Cargando…

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

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 evaluat...

Descripción completa

Detalles Bibliográficos
Autores principales: Pecha, Simon, Flenner, Frederik, Söhren, Klaus-Dieter, Lorenz, Kristina, Eschenhagen, Thomas, Christ, Torsten
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley & Sons, Ltd 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618639/
https://www.ncbi.nlm.nih.gov/pubmed/26516580
http://dx.doi.org/10.1002/prp2.168
Descripción
Sumario: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.