Cardiovascular and metabolic alterations in mice lacking both beta 1-and beta 2-adrenergic receptors

Citation
Dk. Rohrer et al., Cardiovascular and metabolic alterations in mice lacking both beta 1-and beta 2-adrenergic receptors, J BIOL CHEM, 274(24), 1999, pp. 16701-16708
Citations number
48
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
0021-9258 → ACNP
Volume
274
Issue
24
Year of publication
1999
Pages
16701 - 16708
Database
ISI
SICI code
0021-9258(19990611)274:24<16701:CAMAIM>2.0.ZU;2-D
Abstract
The activation state of beta-adrenergic receptors (beta-ARs) in vivo is an important determinant of hemodynamic status, cardiac performance, and metab olic rate. In order to achieve homeostasis in vivo, the cellular signals ge nerated by beta-AR activation are integrated with signals from a number of other distinct receptors and signaling pathways. We have utilized genetic k nockout models to test directly the role of beta 1- and/or beta 2-AR expres sion on these homeostatic control mechanisms. Despite total absence of beta 1- and beta 2-ARs, the predominant cardiovascular beta-adrenergic subtypes , basal heart rate, blood pressure, and metabolic rate do not differ from w ild type controls. However, stimulation of beta-AR function by beta-AR agon ists or exercise reveals significant impairments in chronotropic range, vas cular reactivity, and metabolic rate. Surprisingly, the blunted chronotropi c and metabolic response to exercise seen in pll beta 2-AR double knockouts fails to impact maximal exercise capacity. Integrating the results from si ngle beta 1- and beta 2-AR knockouts as well as the beta 1-/beta 2-AR doubl e knockout suggest that in the mouse, beta-AR stimulation of cardiac inotro py and chronotropy is mediated almost exclusively by the beta 1-AR, whereas vascular relaxation and metabolic rate are controlled by all three beta-AR s (beta 1-, beta 2-, and beta 3-AR), Compensatory alterations in cardiac mu scarinic receptor density and vascular beta 3-AR responsiveness are also ob served in beta 1-/beta 2-AR double knockouts. In addition to its ability to define P-AR subtype-specific functions, this genetic approach is also usef ul in identifying adaptive alterations that serve to maintain critical phys iological setpoints such as heart rate, blood pressure, and metabolic rate when cellular signaling mechanisms are perturbed.