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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

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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, Vol. 169, No. 3, 01.06.2013, p. 528-38.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Molenaar, P, Christ, T, Hussain, RI, Engel, A, Berk, E, Gillette, KT, Chen, L, Galindo-Tovar, A, Krobert, KA, Ravens, U, Levy, FO & Kaumann, AJ 2013, 'PDE3, but not PDE4, reduces β₁ - and β₂ -adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients', BRIT J PHARMACOL, vol. 169, no. 3, pp. 528-38. https://doi.org/10.1111/bph.12167

APA

Molenaar, P., Christ, T., Hussain, R. I., Engel, A., Berk, E., Gillette, K. T., Chen, L., Galindo-Tovar, A., Krobert, K. A., Ravens, U., Levy, F. O., & Kaumann, A. J. (2013). PDE3, but not PDE4, reduces β₁ - and β₂ -adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients. BRIT J PHARMACOL, 169(3), 528-38. https://doi.org/10.1111/bph.12167

Vancouver

Molenaar P, Christ T, Hussain RI, Engel A, Berk E, Gillette KT et al. PDE3, but not PDE4, reduces β₁ - and β₂ -adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients. BRIT J PHARMACOL. 2013 Jun 1;169(3):528-38. https://doi.org/10.1111/bph.12167

Bibtex

@article{ee9a1e141e3b4c3e8b9cde4ac0317c41,
title = "PDE3, but not PDE4, reduces β₁ - and β₂ -adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients",
abstract = "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.",
author = "Peter Molenaar and Torsten Christ and Hussain, {Rizwan I} and Andreas Engel and Emanuel Berk and Gillette, {Katherine T} and Lu Chen and Alejandro Galindo-Tovar and Krobert, {Kurt A} and Ursula Ravens and Levy, {Finn Olav} and Kaumann, {Alberto J}",
note = "Christ f{\"u}r: Tech Univ Dresden, Dept Pharmacol & Toxicol, Dresden, Germany",
year = "2013",
month = jun,
day = "1",
doi = "10.1111/bph.12167",
language = "English",
volume = "169",
pages = "528--38",
journal = "BRIT J PHARMACOL",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
number = "3",

}

RIS

TY - JOUR

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 -