Intrinsic sympathomimetic activity of (-)-pindolol mediated through a (-)-propranolol-resistant site of the beta(1)-adrenoceptor in human atrium and recombinant receptors

Joseph, Shirin S., Lynham, James A., Molenaar, Peter, Grace, Andrew A., Colledge, William H. and Kaumann, Alberto J. (2003) Intrinsic sympathomimetic activity of (-)-pindolol mediated through a (-)-propranolol-resistant site of the beta(1)-adrenoceptor in human atrium and recombinant receptors. Naunyn-Schmiedeberg's Archives of Pharmacology, 368 6: 496-503. doi:10.1007/s00210-003-0835-z


Author Joseph, Shirin S.
Lynham, James A.
Molenaar, Peter
Grace, Andrew A.
Colledge, William H.
Kaumann, Alberto J.
Title Intrinsic sympathomimetic activity of (-)-pindolol mediated through a (-)-propranolol-resistant site of the beta(1)-adrenoceptor in human atrium and recombinant receptors
Journal name Naunyn-Schmiedeberg's Archives of Pharmacology   Check publisher's open access policy
ISSN 0028-1298
Publication date 2003-12
Sub-type Article (original research)
DOI 10.1007/s00210-003-0835-z
Volume 368
Issue 6
Start page 496
End page 503
Total pages 8
Editor M. C. Michel
Place of publication Heidelberg, Germany
Publisher Springer -Verlag
Collection year 2003
Language eng
Subject C1
320502 Basic Pharmacology
730106 Cardiovascular system and diseases
Formatted abstract
 The -blocker (-)-pindolol produces intrinsic sympathomimetic activity manifested clinically by cardiostimulation, but the -adrenoceptor subtype, which mediates these effects, is unknown. Recent work indicates the existence of a (-)-propranolol-resistant site of the cardiac 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 1-adrenoceptors. The effects of (-)-pindolol on paced human atrial trabeculae were studied in the presence of 3-isobutyl-1-methylxanthine (IBMX; 20 M). (-)-Pindolol caused small negative and positive inotropic effects at nanomolar and micromolar concentrations respectively, which were unaffected by NG-monomethyl-L-arginine (L-NMMA, 10 M), inconsistent with an involvement of nitric oxide. (-)-Pindolol, in the presence of (-)-propranolol, increased atrial contractile force and cAMP through recombinant 1-adrenoceptors with identical potency (–logEC50M=6.5). The positive inotropic effects of (-)-pindolol were resistant to blockade by L-748,337 (100 nM), a 3-adrenoceptor antagonist. (-)-CGP12177, known to act through the (-)-propranolol-resistant site of the 1-adrenoceptor, also increased with similar potency atrial contractile force (–logEC50M=7.6) and cAMP at recombinant 1-adrenoceptors (–logEC50M=7.7). (-)-Pindolol blocked the effects of (-)-CGP12177 in human atrium and recombinant 1-adrenoceptors with similar equilibrium dissociation constants (pKB=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 (pKB=9.1) and at recombinant 1-adrenoceptors (pKB=8.6).We conclude that the cardiostimulant effects of (-)-pindolol in human atrial myocardium are mediated through a (-)-propranolol-resistant site of the 1-adrenoceptor with low affinity for (-)-pindolol. In contrast, (-)-pindolol blocks the effects of catecholamines through a high-affinity site of the 1-adrenoceptor. 3-Adrenoceptors are not involved in the atrial effects of (-)-pindolol.
Keyword Pharmacology & Pharmacy
Recombinant Beta(1)-adrenoceptors
Human Atrial Contractility
(-)-pindolol
(-)-cgp12177
(-)-propranolol-resistant Effects
Beta-adrenoceptor Blockers
Heart-rate
Partial Agonist
Knockout Mice
Sleep Stages
Pindolol
Stimulation
Activation
Beta-2-adrenoceptors
Cardiostimulation
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
2004 Higher Education Research Data Collection
School of Medicine Publications
 
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Created: Wed, 15 Aug 2007, 01:19:54 EST