Abolition of (-)-CGP 12177-evoked cardiostimulation in double beta1/beta2-adrenoceptor knockout mice. Obligatory role of beta1-adrenoceptors for putative beta4-adrenoceptor pharmacology

Abstract

Some beta1- and beta2-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 beta4-adrenoceptors or through atypical states of either beta1- or beta2-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, beta2-adrenoceptor knockout and beta1/beta2-adrenoceptor double knockout mice. The cardiostimulant effects of (-)-CGP 12177 were present in wild-type and beta2-adrenoceptor knockout mice but were absent in beta1/beta2-adrenoceptor double knockout mice. Thus, the presence of beta1-adrenoceptors is obligatory for the cardiostimulant effects of (-)-CGP 12177. It appears therefore that an atypical state of the beta1-adrenoceptor contributes to the mediation of the cardiostimulant effects induced by non-conventional partial agonists. Ventricular beta1- and beta2-adrenoceptors, labelled in wild-type with a K(D) approximately 0.5 nmol/l (approximately 16 fmol/mg protein), were absent in beta1/beta2-adrenoceptor double knockout mice. However, a high density binding site (approximately 154-391 fmol/mg protein) that did not saturate completely (K(D) approximately 80-200 nM) was labelled by (-)-[3H]CGP 12177 in the three groups of mice, being distinct from beta1- and beta2-adrenoceptors, as well as from the site mediating the agonist effects of (-)-CGP 12177.