Cardiovascular and metabolic alterations in mice lacking both beta1- and beta2-adrenergic receptors.
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 beta1- and/or beta2-AR expression on these homeostatic control mechanisms. Despite total absence of beta1- and beta2-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 beta1/beta2-AR double knockouts fails to impact maximal exercise capacity. Integrating the results from single beta1- and beta2-AR knockouts as well as the beta1-/beta2-AR double knock-out suggest that in the mouse, beta-AR stimulation of cardiac inotropy and chronotropy is mediated almost exclusively by the beta1-AR, whereas vascular relaxation and metabolic rate are controlled by all three beta-ARs (beta1-, beta2-, and beta3-AR). Compensatory alterations in cardiac muscarinic receptor density and vascular beta3-AR responsiveness are also observed in beta1-/beta2-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.
Rohrer
D K
DK
Department of Molecular Pharmacology, Roche Bioscience, Palo Alto, California 94304, USA.
Chruscinski
A
A
Schauble
E H
EH
Bernstein
D
D
Kobilka
B K
BK
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002245:Carbon Dioxide / Q000378:metabolism; D002320:Cardiovascular Physiological Phenomena; D003433:Crosses, Genetic; D004837:Epinephrine / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D006579:Heterozygote; D006720:Homozygote; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction; D010101:Oxygen Consumption; D010805:Physical Conditioning, Animal; D018342:Receptors, Adrenergic, beta-1 / Q000172:deficiency*; D018343:Receptors, Adrenergic, beta-2 / Q000172:deficiency*; D016276:Ventricular Function
D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D002245:Carbon Dioxide; D007545:Isoproterenol; D004837:Epinephrine