title: Intrinsic sympathomimetic activity of (-)-pindolol mediated through a (-)-propranolol-resistant site of the beta1-adrenoceptor in human atrium and recombinant receptors.
abstract: 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.
authors: Department of Physiology, University of Cambridge, Downing Street, CB2 3EG, Cambridge, UK.
authors: Shirin S
authors: SS
authors: Joseph
authors: James A
authors: JA
authors: Lynham
authors: Peter
authors: P
authors: Molenaar
authors: Andrew A
authors: AA
authors: Grace
authors: William H
authors: WH
authors: Colledge
authors: Alberto J
authors: AJ
authors: Kaumann
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D058671:Adrenergic beta-1 Receptor Antagonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000368:Aged; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000096:biosynthesis; D004347:Drug Interactions; D004351:Drug Resistance; D005260:Female; D006321:Heart / Q000187:drug effects*; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects; D009638:Norepinephrine / Q000037:antagonists & inhibitors; D010869:Pindolol / Q000494:pharmacology*; D011412:Propanolamines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology*; D018342:Receptors, Adrenergic, beta-1 / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013237:Stereoisomerism; D013566:Sympathomimetics / Q000737:chemistry / Q000494:pharmacology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D058671:Adrenergic beta-1 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; D011994:Recombinant Proteins; D013566:Sympathomimetics; D019323:omega-N-Methylarginine; D011433:Propranolol; D010869:Pindolol; D000242:Cyclic AMP; D007545:Isoproterenol; C033394:CGP 12177; D015056:1-Methyl-3-isobutylxanthine; D009638:Norepinephrine