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In-Vitro-Effects of Serotonin Reuptake

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In-Vitro-Effects of Serotonin Reuptake 457 458 CHARACTERISATION OF VARIOUS DRUGS LIKELY TO PLAY A IN-VITRO-EFFECTS OF SEROTONIN REUPTAKE INHIBITORS ON ROLE IN HUMAN SEMINAL VESICLE CONTRACTILITY HUMAN SEMINAL VESICLE AND ITS POTENTIAL ROLE IN THE EJACULATION PROCESS Birowo P.1, Ückert S.1, Meyer M.2, Kedia G.1, Machtens S., Thon W.F.4, Jonas U.1, 5 5 Taher A. , Rahardjo D. Birowo P.1, Ückert S.1, Meyer M.2, Keil C., Mägert H.J., Machtens S.4, Thon W.F.5, Scheller F.6, Jonas U.1, Taher A.7, Rahardjo D.7 1Hanover Medical School, Dept. of Urology, Hanover, Germany, 2FOCUS IP AG, Medical Department, Basel, Switzerland, Marien-Krankenhaus GmbH, Dept. of Urology, Bergisch 1Hanover Medical School, Dept. of Urology, Hanover, Germany, 2FOCUS IP AG, Gladbach, Germany, 4Klinikum Region Hanover-Krankenhaus Siloah, Dept. of Urology, Medical Department, Basel, Switzerland, Anhalt University of Applied Sciences, Dept. of Hanover, Germany, 5University of Indonesia School of Medicine/Cipto Mangunkusumo Biotechnology, Köthen, Germany, 4Marien-Krankenhaus GmbH, Dept. of Urology, Bergisch Hospital, Dept. of Urology, Jakarta, Indonesia Gladbach, Germany, 5Klinikum Region Hanover-Krankenhaus Siloah, Dept. of Urology, Hanover, Germany, 6Hanover Medical School, Dept. of Nuclear Medicine, Hanover, Germany, Introduction & Objectives: Seminal vesicle (SV) contractility is important in ejaculation 7University of Indonesia School of Medicine/Cipto Mangunkusumo Hospital, Dept. of Urology, SURFHVV 'LᚎHUHQW PHFKDQLVPV DUH LQYROYHG LQ KXPDQ 69 +69 FRQWUDFWLOLW\ $GHQRVLQH Jakarta, Indonesia triphosphate (ATP) is known as a contracting agent. Alpha adrenergic receptor blocker, FDOFLXP FKDQQHO EORFNHUV LQRVLWRO WULSKRVSKDW ,3 UHFHSWRU DQWDJRQLVW SRWDVVLXP Introduction & Objectives: It is discussed whether serotonin reuptake inhibitors (SRIs) retard channel openers, and rho kinase receptor inihibitors are known as relaxing agents. However, the ejaculatory response by regulation of seminal vesicle (SV) contractility. To our knowledge, serotonin is known is known to be both contracting and relaxing agent. Up till now, there are there are no data available about the peripheral action of SRIs on human SV (HSV). Therefore, QRGDWDDERXWWKHHᚎHFWRIWKRVHDJHQWVRQ+69FRQWUDFWLOLW\7KHUHIRUHWKHREMHFWLYHRIWKH the objective of this present study was (1) to evaluate the expression of serotonin (5-HT) VWXG\ZDVWRLQYHVWLJDWHWKHHᚎHFWRIWKRVHGUXJVRQ+69VPRRWKPXVFOHPRWLOLW\LQYLWUR UHFHSWRUV LQ WKH +69 WKH HᚎHFW RI FORPLSUDPLQH ᚐXR[HWLQH DQG LPLSUDPLQH RQ WKH UHOD[DWLRQRIQRUHSLQHSKULQH 1( SUHFRQWUDFWHGLVRODWHG+69VWULSVDQG WKHHᚎHFWRIWKRVH Material & Methods: HSV tissue was obtained from 15 patients (mean age 65 years old) SRIs on cAMP production in isolated HSV strips. who had undergone pelvic surgery due to malignancy. Using the organ bath techniques 2 GLᚎHUHQWH[SHULPHQWDOVHWXSVZHUHXVHG &RQWUDFWLRQRI69VPRRWKPXVFOHLQGXFHGE\ Material & Methods: Expression of the 5-HT receptors mRNA was analyzed by reverse increasing concentration (10 nM - 10µM) of ATP and 5-HT was tested. Norepinephrine (NE) transcriptase polymerase chain reaction under standard conditions. Using organ bath was used as standard. (2) HSV strips were pre-incubated with prazosin (alpha adrenergic WHFKQLTXHIROORZLQJSUHFRQWUDFWLRQRI+69VWULSVZLWKw0RI1(UHOD[LQJHᚎHFWVRILQFUHDVLQJ receptor blocker), nifedipine, verapamil (calcium channel blockers), 2-Aminoethoxydiphenyl FRQFHQWUDWLRQV Q0WRw0 RIFORPLSUDPLQHᚐXR[HWLQHRULPLSUDPLQHZHUHVWXGLHG(ᚎHFWRI NE without SRIs was used as control. Relaxation was expressed as percent of the maximum ERUDWH $3%DQ,3UHFHSWRUDQWDJRQLVW FURPDNDOLP SRWDVVLXPFKDQQHORSHQHU < contraction plateau induced by NE. Statistical analysis was performed using one way ANOVA. (rho-kinase inhibitor) or serotonin at 1µM each, followed by cumulative NE application (0,1 HSV strips were incubated with SRIs and following freezing, homogenization and extraction of to 10 µM) for contraction. NE-induced contraction on strips not pre-incubated with the cyclic nucleotides, cAMP was measured by means of radioimmunoassay. respective drugs served as a control (100%). Results: mRNAs were detected for 5-HT1A, 5-HT1B, 5-HT1E, 5-HT2C, 5-HT4, 5-HT6, 5-HT7 Results: Ad (1): HSV smooth muscle strips were dose-dependently contracted by NE, receptors in the HSV samples, but not for the 5HT2A, 5-HT2B and 5-HT1D receptors. The NE ZKHUHDVRQO\PLQRUFRQWUDFWLQJHᚎHFWVZHUHIRXQGIRU$73DQG+7$G 7KHFRQWUDFWLRQ induced contraction was reduced by the SRIs in a dose dependent manner. The rank order of LQGXFHG E\ 1( ZDV HᚎHFWLYHO\ LQKLELWHG WKURXJK SUHLQFXEDWLRQ ZLWK SUD]RVLQ HᚑFDF\DWORZGRVHZDVᚐXR[HWLQH!LPLSUDPLQH!FORPLSUDPLQHZKLOHDWWKHKLJKGRVHLWZDV FURPDNDOLP VHURWRQLQ $3% < 7KHOHDVWQR LPLSUDPLQH! ᚐXR[HWLQH ! FORPLSUDPLQH 7KH LQKLELWRU\ HᚎHFWV E\ ᚐXR[HWLQH LPLSUDPLQH DQG HᚎHFWVZHUHVHHQZLWKQLIHGLSLQH DQGYHUDSDPLO FORPLSUDPLQHZHUHVWDWLVWLFDOO\VLJQLᚏFDQWFRPSDUHGWRFRQWURO S ,QFXEDWLRQRI65,VOHG WRWRIROGLQFUHDVHRIF$03SURGXFWLRQ Conclusions: Our results demonstrate that in contrast to calcium channel blockers, alpha blockers, potassium openers and serotonin decrease the contraction induced by NE thus, Conclusions: Our results support the hypothesis that SRIs inhibit in vitro the NE-induced SRVVLEO\SOD\LQJDUROHLQGHOD\LQJWKHHMDFXODWRU\PHFKDQLVP7KHVHᚏQGLQJVPD\RSHQQHZ contraction of HSV smooth muscle strips probably through binding to 5-HT4, 5-HT6, and/or pharmacological treatment regimens for PE. +7UHFHSWRUVDQGLQWUDFHOOXODUF$03JHQHUDWLRQ7KLVGHPRQVWUDWHVIRUWKHᚏUVWWLPHWKDW SRIs may act on HSV as the peripheral target organ. 459 460 EJACULATION ELICITED BY MICRO STIMULATION OF LUMBAR SELECTIVE ANTAGONISM OF DOPAMINE D3 RECEPTOR SPINOTHALAMIC NEURONS SPECIFICALLY INHIBITS THE EXPULSION PHASE OF EJACULATION IN ANAESTHETISED MALE RATS %RUJGRUᚎ$-1, Bernabe J.1, Alexandre L.1, Denys P.2, Guiliano F.2 Clement P.1, Peeters M.1, Bernabe J.1, Mevell K.1, Denys P.2, Giuliano F.2 1Pelvipharm SAS, R&D, Gif-sur-Yvette, France, 25D\PRQG 3RLQFDU« +RVSLWDO 'HSW RI Physical Medicine and Rehabilitation, Garches, France 1Pelvipharm Laboratories, Dept. of Neuropharmacology, Gif-sur-Yvette, France, 2Poincare Hospital, Dept. of Physical Medicine and Rehabilitation, Garches, France Introduction & Objectives: 1HXURDQDWRPLFDO DQG OHVLRQ VWXGLHV LQ UDW KDYH LGHQWLᚏHG lumbar spinothalamic (LSt) neurons in the spinal cord to be essential for ejaculation. Introduction & Objectives: 7KH UROH RI GRSDPLQH ' UHFHSWRUV LQ WKH FRQWURO RI However, the exact role of LSt neurons in ejaculation and their action on anatomical ejaculation is not fully elucidated. The present study was undertaken to clarify this role structures involved in the two ejaculation phases, emission and expulsion remains unclear. by using a pharmacological model of ejaculation in anaesthetised rats. For this purpose We present evidence that LSt neurons activate the entire sequence of ejaculation. ZHH[SORUHGWKHHᚎHFWVRIDKLJKO\'VHOHFWLYHDQWDJRQLVWRQVH[XDOUHVSRQVHVHOLFLWHG Material & Methods: In adult male rats kept under urethane anesthesia, electrodes were E\LYK\GUR[\ GL1SURS\ODPLQR WHWUDOLQ 2+'3$7 DGRSDPLQH'SUHIHUHQWLDO implanted in the bulbospongiosus muscle (BSM) to record BSM EMG, and catheterization agonist. of the seminal vesicle (SV) lumen was performed to record intraluminal SV pressure. After exposure of the spine at the 4th lumbar (L4) spinal segment, an electrode was stereotaxically Material & Methods: Sexually naive adult male Wistar rats were anaesthetised lowered into spinal area VII/X for the electrical stimulation of LSt neurons. ZLWK LVRᚐXUDQH 6HPLQDO YHVLFOH SUHVVXUH 693 DQG EXOERVSRQJLRVXV PXVFOH %6 electromyogram were recorded as physiological markers of, respectively, emission Results: Brief electrical microstimulation in the LSt neuron area (60-100 of 0.5ms-duration and expulsion phases of ejaculation. Pressure in the corpus cavernosum (ICP) was current pulses, delivered at 200 Hz) evoked the expulsion of semen at the urethral meatus, DOVRPHDVXUHGDVSK\VLRORJLFDOPDUNHURIHUHFWLRQ7KH'VHOHFWLYHDQWDJRQLVW 1> in 17/17 rats, which contained motile spermatozoa in 10 /17 rats. Immediately after >'LFKORURSKHQ\O SLSHUD]LQ\O@EXW\O@+ᚐXRUHQHFDUER[DPLGH 1*% ZDV microstimulation, SV luminal pressure rose and fell, followed by rhythmic BSM contractions GHOLYHUHGLY DQGPJNJQ HDFK PLQSULRUWRLY2+'3$7 PJNJ WKDWODVWHGIRUaVGHPRQVWUDWLQJWKDW/6WQHXURQPLFURVWLPXODWLRQHOLFLWHGWKHHPLVVLRQ Sexual responses were recorded over 20 min following 7-OH-DPAT administration. (SV pressure rise) and the expulsion phases (BSM activity) in a coordinated fashion. Isolating the spinal cord from supraspinal (n = 4) and peripheral (n = 5) sources prior to Results: The recordings in rats treated with NGB2904 showed that BS contractions LSt neuron microstimulation established the spinal origin of the evoked BSM activity. We induced by 7-OH-DPAT were temporarily inhibited whereas SVP and ICP responses injected a small quantity of the GABAA-receptor agonist muscimol, known to suppress ZHUHQRWDOWHUHG,Q1*%PJNJWUHDWHGUDWVLQFLGHQFHRI2+'3$7LQGXFHG local neuron activity, into the LSt neuron area after LSt neuron microstimulation (n = 5). HMDFXODWLRQ ZDV UHGXFHG DQG WKHUH ZDV D IROG LQFUHDVH LQ WKH ᚏUVW HMDFXODWLRQ This stopped the elicited ejaculation in midstream, demonstrating that LSt neurons not only latency to occur following 7-OH-DPAT injection as compared to vehicle animals. This initiate ejaculation, but are also required to maintain it. ZDVDVVRFLDWHGZLWKDVLJQLᚏFDQWGHOD\LQWKHᚏUVW%6UHVSRQVHWRRFFXUDIWHU2+ '3$7GHOLYHU\DQGDVLJQLᚏFDQWGLPLQXWLRQRI%6FRQWUDFWLOHDFWLYLW\7KHRWKHUVH[XDO
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