PDE3, but not PDE4, reduces β₁ - and β₂ -adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients
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PDE3, but not PDE4, reduces β₁ - and β₂ -adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients. / Molenaar, Peter; Christ, Torsten; Hussain, Rizwan I; Engel, Andreas; Berk, Emanuel; Gillette, Katherine T; Chen, Lu; Galindo-Tovar, Alejandro; Krobert, Kurt A; Ravens, Ursula; Levy, Finn Olav; Kaumann, Alberto J.
in: BRIT J PHARMACOL, Jahrgang 169, Nr. 3, 01.06.2013, S. 528-38.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - PDE3, but not PDE4, reduces β₁ - and β₂ -adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients
AU - Molenaar, Peter
AU - Christ, Torsten
AU - Hussain, Rizwan I
AU - Engel, Andreas
AU - Berk, Emanuel
AU - Gillette, Katherine T
AU - Chen, Lu
AU - Galindo-Tovar, Alejandro
AU - Krobert, Kurt A
AU - Ravens, Ursula
AU - Levy, Finn Olav
AU - Kaumann, Alberto J
N1 - Christ für: Tech Univ Dresden, Dept Pharmacol & Toxicol, Dresden, Germany
PY - 2013/6/1
Y1 - 2013/6/1
N2 - BACKGROUND AND PURPOSE: PDE3 and/or PDE4 control ventricular effects of catecholamines in several species but their relative effects in failing human ventricle are unknown. We investigated whether the PDE3-selective inhibitor cilostamide (0.3-1 μM) or PDE4 inhibitor rolipram (1-10 μM) modified the positive inotropic and lusitropic effects of catecholamines in human failing myocardium.EXPERIMENTAL APPROACH: Right and left ventricular trabeculae from freshly explanted hearts of 5 non-β-blocker-treated and 15 metoprolol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through β₁ adrenoceptors (β₂ adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through β₂ adrenoceptors (β₁ adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of PDE inhibitors. Catecholamine potencies were estimated from -logEC50 s.KEY RESULTS: Cilostamide did not significantly potentiate the inotropic effects of the catecholamines in non-β-blocker-treated patients. Cilostamide caused greater potentiation (P = 0.037) of the positive inotropic effects of (-)-adrenaline (0.78 ± 0.12 log units) than (-)-noradrenaline (0.47 ± 0.12 log units) in metoprolol-treated patients. Lusitropic effects of the catecholamines were also potentiated by cilostamide. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline on right and left ventricular trabeculae from metoprolol-treated patients.CONCLUSIONS AND IMPLICATIONS: Metoprolol induces a control by PDE3 of ventricular effects mediated through both β₁ and β₂ adrenoceptors, thereby further reducing sympathetic cardiostimulation in patients with terminal heart failure. Concurrent therapy with a PDE3 blocker and metoprolol could conceivably facilitate cardiostimulation evoked by adrenaline through β₂ adrenoceptors. PDE4 does not appear to reduce inotropic and lusitropic effects of catecholamines in failing human ventricle.LINKED ARTICLE: This article is commented on by Eschenhagen, pp 524-527 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12168.
AB - BACKGROUND AND PURPOSE: PDE3 and/or PDE4 control ventricular effects of catecholamines in several species but their relative effects in failing human ventricle are unknown. We investigated whether the PDE3-selective inhibitor cilostamide (0.3-1 μM) or PDE4 inhibitor rolipram (1-10 μM) modified the positive inotropic and lusitropic effects of catecholamines in human failing myocardium.EXPERIMENTAL APPROACH: Right and left ventricular trabeculae from freshly explanted hearts of 5 non-β-blocker-treated and 15 metoprolol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through β₁ adrenoceptors (β₂ adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through β₂ adrenoceptors (β₁ adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of PDE inhibitors. Catecholamine potencies were estimated from -logEC50 s.KEY RESULTS: Cilostamide did not significantly potentiate the inotropic effects of the catecholamines in non-β-blocker-treated patients. Cilostamide caused greater potentiation (P = 0.037) of the positive inotropic effects of (-)-adrenaline (0.78 ± 0.12 log units) than (-)-noradrenaline (0.47 ± 0.12 log units) in metoprolol-treated patients. Lusitropic effects of the catecholamines were also potentiated by cilostamide. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline on right and left ventricular trabeculae from metoprolol-treated patients.CONCLUSIONS AND IMPLICATIONS: Metoprolol induces a control by PDE3 of ventricular effects mediated through both β₁ and β₂ adrenoceptors, thereby further reducing sympathetic cardiostimulation in patients with terminal heart failure. Concurrent therapy with a PDE3 blocker and metoprolol could conceivably facilitate cardiostimulation evoked by adrenaline through β₂ adrenoceptors. PDE4 does not appear to reduce inotropic and lusitropic effects of catecholamines in failing human ventricle.LINKED ARTICLE: This article is commented on by Eschenhagen, pp 524-527 of this issue. To view this commentary visit http://dx.doi.org/10.1111/bph.12168.
U2 - 10.1111/bph.12167
DO - 10.1111/bph.12167
M3 - SCORING: Journal article
C2 - 23489141
VL - 169
SP - 528
EP - 538
JO - BRIT J PHARMACOL
JF - BRIT J PHARMACOL
SN - 0007-1188
IS - 3
ER -