Abolition of (-)-CGP 12177-evoked cardiostimulation in double beta(1)/beta(2)-adrenoceptor knockout mice. Obligatory role of beta(1)-adrenoceptors for putative beta 4-adrenoceptor pharmacology

Kaumann, AJ, Engelhardt, S, Hein, L, Molenaar, P and Lohse, M (2001) Abolition of (-)-CGP 12177-evoked cardiostimulation in double beta(1)/beta(2)-adrenoceptor knockout mice. Obligatory role of beta(1)-adrenoceptors for putative beta 4-adrenoceptor pharmacology. Naunyn-schmiedebergs Archives of Pharmacology, 363 1: 87-93.


Author Kaumann, AJ
Engelhardt, S
Hein, L
Molenaar, P
Lohse, M
Title Abolition of (-)-CGP 12177-evoked cardiostimulation in double beta(1)/beta(2)-adrenoceptor knockout mice. Obligatory role of beta(1)-adrenoceptors for putative beta 4-adrenoceptor pharmacology
Journal name Naunyn-schmiedebergs Archives of Pharmacology   Check publisher's open access policy
Publication date 2001
Sub-type Article
DOI 10.1007/s002100000336
Volume number 363
Issue number 1
ISSN 0028-1298
Start page 87
End page 93
Total pages 7
Editor M Goethert
K H Jakobs
Place of publication Heidelberg, Germany
Publisher Springer
Collection year 2001
Language eng
Subject C1
320502 Basic Pharmacology
730106 Cardiovascular system and diseases
Abstract Some beta (1)- and beta (2)-adrenoceptor-blocking agents, such as (-)-CGP 12177, cause cardiostimulant effects at concentrations considerably higher than those that antagonise the effects of catecholamines. The cardiostimulant effects of these non-conventional partial agonists are relatively resistant to blockade by (-)-propranolol and have been proposed to be mediated through putative beta (4)-adrenoceptors or through atypical states of either beta (1)- or beta (2)-adrenoceptors. We investigated the effects of (-)-CGP 12177 on sinoatrial rate and left atrial contractile force as well as the ventricular binding of (-)-[H-3]CGP 12177 in tissues from wild-type, beta (2)-adrenoceptor knockout and beta (1)/beta (2)-adrenoceptor double knockout mice. The cardiostimulant effects of (-)-CGP 12177 were present in wildtype and beta (2)-adrenoceptor knockout mice but were absent in beta (1)/beta (2)-adrenoceptor double knockout mice. Thus, the presence of beta (1)-adrenoceptors is obligatory for the cardiostimulant effects of (-)-CGP 12177. It appears therefore that an atypical state of the beta (1)-adrenoceptor contributes to the mediation of the cardiostimulant effects induced by non-conventional partial agonists. Ventricular beta (1)- and beta (2)-adrenoceptors, labelled in wild-type with a K(D)similar to0.5 nmol/l (similar to 16 fmol/mg protein), were absent in beta (1)/beta (2)-adrenoceptor double knockout mice. However, a high density binding site (similar to 154-391 fmol/mg protein) that did not saturate completely (K(D)similar to 80-200 nM) was labelled by (-)-[H-3]CGP 12177 in the three groups of mice, being distinct from beta (1)- and beta (2)-adrenoceptors, as well as from the site mediating the agonist effects of(-)-CGP 12177.
Keyword Pharmacology & Pharmacy
Beta(1)/beta(2)-adrenoceptor Double Knockout Mice
(-)-cgp 12177 (-)-[h-3]cgp 12177 Binding Site
Cardiostimulation
Obligatory Beta(1)-adrenoceptors
Putative Beta(4)-adrenoceptors
Beta-adrenoceptor
Ventricular Myocytes
Targeted Disruption
Mammalian Heart
Receptor Gene
Rat
Beta(4)-adrenoceptor
Beta(3)-adrenoceptor
Agonists
Beta(2)-adrenoceptor
Q-Index Code C1

Document type: Journal Article
Sub-type: Article
Collection: School of Medicine Publications
 
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