Abolition of (-)-CGP 12177-evoked cardiostimulation in double β12-adrenoceptor knockout mice. Obligatory role of β1-adrenoceptors for putative β4-adrenoceptor pharmacology

A. J. Kaumann, Stefan Engelhardt, Lutz Hein, Peter Molenaar, Martin Lohse

Research output: Contribution to journalArticlepeer-review

109 Scopus citations

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 β12-adrenoceptor double knockout mice. The cardiostimulant effects of (-)-CGP 12177 were present in wild-type and β2-adrenoceptor knockout mice but were absent in β12-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 KD∼0.5 nmol/l (∼16 fmol/mg protein), were absent in β12-adrenoceptor double knockout mice. However, a high density binding site (∼154-391 fmol/mg protein) that did not saturate completely (KD∼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.

Original languageEnglish
Pages (from-to)87-93
Number of pages7
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume363
Issue number1
DOIs
StatePublished - 2001
Externally publishedYes

Keywords

  • (-)-CGP 12177
  • (-)-[H]CGP 12177 binding site
  • Cardiostimulation
  • Obligatory β-adrenoceptors
  • Putative β-adrenoceptors
  • β/β-Adrenoceptor double knockout mice

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