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

Kaumann, Alberto J. & Molenaar, Peter (2008) The low-affinity site of the β1-adrenoceptor and its relevance to cardiovascular pharmacology. Pharmacology and Therapeutics, 118(3), pp. 303-336.

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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.

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35 citations in Web of Science®

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ID Code: 40604
Item Type: Journal Article
Keywords: ffinity states; Arrhythmias; β-Blockers; Bucindolol; Bupranolol; Ca2+ currents; Ca2+ transients; Cardiovascular; CGP12177; [3H]-(−)-CGP12177; Heart; Human heart; Human heart failure; Heart rate; Mutagenesis; Non-conventional partial agonists; Pindolol; Ph
DOI: 10.1016/j.pharmthera.2008.03.009
ISSN: 0163-7258
Subjects: Australian and New Zealand Standard Research Classification > MEDICAL AND HEALTH SCIENCES (110000) > NEUROSCIENCES (110900)
Divisions: Past > QUT Faculties & Divisions > Faculty of Science and Technology
Copyright Owner: Copyright 2008 Elsevier
Deposited On: 09 Mar 2011 12:55
Last Modified: 29 Feb 2012 23:42

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