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  μ mol/L) shifted the CRC to the left, but did not enlarge the ICI 118,551 shift, indicating exclusive β 1 ‐ AR mediation even when PDE 4 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.