{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T10:41:55Z","timestamp":1776422515632,"version":"3.51.2"},"reference-count":41,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2009,1,29]],"date-time":"2009-01-29T00:00:00Z","timestamp":1233187200000},"content-version":"vor","delay-in-days":3561,"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":[[1999,5]]},"abstract":"<jats:p>\n<jats:list list-type=\"explicit-label\">\n<jats:list-item>\n<jats:p>The effects of several phosphodiesterase (PDE) inhibitors on the L\u2010type Ca current (<jats:italic>I<\/jats:italic><jats:sub>Ca<\/jats:sub>) and intracellular cyclic AMP concentration ([cAMP]<jats:sub>i<\/jats:sub>) were examined in isolated rat ventricular myocytes. The presence of mRNA transcripts encoding for the different cardiac PDE subtypes was confirmed by RT\u2013PCR.<\/jats:p>\n<\/jats:list-item>\n<jats:list-item>\n<jats:p>IBMX (100\u2003\u03bc<jats:sc>M<\/jats:sc>), a broad\u2010spectrum PDE inhibitor, increased basal <jats:italic>I<\/jats:italic><jats:sub>Ca<\/jats:sub> by 120% and [cAMP]<jats:sub>i<\/jats:sub> by 70%, similarly to a saturating concentration of the \u03b2\u2010adrenoceptor agonist isoprenaline (1\u2003\u03bc<jats:sc>M<\/jats:sc>). However, MIMX (1\u2003\u03bc<jats:sc>M<\/jats:sc>), a PDE1 inhibitor, EHNA (10\u2003\u03bc<jats:sc>M<\/jats:sc>), a PDE2 inhibitor, cilostamide (0.1\u2003\u03bc<jats:sc>M<\/jats:sc>), a PDE3 inhibitor, or Ro 20\u20131724 (0.1\u2003\u03bc<jats:sc>M<\/jats:sc>), a PDE4 inhibitor, had no effect on basal <jats:italic>I<\/jats:italic><jats:sub>Ca<\/jats:sub> and little stimulatory effects on [cAMP]<jats:sub>i<\/jats:sub> (20\u201330%).<\/jats:p>\n<\/jats:list-item>\n<jats:list-item>\n<jats:p>Each selective PDE inhibitor was then tested in the presence of another inhibitor to examine whether a concomitant inhibition of two PDE subtypes had any effect on <jats:italic>I<\/jats:italic><jats:sub>Ca<\/jats:sub> or [cAMP]<jats:sub>i<\/jats:sub>. While all combinations tested significantly increased [cAMP]<jats:sub>i<\/jats:sub> (40\u201350%), only cilostamide (0.1\u2003\u03bc<jats:sc>M<\/jats:sc>)+Ro20\u20101724 (0.1\u2003\u03bc<jats:sc>M<\/jats:sc>) produced a significant stimulation of <jats:italic>I<\/jats:italic><jats:sub>Ca<\/jats:sub> (50%). Addition of EHNA (10\u2003\u03bc<jats:sc>M<\/jats:sc>) to this mix increased <jats:italic>I<\/jats:italic><jats:sub>Ca<\/jats:sub> to 110% and [cAMP]<jats:sub>i<\/jats:sub> to 70% above basal, i.e. to similar levels as obtained with IBMX (100\u2003\u03bc<jats:sc>M<\/jats:sc>) or isoprenaline (1\u2003\u03bc<jats:sc>M<\/jats:sc>).<\/jats:p>\n<\/jats:list-item>\n<jats:list-item>\n<jats:p>When tested on top of a sub\u2010maximal concentration of isoprenaline (1\u2003n<jats:sc>M<\/jats:sc>), which increased <jats:italic>I<\/jats:italic><jats:sub>Ca<\/jats:sub> by (\u223c40% and had negligible effect on [cAMP]<jats:sub>i<\/jats:sub>, each selective PDE inhibitor induced a clear stimulation of [cAMP]<jats:sub>i<\/jats:sub> and an additional increase in <jats:italic>I<\/jats:italic><jats:sub>Ca<\/jats:sub>. Maximal effects on <jats:italic>I<\/jats:italic><jats:sub>Ca<\/jats:sub> were \u223c8% for MIMX (3\u2003\u03bc<jats:sc>M<\/jats:sc>), \u223c20% for EHNA (1\u20133\u2003\u03bc<jats:sc>M<\/jats:sc>), \u223c30% for cilostamide (0.3\u20131\u2003\u03bc<jats:sc>M<\/jats:sc>) and \u223c50% for Ro20\u20101724 (0.1\u2003\u03bc<jats:sc>M<\/jats:sc>).<\/jats:p>\n<\/jats:list-item>\n<jats:list-item>\n<jats:p>Our results demonstrate that PDE1\u20104 subtypes regulate <jats:italic>I<\/jats:italic><jats:sub>Ca<\/jats:sub> in rat ventricular myocytes. While PDE3 and PDE4 are the dominant PDE subtypes involved in the regulation of basal <jats:italic>I<\/jats:italic><jats:sub>Ca<\/jats:sub>, all four PDE subtypes determine the response of <jats:italic>I<\/jats:italic><jats:sub>Ca<\/jats:sub> to a stimulus activating cyclic AMP production, with the rank order of potency PDE4&gt;PDE3&gt;PDE2&gt;PDE1.<\/jats:p>\n<\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (1999) <jats:bold>127<\/jats:bold>, 65\u201374; doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0702506\">10.1038\/sj.bjp.0702506<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0702506","type":"journal-article","created":{"date-parts":[[2005,1,28]],"date-time":"2005-01-28T20:03:02Z","timestamp":1106942582000},"page":"65-74","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":158,"title":["Characterization of the cyclic nucleotide phosphodiesterase subtypes involved in the regulation of the L\u2010type Ca<sup>2+<\/sup> current in rat ventricular myocytes"],"prefix":"10.1111","volume":"127","author":[{"given":"Ignacio","family":"Verde","sequence":"first","affiliation":[]},{"given":"Gr\u00e9goire","family":"Vandecasteele","sequence":"additional","affiliation":[]},{"given":"Frank","family":"Lezoualc'h","sequence":"additional","affiliation":[]},{"given":"Rodolphe","family":"Fischmeister","sequence":"additional","affiliation":[]}],"member":"311","published-online":{"date-parts":[[2009,1,29]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.90.1.469"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.1995.75.4.725"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.68.4.1070"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-199304000-00003"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(94)00788-8"},{"key":"e_1_2_7_7_1","first-page":"426","article-title":"Regulation of calcium current by low\u2010Km cyclic AMP phosphodiesterases in cardiac cells","volume":"38","author":"FISCHMEISTER R.","year":"1990","journal-title":"Mol. 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