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

Naunyn Schmiedebergs Arch Pharmacol. 2001 Jan;363(1):87-93. doi: 10.1007/s002100000336.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-3-isobutylxanthine / pharmacology
  • Adrenergic beta-Agonists / pharmacology
  • Adrenergic beta-Antagonists / pharmacology*
  • Animals
  • Atrial Function
  • Binding, Competitive / drug effects
  • Bucladesine / pharmacology
  • Dose-Response Relationship, Drug
  • Female
  • Genotype
  • Heart Atria / drug effects*
  • Heart Atria / metabolism
  • In Vitro Techniques
  • Isoproterenol / pharmacology
  • Male
  • Membranes / drug effects
  • Membranes / metabolism
  • Mice
  • Mice, Knockout
  • Myocardial Contraction / drug effects
  • Pindolol / analogs & derivatives*
  • Pindolol / pharmacology
  • Propanolamines / metabolism
  • Propanolamines / pharmacology*
  • Receptors, Adrenergic, beta / drug effects
  • Receptors, Adrenergic, beta-1 / genetics
  • Receptors, Adrenergic, beta-1 / physiology
  • Receptors, Adrenergic, beta-2 / genetics
  • Receptors, Adrenergic, beta-2 / physiology
  • Sinoatrial Node / drug effects
  • Sinoatrial Node / physiology
  • Tritium


  • Adrenergic beta-Agonists
  • Adrenergic beta-Antagonists
  • Propanolamines
  • Receptors, Adrenergic, beta
  • Receptors, Adrenergic, beta-1
  • Receptors, Adrenergic, beta-2
  • Tritium
  • cyanopindolol
  • Bucladesine
  • Pindolol
  • Isoproterenol
  • CGP 12177
  • 1-Methyl-3-isobutylxanthine