The low-affinity site of the β1-adrenoceptor and its relevance to cardiovascular pharmacology

Kaumann, Alberto J. and Molenaar, Peter (2008) The low-affinity site of the β1-adrenoceptor and its relevance to cardiovascular pharmacology. Pharmacology and Therapeutics, 118 3: 303-336. doi:10.1016/j.pharmthera.2008.03.009


Author Kaumann, Alberto J.
Molenaar, Peter
Title The low-affinity site of the β1-adrenoceptor and its relevance to cardiovascular pharmacology
Formatted title
The low-affinity site of the β1-adrenoceptor and its relevance to cardiovascular pharmacology
Journal name Pharmacology and Therapeutics   Check publisher's open access policy
ISSN 0163-7258
1879-016X
Publication date 2008-06-01
Sub-type Critical review of research, literature review, critical commentary
DOI 10.1016/j.pharmthera.2008.03.009
Volume 118
Issue 3
Start page 303
End page 336
Total pages 34
Place of publication Philadelphia, PA, United States
Publisher Elsevier
Formatted abstract
β-Adrenoceptor blocking agents (β-blockers) that at low concentrations antagonize cardiostimulant effects of catecholamines, but at high concentrations also cause cardiostimulation, have been appearing since the late 1960s. These cardiostimulant β-blockers, coined non-conventional partial agonists, antagonize the effects of catecholamines through a high-affinity site (β1HAR), but cause cardiostimulation mainly through a low-affinity site (β1LAR) of the myocardial β1-adrenoceptor. The experimental non-conventional partial agonist (-)-CGP12177 increases cardiac L-type Ca2+ current density and Ca2+ transients, shortens action potential duration but augments action potential plateau, increases heart rate and force, as well as causes arrhythmic Ca2+ transients and arrhythmic cardiocyte contractions. Other β-blockers, which do not cause cardiostimulation, consistently have lower affinity for β1LAR than β1HAR. These sites were verified and the cardiac pharmacology of non-conventional partial agonists confirmed on recombinant β1-adrenoceptors and on β1-adrenoceptors overexpressed into the heart. A targeted mutation of Asp138 to Glu138 virtually abolished the pharmacology of β1HAR but left intact the pharmacology of β1LAR. Non-conventional partial agonists may be beneficial for the treatment of peripheral autonomic neuropathy but probably due to their arrhythmic propensities, may be harmful for the treatment of chronic heart failure.
Keyword β-Blockers
[3H]-(-)-CGP12177
Affinity states
Arrhythmias
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Critical review of research, literature review, critical commentary
Collection: School of Medicine Publications
 
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