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J Biol Chem, Vol. 274, Issue 24, 16701-16708, June 11, 1999
1- and 2-Adrenergic Receptors
,
,, and
From the The activation state of Department of Molecular Pharmacology, Roche
Bioscience, Palo Alto, California 94304, the § Howard
Hughes Medical Institute, Division
of Pediatric Cardiology,
-adrenergic receptors
(-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 -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 1-
and/or 2-AR expression on these homeostatic control mechanisms.
Despite total absence of 1- and 2-ARs, the predominant
cardiovascular -adrenergic subtypes, basal heart rate, blood
pressure, and metabolic rate do not differ from wild type controls.
However, stimulation of -AR function by -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 1/2-AR double
knockouts fails to impact maximal exercise capacity. Integrating the
results from single 1- and 2-AR knockouts as well as the
1-/2-AR double knock-out suggest that in the mouse, -AR
stimulation of cardiac inotropy and chronotropy is mediated almost
exclusively by the 1-AR, whereas vascular relaxation and metabolic
rate are controlled by all three -ARs (1-, 2-, and 3-AR).
Compensatory alterations in cardiac muscarinic receptor density and
vascular 3-AR responsiveness are also observed in 1-/2-AR
double knockouts. In addition to its ability to define -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.
Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.
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