title: β 1 Adrenoceptor antagonistic effects of the supposedly selective β 2 adrenoceptor antagonist ICI 118,551 on the positive inotropic effect of adrenaline in murine hearts.
abstract: Studies on the relative contribution of β 1- and β 2-adrenoceptors (AR) generally employ selective β 1- and β 2-AR antagonists such as CGP 20712A and ICI 118,551, respectively, and assume that antagonism by one of these compounds indicates mediation by the respective AR subtype. Here, we evaluated the β 2-AR-selectivity of ICI 118,551 in ventricular muscle strips of transgenic mice lacking β 1-AR (β 1-KO), β 2-AR (β 2-KO), or both (β 1/β 2-KO). Strips were electrically driven and force development was measured. In wild type (WT), ICI 118,551 (100 nmol/L) shifted the concentration-response curve (CRC) for adrenaline by about 0.5 log units to the right, corresponding to the known affinity of ICI 118,551 to β 1-AR but not to β 2-AR. Conversely, the phosphodiesterase inhibitor rolipram (10 μmol/L) shifted the CRC to the left, but did not enlarge the ICI 118,551 shift, indicating exclusive β 1-AR mediation even when PDE4 is inactive. In line with this, rolipram and ICI 118,551 had similar effects in β 2-KO than in WT. In contrast, β 1-KO did not show any inotropic reaction to adrenaline (+/- rolipram). In WT, the β 1-AR selective antagonist CGP 20712A (100 nmol/L) shifted the CRC for isoprenaline by 2.1 log units, corresponding to the affinity of CGP 20712A to β 1-AR. Rolipram increased the sensitivity to adrenaline independently of the presence of CGP 20712A. We conclude that effects sensitive to the β 2-AR antagonist ICI 118,551 are not necessarily β 2-AR-mediated and CGP 20712A-resistant effects cannot be simply interpreted as β 2-AR-mediated. Catecholamine effects in murine ventricles strictly depend on β 1-AR, even if PDE 4 is blocked.
authors.affiliation: Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf Hamburg, Germany ; Department of Cardiovascular Surgery, University Heart Center Hamburg Hamburg, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Pecha
authors.affiliation: Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf Hamburg, Germany ; DZHK (German Centre for Cardiovascular Research) Hamburg/Kiel/Lübeck, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Flenner
authors.affiliation: Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf Hamburg, Germany ; DZHK (German Centre for Cardiovascular Research) Hamburg/Kiel/Lübeck, Germany.
authors.forename: Klaus-Dieter
authors.initials: KD
authors.lastname: Söhren
authors.affiliation: Department of Pharmacology and Toxicology, University of Wuerzburg Wuerzburg, Germany ; Comprehensive Heart Failure Center, University of Wuerzburg Wuerzburg, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Lorenz
authors.affiliation: Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf Hamburg, Germany ; DZHK (German Centre for Cardiovascular Research) Hamburg/Kiel/Lübeck, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
authors.affiliation: Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg-Eppendorf Hamburg, Germany ; DZHK (German Centre for Cardiovascular Research) Hamburg/Kiel/Lübeck, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Christ
keywords: Adrenaline; CGP 20712A; ICI 118,551; heart; isoprenaline; mice; phosphodiesterase 4; phosphoinositide-3-kinase-γ; rolipram; β1-adrenoceptor knockout