Abolition of (-)-CGP 12177-evoked cardiostimulation in double β₁/β₂-adrenoceptor knockout mice. Obligatory role of β₁-adrenoceptors for putative β₄-adrenoceptor pharmacology

Abstract.

Some β₁- and β₂-adrenoceptor-blocking agents, such as (-)-CGP 12177, cause cardiostimulant effects at concentrations considerably higher than those that antagonise the effects of catecholamines. The cardiostimulant effects of these non-conventional partial agonists are relatively resistant to blockade by (-)-propranolol and have been proposed to be mediated through putative β₄-adrenoceptors or through atypical states of either β₁- or β₂-adrenoceptors. We investigated the effects of (-)-CGP 12177 on sinoatrial rate and left atrial contractile force as well as the ventricular binding of (-)-[³H]CGP 12177 in tissues from wild-type, β₂-adrenoceptor knockout and β₁/β₂-adrenoceptor double knockout mice. The cardiostimulant effects of (-)-CGP 12177 were present in wild-type and β₂-adrenoceptor knockout mice but were absent in β₁/β₂-adrenoceptor double knockout mice. Thus, the presence of β₁-adrenoceptors is obligatory for the cardiostimulant effects of (-)-CGP 12177. It appears therefore that an atypical state of the β₁-adrenoceptor contributes to the mediation of the cardiostimulant effects induced by non-conventional partial agonists. Ventricular β₁- and β₂-adrenoceptors, labelled in wild-type with a K _D~0.5 nmol/l (~16 fmol/mg protein), were absent in β₁/β₂-adrenoceptor double knockout mice. However, a high density binding site (~154–391 fmol/mg protein) that did not saturate completely (K _D~80–200 nM) was labelled by (-)-[³H]CGP 12177 in the three groups of mice, being distinct from β₁- and β₂-adrenoceptors, as well as from the site mediating the agonist effects of (-)-CGP 12177.