(-)-CGP 12177 increases contractile force and hastens relaxation of human myocardial preparations through a propranolol-resistant state of the beta 1-adrenoceptor

Naunyn Schmiedebergs Arch Pharmacol. 2003 Jan;367(1):10-21. doi: 10.1007/s00210-002-0652-9. Epub 2002 Dec 7.


Two forms of the activated beta1-adrenoceptor exist, one that is stabilized by (-)-noradrenaline and is sensitive to blockade by (-)-propranolol and another which is stabilized by partial agonists such as (-)-pindolol and (-)-CGP 12177 but is relatively insensitive to (-)-propranolol. We investigated the effects of stimulation of the propranolol-resistant beta1-adrenoceptor in the human heart. Myocardium from non-failing and failing human hearts were set up to contract at 1 Hz. In right atrium from non-failing hearts in the presence of 200 nM (-)-propranolol, (-)-CGP 12177 caused concentration-dependent increases in contractile force (-logEC50[M] 7.3+/-0.1, E(max) 23+/-1% relative to maximal (-)-isoprenaline stimulation of beta1- and beta2-adrenoceptors, n=86 patients), shortening of the time to reach peak force (-logEC50[M] 7.4+/-0.1, E(max) 37+/-5%, n=61 patients) and shortening of the time to reach 50% relaxation ( t(50%), -logEC50[M] 7.3+/-0.1, E(max) 33+/-2%, n=61 patients). The potency and maxima of the positive inotropic effects were independent of Ser49Gly- and Gly389Arg-beta1-adrenoceptor polymorphisms but were potentiated by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (-logEC50[M] 7.7+/-0.1, E(max) 68+/-6%, n=6 patients, P<0.0001). In the presence of (-)-propranolol and 3-isobutyl-1-methylxanthine, the potency (-logEC50[M] 7.4+/-0.1, P=0.0013, n=9 patients) but not the maximal effect of (-)-CGP 12177 was reduced in right atrium from failing hearts, which was associated with 64% and 52% reductions in the densities of low-affinity and high-affinity (-)-[3H]CGP 12177 binding sites. In the presence of (-)-propanolol and 3-isobutyl-1-methylxanthine, (-)-CGP 12177 increased atrial cyclic AMP levels and activated cyclic AMP-dependent protein kinase in right atrium from non-failing hearts. In right ventricle from failing hearts (-)-CGP 12177 increased contractile force (-logEC50[M] 7.4+/-0.1, E(max) 34+/-3%, n=13 patients) and hastened the time to peak force (-logEC50[M] 7.6+/-0.1) and time to reach 50% relaxation (-logEC50[M] 7.4+/-0.1) in the presence of (-)-propranolol and 3-isobutyl-1-methylxanthine. Our results show that (-)-CGP 12177 increases contractility and hastens relaxation through a cyclic AMP pathway in human myocardium, consistent with mediation through a (-)-propranolol-resistant state of the beta1-adrenoceptor. The reduction in heart failure of atrial inotropic potency of (-)-CGP 12177, as well as of the high-affinity and low-affinity binding sites for (-)-[3H]CGP 12177, is consistent with the beta1-adrenoceptor nature of these sites.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-1 Receptor Agonists
  • Adrenergic beta-1 Receptor Antagonists
  • Adult
  • Aged
  • Dose-Response Relationship, Drug
  • Female
  • Humans
  • In Vitro Techniques
  • Male
  • Middle Aged
  • Muscle Relaxation / drug effects*
  • Muscle Relaxation / physiology
  • Myocardial Contraction / drug effects*
  • Myocardial Contraction / physiology
  • Myocardium / metabolism
  • Propanolamines / metabolism
  • Propanolamines / pharmacology*
  • Propranolol / pharmacology*
  • Protein Binding
  • Receptors, Adrenergic, beta-1 / metabolism*
  • Stimulation, Chemical


  • Adrenergic beta-1 Receptor Agonists
  • Adrenergic beta-1 Receptor Antagonists
  • Propanolamines
  • Receptors, Adrenergic, beta-1
  • Propranolol
  • CGP 12177