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DOI: 10.1055/s-0036-1571603
β1 Adrenoceptor Antagonistic Effects of ICI 118,551 on the Positive Inotropic Effect of Adrenaline in Murine Hearts
Objectives: Studies on the relative contribution of β1- and β2-adrenoceptors (AR) generally employ selective β1- and β2-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 β2-AR-selectivity of ICI 118,551 in ventricular muscle strips of transgenic mice lacking β1-AR (β1-KO), β2-AR (β2-KO) or both (β1/β2-KO).
Methods: Mice with homozygous deletions of b1-or b2-AR were generated in Dr. Brian Kobilka's laboratory. We bred b1-KO and b2-KO mice in mixed C57BL6J/FVB/N backgrounds. Wildtype mice were on an inbreed C57BL6J background. Strips of free wall of right and intact left ventricular mice papillary muscles were rapidly dissected and mounted as pairs in an organ bath. Strips were electrically driven and contractile force development was measured.
Results: In wildtype (WT), ICI 118,551 (100 nM) shifted the concentration-response curve (CRC) for adrenaline by ∼0.5 log units to the right, corresponding to the known affinity of ICI 118,551 to β1-AR but not to β2-AR. Conversely, the phosphodiesterase inhibitor rolipram (10 µM) shifted the CRC to the left, but did not enlarge the ICI 118,551 shift, indicating exclusive β1-AR mediation even when PDE4 is inactive. In line with this, rolipram and ICI 118,551 had similar effects in β2-KO than in WT. In contrast, β1-KO did not show any inotropic reaction to adrenaline (+/− rolipram). In WT, the β1-AR selective antagonist CGP 20712A (100 nM) shifted the CRC for isoprenaline by 2.1 log units, corresponding to the affinity of CGP 20712A to β1-AR. Rolipram increased the sensitivity to adrenaline independently of the presence of CGP 20712A.
Conclusion: We conclude that effects sensitive to the β2-AR antagonist ICI 118,551 are not necessarily β2-AR-mediated and CGP 20712A-resistant effects cannot be simply interpreted as β2-AR-mediated. Catecholamine effects in murine ventricles strictly depend on β1-AR, even if PDE 4 is blocked.