TISSUE SELECTIVITY OF KMD-3213, AN α1-ADRENOCEPTOR ANTAGONIST, IN HUMAN PROSTATE AND VASCULATURE

No AccessJournal of UrologyINVESTIGATIVE UROLOGY1 Aug 2000TISSUE SELECTIVITY OF KMD-3213, AN α1-ADRENOCEPTOR ANTAGONIST, IN HUMAN PROSTATE AND VASCULATURE SATOSHI MURATA, TAKANOBU TANIGUCHI, MASAHIKO TAKAHASHI, KENICHIRO OKADA, KATSUYOSHI AKIYAMA, and IKUNOBU MURAMATSU SATOSHI MURATASATOSHI MURATA , TAKANOBU TANIGUCHITAKANOBU TANIGUCHI , MASAHIKO TAKAHASHIMASAHIKO TAKAHASHI , KENICHIRO OKADAKENICHIRO OKADA , KATSUYOSHI AKIYAMAKATSUYOSHI AKIYAMA , and IKUNOBU MURAMATSUIKUNOBU MURAMATSU View All Author Informationhttps://doi.org/10.1016/S0022-5347(05)67426-5AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract Purpose: We evaluated the binding and functional affinity of KMD-3213 and other α1-adrenoceptor (AR) antagonists such as prazosin or tamsulosin, to compare the tissue selectivity of these antagonists between human prostate and vasculature. Materials and Methods: In the binding experiments, saturation experiments using [3H]-KMD and [3H]-prazosin (PZ) were performed, and competition of [3H]-PZ binding by antagonists was also examined in human prostatic and aortic membranes. In the functional study, contractile responses to noradrenaline were evaluated in human prostate and mesenteric artery. Results: [3H]-PZ bound to human prostatic and aortic membranes with subnanomolar affinity. [3H]-KMD also bound to human prostate, with higher affinity than [3H]-PZ; whereas it did not bind sufficiently to human aorta. Competition of [3H]-PZ binding revealed that KMD-3213 had more than 200-fold higher affinity for human prostate than for aorta. Binding profiles of antagonists revealed that human prostate predominantly expressed α1A-AR, whereas human aorta expressed α1B-AR mainly. In functional experiments, KMD-3213 potently inhibited the noradrenaline-induced contraction in human prostate as potently as tamsulosin, although prazosin showed relatively low affinity. Comparing these functional affinities with those in the mesenteric artery, only KMD-3213 exhibited substantial tissue selectivity, showing more than 100-fold higher affinity for human prostate than for mesenteric artery. Functional affinity of each antagonist suggested that noradrenaline-induced contractions were mainly mediated by α1L-AR in the human prostate and by α1B-AR in the mesenteric artery. Conclusion: These results suggest that KMD-3213 is a substantially prostate-selective α1-AR antagonist in human tissues compared with other α1-AR antagonists. References 1 : Characterization of alpha 1-adrenoceptor subtypes in tension response of human prostate to electrical field stimulation. Br J Pharmacol1995; 115: 142. 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Google Scholar From the Departments of Pharmacology and Urology, School of Medicine, Fukui Medical University, Matsuoka, Fukui, and the Pharmacology Research Laboratory, Kissei Pharmaceutical Co., Ltd., Hotaka, Nagano, Japan.© 2000 by American Urological Association, Inc.FiguresReferencesRelatedDetailsCited byMarks L, Gittelman M, Hill L, Volinn W and Hoel G (2018) Rapid Efficacy of the Highly Selective α1A-Adrenoceptor Antagonist Silodosin in Men With Signs and Symptoms of Benign Prostatic Hyperplasia: Pooled Results of 2 Phase 3 StudiesJournal of Urology, VOL. 189, NO. 1S, (S122-S128), Online publication date: 1-Jan-2013.Morishima S, Suzuki F, Nishimune A, Yoshiki H, Akino H, Yokoyama O and Muramatsu I (2009) Visualization and Tissue Distribution of α1L-Adrenoceptor in Human Prostate by the Fluorescently Labeled Ligand Alexa-488-SilodosinJournal of Urology, VOL. 183, NO. 2, (812-819), Online publication date: 1-Feb-2010.Marks L, Gittelman M, Hill L, Volinn W and Hoel G (2009) Rapid Efficacy of the Highly Selective α1A-Adrenoceptor Antagonist Silodosin in Men With Signs and Symptoms of Benign Prostatic Hyperplasia: Pooled Results of 2 Phase 3 StudiesJournal of Urology, VOL. 181, NO. 6, (2634-2640), Online publication date: 1-Jun-2009.Morishima S, Tanaka T, Yamamoto H, Suzuki F, Akino H, Yokoyama O and Muramatsu I (2018) Identification of α-1L and α-1A Adrenoceptors in Human Prostate by Tissue Segment BindingJournal of Urology, VOL. 177, NO. 1, (377-381), Online publication date: 1-Jan-2007. Volume 164Issue 2August 2000Page: 578-583 Advertisement Copyright & Permissions© 2000 by American Urological Association, Inc.Keywordsα1-adrenoceptorhumanprazosinKMD-3213tamsulosinMetricsAuthor Information SATOSHI MURATA More articles by this author TAKANOBU TANIGUCHI More articles by this author MASAHIKO TAKAHASHI More articles by this author KENICHIRO OKADA More articles by this author KATSUYOSHI AKIYAMA More articles by this author IKUNOBU MURAMATSU More articles by this author Expand All Advertisement PDF downloadLoading ...