{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T18:47:53Z","timestamp":1773859673096,"version":"3.50.1"},"reference-count":39,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2009,2,10]],"date-time":"2009-02-10T00:00:00Z","timestamp":1234224000000},"content-version":"vor","delay-in-days":3999,"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":[[1998,3]]},"abstract":"<jats:p>\n<jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>The responses of the electrically\u2010driven right ventricle strip of the guinea\u2010pig heart to diazepam were recorded in the absence and in the presence of different selective cyclic nucleotide phosphodiesterase (PDE) inhibitors.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Diazepam, at concentrations ranging from 1\u2003\u03bc<jats:sc>M<\/jats:sc> to 100\u2003\u03bc<jats:sc>M<\/jats:sc>, was devoid of effect on the contractile force in this preparation.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Conversely, diazepam (5\u2003\u03bc<jats:sc>M<\/jats:sc>\u2013100\u2003\u03bc<jats:sc>M<\/jats:sc>) produced a consistent positive inotropic response in the presence of a concentration (1\u2003\u03bc<jats:sc>M<\/jats:sc>), that was without effect in the absence of diazepam, of either of the selective PDE 3 inhibitors milrinone or SK&amp;F 94120, but not in the presence of the selective PDE 4 inhibitor rolipram.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>This effect of diazepam was not \u03b3\u2010aminobutyric acid (GABA)\u2010dependent, since it was neither mimicked nor potentiated by GABA, and was not affected by either a high concentration (5\u2003\u03bc<jats:sc>M<\/jats:sc>) of the antagonists of the benzodiazepine\/GABA\/channel chloride receptor complex, picrotoxin, flumazenil and \u03b2\u2010carboline\u20103\u2010carboxylic acid methyl ester (\u03b2CCMe), or by the inverse agonists, \u03b2\u2010carboline\u20103\u2010carboxylic acid N\u2010methylamide (\u03b2CCMa) and methyl 6,7\u2010dimethoxy\u20104\u2010ethyl\u2010\u03b2\u2010carboline\u20103\u2010carboxylate (DMCM, 0.1\u2003\u03bc<jats:sc>M<\/jats:sc>). Furthermore, a specific antagonist of the peripheral benzodiazepine receptors, PK 11195 (5\u2003\u03bc<jats:sc>M<\/jats:sc>), did not influence the effect of diazepam.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Biochemical studies with isolated PDEs, confirmed that diazepam selectively inhibits type 4 PDE from guinea\u2010pig right ventricle rather than the other PDEs present in that tissue. The compound inhibited this enzyme in a non\u2010competitive manner. Diazepam was also able to inhibit PDE 5, the cyclic GMP specific PDE absent from cardiac muscle, with a potency close to that shown for PDE 4.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Diazepam displaced the selective type 4 PDE inhibitor, rolipram from its high affinity binding site in rat brain cortex membranes, and also potentiated the rise in cyclic AMP levels induced by isoprenaline in guinea\u2010pig eosinophils, where only type 4 PDE is present.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The PDE inhibitory properties of diazepam were shared, although with lower potency, by other structurally\u2010related benzodiazepines, that also displaced [<jats:sup>3<\/jats:sup>H]\u2010rolipram from its high affinity binding site. The order of potency found for these compounds in these assays was not related to their potencies as modulators of the GABA receptor through its benzodiazepine binding site.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>The pharmacological and biochemical data presented in this study indicate that diazepam behaves as a selective type 4 PDE inhibitor in cardiac tissue and this effect seems neither to be mediated by the benzodiazepine\/GABA\/channel chloride receptor complex nor by peripheral type benzodiazepine receptors.<\/jats:p><\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (1998) <jats:bold>123<\/jats:bold>, 1047\u20131054; doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0701698\">10.1038\/sj.bjp.0701698<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0701698","type":"journal-article","created":{"date-parts":[[2005,1,28]],"date-time":"2005-01-28T19:25:05Z","timestamp":1106940305000},"page":"1047-1054","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Functional and biochemical evidence for diazepam as a cyclic nucleotide phosphodiesterase type 4 inhibitor"],"prefix":"10.1111","volume":"123","author":[{"given":"M","family":"Carmen Collado","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jorge","family":"Beleta","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ester","family":"Martinez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Montse","family":"Miralpeix","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"Dom\u00e8nech","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jos\u00e9","family":"Maria Palacios","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jes\u00fas","family":"Hern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,2,10]]},"reference":[{"key":"e_1_2_6_2_1","first-page":"1396","article-title":"Inhibitors of phosphodiesterase Iv (PDe Iv) increase acid secretion in rabbit isolated gastric glands: correlation between function and interaction with a high\u2010affinity rolipram binding site","volume":"273","author":"Barnette M.S.","year":"1995","journal-title":"J. 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