title: Carvedilol induces greater control of β2- than β 1-adrenoceptor-mediated inotropic and lusitropic effects by PDE3, while PDE4 has no effect in human failing myocardium.
abstract: The β-blockers carvedilol and metoprolol provide important therapeutic strategies for heart failure treatment. Therapy with metoprolol facilitates the control by phosphodiesterase PDE3, but not PDE4, of inotropic effects of catecholamines in human failing ventricle. However, it is not known whether carvedilol has the same effect. We investigated whether the PDE3-selective inhibitor cilostamide (0.3 μM) or PDE4-selective inhibitor rolipram (1 μM) modified the positive inotropic and lusitropic effects of catecholamines in ventricular myocardium of heart failure patients treated with carvedilol. Right ventricular trabeculae from explanted hearts of nine carvedilol-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 the PDE inhibitors. The inotropic potency, estimated from -logEC50s, was unchanged for (-)-noradrenaline but decreased 16-fold for (-)-adrenaline in carvedilol-treated compared to non-β-blocker-treated patients, consistent with the previously reported β2-adrenoceptor-selectivity of carvedilol. Cilostamide caused 2- to 3-fold and 10- to 35-fold potentiations of the inotropic and lusitropic effects of (-)-noradrenaline and (-)-adrenaline, respectively, in trabeculae from carvedilol-treated patients. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline. Treatment of heart failure patients with carvedilol induces PDE3 to selectively control the positive inotropic and lusitropic effects mediated through ventricular β2-adrenoceptors compared to β1-adrenoceptors. The β2-adrenoceptor-selectivity of carvedilol may provide protection against β2-adrenoceptor-mediated ventricular overstimulation in PDE3 inhibitor-treated patients. PDE4 does not control β1- and β2-adrenoceptor-mediated inotropic and lusitropic effects in carvedilol-treated patients.
authors.affiliation: Faculty of Health, QUT, Brisbane; School of Medicine, University of Queensland and Critical Care Research Group, The Prince Charles Hospital, Chermside, QLD, 4032, Australia, peter.molenaar@qut.edu.au.
authors.forename: Peter
authors.initials: P
authors.lastname: Molenaar
authors.forename: Torsten
authors.initials: T
authors.lastname: Christ
authors.forename: Emanuel
authors.initials: E
authors.lastname: Berk
authors.forename: Andreas
authors.initials: A
authors.lastname: Engel
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Gillette
authors.forename: Alejandro
authors.initials: A
authors.lastname: Galindo-Tovar
authors.forename: Ursula
authors.initials: U
authors.lastname: Ravens
authors.forename: Alberto J
authors.initials: AJ
authors.lastname: Kaumann
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000328:Adult; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000502:physiology*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000502:physiology; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D006333:Heart Failure / Q000503:physiopathology*; D016027:Heart Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000494:pharmacology; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology; D058988:Phosphodiesterase 4 Inhibitors / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology*; D018343:Receptors, Adrenergic, beta-2 / Q000502:physiology*; D020889:Rolipram / Q000494:pharmacology
chemical_list: D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D011412:Propanolamines; D015363:Quinolones; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D000077261:Carvedilol; C021294:cilostamide; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; D009638:Norepinephrine; D004837:Epinephrine