Cardiovascular and Metabolic Alterations in Mice Lacking Both beta 1- and beta 2-Adrenergic Receptors

• Published in: The Journal of biological chemistry 1999-06, Vol.274 (24), p.16701-16708
• Main Authors: Rohrer, D K, Chruscinski, A, Schauble, E H, Bernstein, D, Kobilka, B K
• Format: Article
• Language: English
• Subjects: b1-adrenergic receptors; b2-adrenergic receptors
• ISSN: 0021-9258
• DOI: 10.1074/jbc.274.24.16701

The activation state of beta -adrenergic receptors ( beta -ARs) in vivo is an important determinant of hemodynamic status, cardiac performance, and metabolic rate. In order to achieve homeostasis in vivo, the cellular signals generated by beta -AR activation are integrated with signals from a number of other distinct receptors and signaling pathways. We have utilized genetic knockout models to test directly the role of beta 1- and/or beta 2-AR expression 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 wild type controls. However, stimulation of beta -AR function by beta -AR agonists or exercise reveals significant impairments in chronotropic range, vascular reactivity, and metabolic rate. Surprisingly, the blunted chronotropic and metabolic response to exercise seen in beta 1/ beta 2-AR double knockouts fails to impact maximal exercise capacity. Integrating the results from single beta 1- and beta 2-AR knockouts as well as the beta 1-/ beta 2-AR double knock-out suggest that in the mouse, beta -AR stimulation of cardiac inotropy and chronotropy is mediated almost exclusively by the beta 1-AR, whereas vascular relaxation and metabolic rate are controlled by all three beta -ARs ( beta 1-, beta 2-, and beta 3-AR). Compensatory alterations in cardiac muscarinic receptor density and vascular beta 3-AR responsiveness are also observed in beta 1-/ beta 2-AR double knockouts. In addition to its ability to define beta -AR subtype-specific functions, this genetic approach is also useful in identifying adaptive alterations that serve to maintain critical physiological setpoints such as heart rate, blood pressure, and metabolic rate when cellular signaling mechanisms are perturbed.