Document Detail

Putative beta 4-adrenoceptors in rat ventricle mediate increases in contractile force and cell Ca2+: comparison with atrial receptors and relationship to (-)-[3H]-CGP 12177 binding.
MedLine Citation:
PMID:  10602323     Owner:  NLM     Status:  MEDLINE    
1. We identified putative beta4-adrenoceptors by radioligand binding, measured increases in ventricular contractile force by (-)-CGP 12177 and (+/-)-cyanopindolol and demonstrated increased Ca2+ transients by (-)-CGP 12177 in rat cardiomyocytes. 2. (-)-[3H]-CGP 12177 labelled 13 - 22 fmol mg-1 protein ventricular beta1, beta2-adrenoceptors (pKD approximately 9.0) and 50 - 90 fmol mg-1 protein putative beta4-adrenoceptors (pKD approximately 7.3). The affinity values (pKi) for (beta1,beta2-) and putative beta4-adrenoceptors, estimated from binding inhibition, were (-)-propranolol 8.4, 5.7; (-)-bupranolol 9.7, 5.8; (+/-)-cyanopindolol 10.0,7.4. 3. In left ventricular papillary muscle, in the presence of 30 microM 3-isobutyl-1-methylxanthine, (-)-CGP 12177 and (+/-)-cyanopindolol caused positive inotropic effects, (pEC50, (-)-CGP 12177, 7.6; (+/-)-cyanopindolol, 7.0) which were antagonized by (-)-bupranolol (pKB 6.7 - 7.0) and (-)-CGP 20712A (pKB 6.3 - 6.6). The cardiostimulant effects of (-)-CGP 12177 in papillary muscle, left and right atrium were antagonized by (+/-)-cyanopindolol (pKP 7.0 - 7.4). 4. (-)-CGP 12177 (1 microM) in the presence of 200 nM (-)-propranolol increased Ca2+ transient amplitude by 56% in atrial myocytes, but only caused a marginal increase in ventricular myocytes. In the presence of 1 microM 3-isobutyl-1-methylxanthine and 200 nM (-)-propranolol, 1 microM (-)-CGP 12177 caused a 73% increase in Ca2+ transient amplitude in ventricular myocytes. (-)-CGP 12177 elicited arrhythmic transients in some atrial and ventricular myocytes. 5. Probably by preventing cyclic AMP hydrolysis, 3-isobutyl-1-methylxanthine facilitates the inotropic function of ventricular putative beta4-adrenoceptors, suggesting coupling to Gs protein-adenylyl cyclase. The receptor-mediated increases in contractile force are related to increases of Ca2+ in atrial and ventricular myocytes. The agreement of binding affinities of agonists with cardiostimulant potencies is consistent with mediation through putative beta4-adrenoceptors labelled with (-)-[3H]-CGP 12177.
D Sarsero; P Molenaar; A J Kaumann; N S Freestone
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Publication Detail:
Type:  Comparative Study; In Vitro; Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  128     ISSN:  0007-1188     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  1999 Dec 
Date Detail:
Created Date:  2000-02-03     Completed Date:  2000-02-03     Revised Date:  2013-06-11    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  1445-60     Citation Subset:  IM    
Department of Pharmacology, University of Melbourne, Parkville, 3052, Victoria, Australia.
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MeSH Terms
1-Methyl-3-isobutylxanthine / pharmacology
Adrenergic beta-Agonists / metabolism*,  pharmacology
Adrenergic beta-Antagonists / metabolism*,  pharmacology
Arrhythmias, Cardiac / physiopathology
Calcium / metabolism*
Cardiotonic Agents / metabolism,  pharmacology
Heart Atria / drug effects,  metabolism
Heart Ventricles / drug effects,  metabolism
Myocardial Contraction / drug effects*
Norepinephrine / antagonists & inhibitors,  pharmacology
Papillary Muscles / drug effects
Propanolamines / metabolism*,  pharmacology
Radioligand Assay
Rats, Sprague-Dawley
Receptors, Adrenergic, beta / metabolism,  physiology*
Reg. No./Substance:
0/Adrenergic beta-Agonists; 0/Adrenergic beta-Antagonists; 0/Cardiotonic Agents; 0/Propanolamines; 0/Receptors, Adrenergic, beta; 0/adrenergic beta-4 receptor; 10028-17-8/Tritium; 28822-58-4/1-Methyl-3-isobutylxanthine; 51-41-2/Norepinephrine; 7440-70-2/Calcium; 81047-99-6/CGP 12177

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