{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T14:30:54Z","timestamp":1772893854617,"version":"3.50.1"},"reference-count":34,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2009,1,29]],"date-time":"2009-01-29T00:00:00Z","timestamp":1233187200000},"content-version":"vor","delay-in-days":1642,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2004,8]]},"abstract":"<jats:p>\n<jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>7\u2010[2\u2010[4\u2010(2\u2010chlorophenyl)piperazinyl]ethyl]\u20101,3\u2010dimethylxanthine (KMUP\u20101) produces tracheal relaxation, intracellular accumulation of cyclic nucleotides, inhibition of phosphodiesterases (PDEs) and activation of K<jats:sup>+<\/jats:sup> channels.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>KMUP\u20101 (0.01\u2013100 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc>) induced concentration\u2010dependent relaxation responses in guinea\u2010pig epithelium\u2010intact trachea precontracted with carbachol. Relaxation responses were also elicited by the PDE inhibitors theophylline, 3\u2010isobutyl\u20101\u2010methylxanthine (IBMX), milrinone, rolipram and zaprinast (100 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc>), and a K<jats:sub>ATP<\/jats:sub> channel opener, levcromakalim.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Tracheal relaxation induced by KMUP\u20101 was attenuated by epithelium removal and by pretreatment with inhibitors of soluble guanylate cyclase (sGC) (1H\u2010[1,2,4]oxadiazolo[4,3\u2010a]quinoxalin\u20101\u2010one (ODQ), 1 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc>), nitric oxide synthase (<jats:italic>N<\/jats:italic><jats:sup><jats:italic>\u03c9<\/jats:italic><\/jats:sup>\u2010nitro\u2010<jats:sc>L<\/jats:sc>\u2010arginine methyl ester, 100 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc>), K<jats:sup>+<\/jats:sup> channels (tetraethylammonium, 10 m<jats:sc>M<\/jats:sc>), K<jats:sub>ATP<\/jats:sub> channels (glibenclamide, 1 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc>), voltage\u2010dependent K<jats:sup>+<\/jats:sup> channels (4\u2010aminopyridine, 100 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc>) and Ca<jats:sup>2+<\/jats:sup>\u2010dependent K<jats:sup>+<\/jats:sup> channels (charybdotoxin, 0.1 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc> or apamin, 1 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc>).<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Both KMUP\u20101 (10 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc>) and theophylline nonselectively and slightly inhibited the enzyme activity of PDE3, 4 and 5, suggesting that they are able to inhibit the metabolism of adenosine 3\u2032,5\u2032\u2010cyclic monophosphate (cyclic AMP) and guanosine 3\u2032,5\u2032\u2010cyclic monophosphate (cyclic GMP). Likewise, the effects of IBMX were also measured and its IC<jats:sub>50<\/jats:sub> values for PDE3, 4 and 5 were 6.5\u00b11.2, 26.3\u00b13.9 and 31.7\u00b15.3 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc>, respectively.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>KMUP\u20101 (0.01\u201310 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc>) augmented intracellular cyclic AMP and cyclic GMP levels in guinea\u2010pig cultured tracheal smooth muscle cells. These increases in cyclic AMP and cyclic GMP were abolished in the presence of an adenylate cyclase inhibitor SQ 22536 (100 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc>) and an sGC inhibitor ODQ (10 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc>), respectively.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>KMUP\u20101 (10 <jats:italic>\u03bc<\/jats:italic><jats:sc>M<\/jats:sc>) increased the expression of protein kinase A (PKA<jats:sub>RI<\/jats:sub>) and protein kinase G (PKG<jats:sub>1<jats:italic>\u03b1<\/jats:italic>1<jats:italic>\u03b2<\/jats:italic><\/jats:sub>) in a time\u2010dependent manner, but this was only significant for PKG after 9 h.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Intratracheal administration of tumour necrosis factor\u2010<jats:italic>\u03b1<\/jats:italic> (TNF\u2010<jats:italic>\u03b1<\/jats:italic>, 0.01 mg kg<jats:sup>\u22121<\/jats:sup>) induced bronchoconstriction and exhibited a time\u2010dependent increase in lung resistance (<jats:italic>R<\/jats:italic><jats:sub>L<\/jats:sub>) and decrease in dynamic lung compliance (<jats:italic>C<\/jats:italic><jats:sub>dyn<\/jats:sub>). KMUP\u20101 (1.0 mg kg<jats:sup>\u22121<\/jats:sup>), injected intravenously for 10 min before the intratracheal TNF\u2010<jats:italic>\u03b1<\/jats:italic>, reversed these changes in <jats:italic>R<\/jats:italic><jats:sub>L<\/jats:sub> and <jats:italic>C<\/jats:italic><jats:sub>dyn<\/jats:sub>.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>These data indicate that KMUP\u20101 activates sGC, produces relaxation that was partly dependent on an intact epithelium, inhibits PDEs and increases intracellular cyclic AMP and cyclic GMP, which then increases PKA and PKG, leading to the opening of K<jats:sup>+<\/jats:sup> channels and resulting tracheal relaxation.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2004) <jats:bold>142<\/jats:bold>, 1105\u20131114. doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0705791\">10.1038\/sj.bjp.0705791<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0705791","type":"journal-article","created":{"date-parts":[[2004,7,29]],"date-time":"2004-07-29T20:52:18Z","timestamp":1091134338000},"page":"1105-1114","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["KMUP\u20101, a xanthine derivative, induces relaxation of guinea\u2010pig isolated trachea: the role of the epithelium, cyclic nucleotides and K<sup>+<\/sup> channels"],"prefix":"10.1111","volume":"142","author":[{"given":"Bin\u2010Nan","family":"Wu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rong\u2010Jyh","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi\u2010Ching","family":"Lo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kuo\u2010Pyng","family":"Shen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao\u2010Chuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Young\u2010Tso","family":"Lin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ing\u2010Jun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,1,29]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1165\/ajrcmb.19.3.2996"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1986.tb10273.x"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1988.tb11702.x"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.95.08030457"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1995.75.4.725"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0702779"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/368850a0"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1984.sp015262"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1992.tb14451.x"},{"key":"e_1_2_7_11_1","first-page":"334","article-title":"Airway epithelium: more than just a barrier!Trends Pharmacol","volume":"19","author":"FOLKERTS G.","year":"1998","journal-title":"Sci."},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm\/139.5.1192"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118708"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2744(76)90296-5"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(98)00690-6"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0702830"},{"key":"e_1_2_7_17_1","first-page":"330","article-title":"Regulation of adenosine cyclic 3\u2032,5\u2032\u2010monophosphate and guanosine cyclic 3\u2032,5\u2032\u2010monophosphate levels and contractility in bovine tracheal smooth muscle","volume":"13","author":"KATSUKI S.","year":"1977","journal-title":"Mol. Pharmacol."},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.74.3.471"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0704554"},{"key":"e_1_2_7_20_1","first-page":"129","article-title":"Towards an understanding of the mechanism of action of cyclic AMP and cyclic GMP in smooth muscle relaxation","volume":"28","author":"LINCOLN T.M.","year":"1991","journal-title":"Blood Vessels"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0014-2999(99)00872-9"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1989.tb12641.x"},{"key":"e_1_2_7_23_1","first-page":"145","article-title":"Guanylate cyclase: activation by azide, nitrocompounds, nitric oxide, and hydroxyl radical and inhibition by hemoglobin and myoglobin","volume":"9","author":"MURAD F.","year":"1978","journal-title":"Adv. Cyclic Nucleotide Res."},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1995.sp020789"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00373.2001"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm\/148.3.727"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(85)90301-6"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.95.08040637"},{"key":"e_1_2_7_29_1","first-page":"659","volume-title":"Goodman and Gilman's The Pharmacological Basis of Therapeutics","author":"SERAFIN W.E.","year":"1996"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1681.1991.tb01427.x"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1990.tb14072.x"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1997.sp022047"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(94)90229-1"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0704231"},{"key":"e_1_2_7_35_1","first-page":"972","article-title":"Relationship between cyclic guanosine monophosphate accumulation and relaxation of canine trachealis induced by nitrovasodilators","volume":"258","author":"ZHOU H.L.","year":"1991","journal-title":"J. Pharmacol. Exp. Ther."}],"container-title":["British Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1038%2Fsj.bjp.0705791","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1038%2Fsj.bjp.0705791","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/pdf\/10.1038\/sj.bjp.0705791","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,13]],"date-time":"2023-10-13T20:56:40Z","timestamp":1697230600000},"score":1,"resource":{"primary":{"URL":"https:\/\/bpspubs.onlinelibrary.wiley.com\/doi\/10.1038\/sj.bjp.0705791"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,8]]},"references-count":34,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2004,8]]}},"alternative-id":["10.1038\/sj.bjp.0705791"],"URL":"https:\/\/doi.org\/10.1038\/sj.bjp.0705791","archive":["Portico"],"relation":{},"ISSN":["0007-1188","1476-5381"],"issn-type":[{"value":"0007-1188","type":"print"},{"value":"1476-5381","type":"electronic"}],"subject":[],"published":{"date-parts":[[2004,8]]},"assertion":[{"value":"2009-01-29","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}