MP31-12 TAMSULOSIN IMPROVES MEMORY FUNCTION BY ACTIVATING NMDA RECEPTORS IN RAT HIPPOCAMPUS

Abstract

INTRODUCTION AND OBJECTIVES: Prostate smooth muscle contraction may be critical for pathophysiology and therapy of lower urinary tract symptoms (LUTS) suggestive of benign prostate hyperplasia. Although application of a1-blockers represents the goldstandard for medical treatment, their effects are limited to max. 50%. The reasons are unknown, while only little is known about contributions of nonadrenergic mediators to prostate contraction. In vivo, different mediators probably do not occur separately, but rather act simultaneously on smooth muscle cells. Here, we compared different contractile mediators with norepinephrine, and adressed their cooperative effects in contraction of human prostate smooth muscle. METHODS: Prostate tissues were obtained from radical prostatectomy (n1⁄472 patients). Contractility of prostate strips was assessed in an organ bath. Receptor expression was detected by Western blot analysis and fluorescence staining. RESULTS: Maximum endothelin-1 (ET-1)(0.1-3 mM), endothelin-2 (ET-2)(0.1-3 mM), and norepinephrine (NE)(0.1-100 mM) induced contractions were of similar magnitude (ET-1 116 23% of KCl-induced contraction; ET-2 86 17%; NE 117 18%). Maximum contractions by the thromboxane analogue, U46619 (10 mM) amounted on average around 50% of NE-induced contraction (63 9% of KCl). ET-1or ET-2-induced contractions were not affected by the a1-blocker tamsulosin (300 nM), while NE-induced contraction was virtually completely abolished and U46619-induced contraction was slightly inhibited. Dopamine (0.1-300 mM) and serotonin (0.1-300 mM) induced only very slight contractions (22 4% and 9 2% of KCl) of prostate strips, which may be of minor or local relevance. Carbachol and uridine adenosine tetraphosphate did not induce contractions. After maximumNE-induced precontraction, ET-1 did not further increase tension. In contrast, contractile effects of ET-1 (3 mM) and U46619 (10 mM) were additive, so that tension after combined application of ET-1 and U46619 (172 25% of KCl) was higher than maximumNE(100 mM) induced tension (p<0.05). Endothelin receptor A and B were detectable by Western blot in all samples. Double fluorescence staining suggests expression in stromal smooth muscle cells. CONCLUSIONS: NE-induced contraction of human prostate smooth muscle can be exceeded by cooperative actions of endothelins and thromboxane. These contractions may even occur under treatment with a1-blockers. Such contributions of non-adrenergic mediators might explain the limited efficacy of a1-blockers.