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 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.