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Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 363, Issue 1, pp 87–93 | Cite as

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

  • Alberto J. Kaumann
  • Stefan Engelhardt
  • Lutz Hein
  • Peter Molenaar
  • Martin Lohse
Original Article

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 K D~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 (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.

β1/β2-Adrenoceptor double knockout mice (-)-CGP 12177 (-)-[3H]CGP 12177 binding site Cardiostimulation Obligatory β1-adrenoceptors Putative β4-adrenoceptors 

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Copyright information

© Springer-Verlag 2000

Authors and Affiliations

  • Alberto J. Kaumann
    • 1
  • Stefan Engelhardt
    • 2
  • Lutz Hein
    • 2
  • Peter Molenaar
    • 3
  • Martin Lohse
    • 2
  1. 1.Babraham Institute, Cambridge CB2 4AT and Department of Physiology, University of Cambridge, Cambridge CB2 3EG, UK
  2. 2.Pharmakologisches Institut der Universität Würzburg, Würzburg, Germany
  3. 3.Departments of Medicine, Physiology and Pharmacology, University of Queensland, Brisbane, Australia

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