NDLI: Treatment with inverse agonists enhances baseline atrial contractility in transgenic mice with chronic beta2-adrenoceptor activation

Content Provider	PubMed Central
Author	Nagaraja, Savitha Iyer, Srinivas Liu, Xiushi Eichberg, Joseph Bond, Richard A.
Copyright Year	1999
Abstract	In this study, we investigate whether chronic treatment with β-adrenoceptor (βAR) ligands with inverse agonist activity enhances myocardial β2AR-mediated atrial tension more than neutral antagonists in transgenic mice (TG35). These mice exhibit chronic adrenoceptor activation because they possess a greater number of constitutively active receptors than wild type mice due to cardiac-specific overexpression of human β2ARs. TG35 and wild type mice were chronically treated for 90 h with three inverse agonists, ICI-118,551, propranolol, and carvedilol, and one neutral antagonist, alprenolol. After 96 h, we compared the basal and isoprenaline-stimulated (10 μM) increase in atrial tension in treated or untreated TG35 mice and wild type mice. In parallel, to determine the effect of chronic βAR ligand treatment on the amounts of G protein receptor kinase-2 (GRK-2) and G proteins, we performed Western blotting on myocardial cytosolic and membrane proteins. Atria from the TG35 mice treated with inverse agonists showed increases in the baseline tension compared to those from alprenolol/vehicle-treated mice. ICI-118,551 and propranolol treatment restored the elevated myocardial G-inhibitory protein (Giα) levels to that of wild type. Also, treatment with inverse agonists upregulated G-stimulatory protein (Gsα) levels and GRK2 above those levels in vehicle-treated TG35 or wild type mice. The increased baseline atrial tension was reversed by the addition of ICI-118,551. Overall, our data suggests that inverse agonists enhance baseline atrial tension more than neutral antagonists. Based on this, we propose that upregulation of the active conformation of the β2ARs, Gsα protein and restoration of Giα as three possible mechanisms to explain this enhanced receptor activity. Therefore, the favourable effects of some ligands used in pathological conditions involving chronic adrenoceptor activation may be due to the inverse agonist activity of the ligand.
Related Links	http://dx.doi.org/10.1038/sj.bjp.0702645
Ending Page	1104
Page Count	6
Starting Page	1099
File Format	PDF
ISSN	00071188
Journal	British Journal of Pharmacology
Issue Number	5
Volume Number	127
Language	English
Publisher Date	1999-07-01
Access Restriction	Open
Subject Keyword	Pharmacology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Pharmacology

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