Abolition of (-)-CGP 12177-evoked cardiostimulation in double ? 1 /? 2 -adrenoceptor knockout mice. Obligatory role of ? 1 -adrenoceptors for putative ? 4 -adrenoceptor pharmacology

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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.

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