drugs block the reuptake of both 5HT and NE Por otro lado, en condiciones normales, el único efecto with differing selectivity. Whereas milnacipran blocks significativo sobre la SAS-EMG que se vio, fue con 2 5HT and NE reuptake with equal affinity, duloxetine mg./Kg. de duloxetina en hembras. has a 10-fold selectivity for 5HT and venlafaxine a CONCLUSIONES: Duloxetina produce un efecto mar- 30-fold selectivity for 5HT (6). Duloxetine increases cado sobre la SAS-EMG en conejas en condiciones striated sphincter activity through central actions in the irritativas. En estas mismas condiciones, clomipramina spinal cord, showing urine-storage-promoting effects tiene mayor efecto relajante sobre el detrusor, reducien- (2,7). It shows a weak or non-appreciable binding do la presión intravesical. affinity for neurotransmitter receptors like muscarinics, histaminergics, α1-adrenergics, dopaminergics and opioids (8-10). The ability of duloxetine to stimulate Palabras clave: Incontinencia urinaria. Clomiprami- pudendal motor neurons and increase striated sphinc- na. Duloxetina. Tracto urinario inferior. ter contractility is the basis for its efficacy in women with SUI (11). The storage-promoting effects are unique to dual reuptake inhibition in a single molecule and are INTRODUCTION not duplicated by the administration of 2 single-reup- take inhibitors (12). In the light of the compelling as- Involuntary leakage of urine due to effort, sociation between 5HT and NE systems and LUT func- exertion, sneezing or coughing is the most common tion, clomipramine and duloxetine were examined in type of urinary incontinence in women, with 78% of male and female rabbits to compare their effects on them presenting symptoms of stress urinary inconti- detrusor and striated sphincter function under both nence (SUI) in a pure (49%) or mixed (29%) form nonirritated bladder conditions (transvesical infusion (1). Treatment for SUI is limited to pelvic floor muscle of saline) and irritative conditions (i.e., transvesical training, various types of devices, behavioral inter- infusion of 0.5% acetic acid). 841 COMPARATIVE EFFECTS OF CLOMIPRAMINE AND DULOXETINE ON DETRUSOR... MATERIALS AND METHODS At the beginning of the cystometry the bladder was emptied. The liquid infusion to stabilize the cyclic Animals. A total of 32 male and 32 fema- voidings was maintained at least for 60 minutes, le New Zealand White rabbits weighing 2.5 to 3.5 continuously recording the cystometrogram. Then, Kg. were separated into groups of 8 each and were placebo was intravenously administered,