Intrinsic sympathomimetic activity of (-)-pindolol mediated through a (-)-propranolol-resistant site of the beta1-adrenoceptor in human atrium and recombinant receptors

Naunyn Schmiedebergs Arch Pharmacol. 2003 Dec;368(6):496-503. doi: 10.1007/s00210-003-0835-z. Epub 2003 Nov 8.


The beta-blocker (-)-pindolol produces intrinsic sympathomimetic activity manifested clinically by cardiostimulation, but the beta-adrenoceptor subtype, which mediates these effects, is unknown. Recent work indicates the existence of a (-)-propranolol-resistant site of the cardiac beta(1)-adrenoceptor and we propose that it mediates the cardiostimulation evoked by (-)-pindolol. We compared the interaction of (-)-pindolol both with human atrial myocardium and with recombinant beta(1)-adrenoceptors. The effects of (-)-pindolol on paced human atrial trabeculae were studied in the presence of 3-isobutyl-1-methylxanthine (IBMX; 20 microM). (-)-Pindolol caused small negative and positive inotropic effects at nanomolar and micromolar concentrations respectively, which were unaffected by N(G)-monomethyl-L-arginine (L-NMMA, 10 microM), inconsistent with an involvement of nitric oxide. (-)-Pindolol, in the presence of (-)-propranolol, increased atrial contractile force and cAMP through recombinant beta(1)-adrenoceptors with identical potency (-logEC(50)M=6.5). The positive inotropic effects of (-)-pindolol were resistant to blockade by L-748,337 (100 nM), a beta(3)-adrenoceptor antagonist. (-)-CGP12177, known to act through the (-)-propranolol-resistant site of the beta(1)-adrenoceptor, also increased with similar potency atrial contractile force (-logEC(50)M=7.6) and cAMP at recombinant beta(1)-adrenoceptors (-logEC(50)M=7.7). (-)-Pindolol blocked the effects of (-)-CGP12177 in human atrium and recombinant beta(1)-adrenoceptors with similar equilibrium dissociation constants (pK(B)=6.5 and 6.3). Thus, stimulant potency and blocking potency of (-)-pindolol against (-)-CGP12177 agree. In contrast, (-)-pindolol was 200-400 times more effective at blocking the effects of a catecholamine than the effects of (-)-CGP12177 in both human atrium (pK(B)=9.1) and at recombinant beta(1)-adrenoceptors (pK(B)=8.6). We conclude that the cardiostimulant effects of (-)-pindolol in human atrial myocardium are mediated through a (-)-propranolol-resistant site of the beta(1)-adrenoceptor with low affinity for (-)-pindolol. In contrast, (-)-pindolol blocks the effects of catecholamines through a high-affinity site of the beta(1)-adrenoceptor. beta(3)-Adrenoceptors are not involved in the atrial effects of (-)-pindolol.

Publication types

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

MeSH terms

  • 1-Methyl-3-isobutylxanthine / pharmacology
  • Adrenergic beta-1 Receptor Antagonists
  • Adrenergic beta-Agonists / pharmacology
  • Adrenergic beta-Antagonists / pharmacology
  • Aged
  • Animals
  • Binding Sites
  • CHO Cells
  • Cricetinae
  • Cyclic AMP / biosynthesis
  • Drug Interactions
  • Drug Resistance
  • Female
  • Heart / drug effects*
  • Heart Atria / drug effects
  • Heart Atria / metabolism
  • Humans
  • In Vitro Techniques
  • Isoproterenol / antagonists & inhibitors
  • Isoproterenol / pharmacology
  • Male
  • Middle Aged
  • Myocardial Contraction / drug effects
  • Norepinephrine / antagonists & inhibitors
  • Pindolol / pharmacology*
  • Propanolamines / antagonists & inhibitors
  • Propanolamines / pharmacology
  • Propranolol / pharmacology*
  • Receptors, Adrenergic, beta-1 / physiology*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Stereoisomerism
  • Sympathomimetics / chemistry
  • Sympathomimetics / pharmacology*
  • omega-N-Methylarginine / pharmacology


  • Adrenergic beta-1 Receptor Antagonists
  • Adrenergic beta-Agonists
  • Adrenergic beta-Antagonists
  • Propanolamines
  • Receptors, Adrenergic, beta-1
  • Recombinant Proteins
  • Sympathomimetics
  • omega-N-Methylarginine
  • Propranolol
  • Pindolol
  • Cyclic AMP
  • Isoproterenol
  • CGP 12177
  • 1-Methyl-3-isobutylxanthine
  • Norepinephrine