Inhibition of interleukin-6 attenuates erectile dysfunction in a rat model of nerve-sparing radical prostatectomy.

INTRODUCTION: The precise mechanisms underlying erectile dysfunction (ED) occurring after cavernous nerve (CN)-sparing surgery remain to be determined. Aim. To evaluate the expression of interleukin-6 (IL-6) and IL-6 receptor (IL-6R) after CN injury, and the effect of inhibiting IL-6 bioactivity on nerve injury-related ED. METHODS: Male Sprague-Dawley rats were divided into three groups: sham operation; bilateral CN dissection without crushing or cutting; and bilateral CN resection. In the interventional experiment, male rats underwent bilateral CN dissection, and anti-rat IL-6 antibody in phosphate-buffered saline (PBS) or vehicle alone was injected intraperitoneally immediately and 24 hours after CN dissection. MAIN OUTCOME MEASURES: One, 3, 7, 28, and 56 days after surgery, the expression of IL-6 and IL-6R in the major pelvic ganglion (MPG) was examined by real-time polymerase chain reaction. In the interventional experiment, erectile function was assessed by determining intracavernous pressure divided by arterial pressure (ICP/AP) during electrical pelvic nerve stimulation at 4 weeks after surgery in the anti-IL-6-injected rats and PBS-injected rats. The degree of nerve injury was also evaluated by retrograde dye tracing with Fluorogold. RESULTS: The expression levels of IL-6 and IL-6R were increased in the early period of CN injury, as compared with the sham group. IL-6 expression on day 1 was particularly enhanced. Four weeks after CN dissection, the anti-IL-6 group had greater ICP/AP and more FG-positive cells than the PBS group. CONCLUSIONS: Expression levels of IL-6 in the MPG were increased in the acute phase following CN injury. Inhibition of IL-6 bioactivity attenuated ED following CN dissection. Thus, the suppression of excess inflammatory responses in the acute phase may lead to improvements in ED occurring after nerve-sparing radical prostatectomy.

Bases moleculares de la disfunción eréctil / Molecular mechanisms of penile erection

Los estados fisiológicos de flacidez o de erección del pene resultan de contracción o la relajación, respectivamente, de las células musculares lisas del cuerpo cavernoso (CSMCs). Son determinados por la interacción de diversas vías de señalización molecular inter- e intracelulares.En el estado más frecuente, de flacidez, predomina una actividad tónica de la inervación simpática, con liberación de noradrenalina (NA) y otros mensajeros que generan señales contráctiles en el músculo liso cavernoso, con la cooperación probable de otras procedentes del endotelio. Todas ellas activan receptores de membrana en las CSMCs que generan los mensajeros intracelulares inositol trifosfato (IP3) y diacilglicerol (DAG). El resultado es un aumento transitorio de la concentración intracitosólica de calcio ([Ca+2]i) que inicia la respuesta contráctil así como la activación de un mecanismo de “sensibilización al calcio” operado por la vía RhoA/ROCK que la mantiene. La sobre-expresión de dicho mecanismo parece contribuir a la patogenia de diversos trastornos vasculares como la hipertensión, el vasoespasmo o la disfunción eréctil(AU)

La estimulación sexual hace que los nervios erectores liberen óxido nítrico (NO), que inicia la respuesta eréctil. Los nervios erectores liberan también acetilcolina que activa la producción, más sotenida, de NO por el endotelio, que se suma al de origen neural. La entrada de NO por difusión a las células musculares lisas genera en ellas guanosín monofosfato cíclico (cGMP) que induce una serie de reacciones que llevan a la disminución de [Ca+2]i y la inactivación del mecanismo de sensibilización al calcio, lo que relaja las CSMCs. A este sistema principal de señalización erectogénica se añade, con efectos similares, el del adenosín monofosfato cíclo (cAMP), activado por diversos mensajeros intercelulares de origen neural y paracrino, como la prostaglandina E (PGE). Diversas fosfodiesterases (PDEs) inactivan dichos nucleótidos cíclicos, limitando su acción erectogénica. La inhibición farmacológica, particularmente de la PDE5 (específica del cGMP), facilita considerablemente la respuesta eréctil. Hay mecanismos de intercomunicación entre ambas vías de señalización erectogénica (cGMP y cAMP) que pueden aprovecharse en la terapia farmacológica de la disfunción eréctil(AU)

The penis physiological states of flaccidity or erection, result from the contraction or relaxation, respec-tively, of smooth muscle cells in the corpora cavernosa (CSMCs). They result from the interaction of various inter- and intracellular molecular signaling pathways.During the more usual state of flaccidity seems to pre-dominate a tonic sympathetic activity, releasing nora-drenaline (NA) and other agonists that generate con-tractile signals in the CSMCs, with the likely cooperation of endothelium-derived messengers. Through activation of membrane receptors in the CSMCs they raise the in-tracellular messengers inositol triphosphate (IP3) and diacylglycerol (DAG). This results in a transient increase in cytosolic calcium concentration [Ca2+]i that starts the contractile response which is further sustained by the parallel agonist-induced activation of a “calcium sensi-tizing” mechanism involving the RhoA/Rho-kinase pa-thway. Overexpression of the latter might contribute to several vascular disorders as hypertension, vasospasm or erectile dysfunction(AU)

On sexual stimulation the cavernous nerves release nitric oxide (NO) that starts the erectile response. They also release acetylcholine that stimulates the endothelium to generate a more sustained release of NO. NO diffuses into CSMCs and increases their intracellular levels of cyclic guanosin monophosphate (cGMP) which decrea-ses [Ca2+]i and deactivates the calcium sensitizing mechanism, thus relaxing CSMCs. This main physiolo-gical pathway for CSMCs relaxation is helped by the cyclic adenosin monophosphate (cAMP) pathway ac-tivated by various intercellular messengers from neural or paracrine sources, including prostaglandins E (PGE). Different phosphodiesterase enzymes (PDEs) inactivate the cyclic nucleotides thereby limiting their erectogenic action. Indeed the pharmacological inhibition of PDEs, especially the cGMP- specific PDE5, greatly enhances the erectile responses. There are cross-talk mechanisms between the cGMP and cAMP signaling pathways that offer additional possibilities for the pharmacotherapy of erectile dysfunction(AU)