beta-Adrenergic receptors (beta-ARs) are members of the superfamily of G-pr
otein-coupled receptors that mediate the effects of catecholamines in the s
ympathetic nervous system. Three distinct beta-AR subtypes have been identi
fied (beta 1-AR, beta 2-AR, and beta 3-AR), In order to define further the
role of the different P-AR subtypes, we have used gene targeting to inactiv
ate selectively the beta 2-AR gene in mice. Based on intercrosses of hetero
zygous knockout (beta 2-AR +/-) mice, there is no prenatal lethality associ
ated with this mutation. Adult knockout mice (beta 2-AR -/-) appear grossly
normal and are fertile. Their resting heart rate and blood pressure are no
rmal, and they have a normal chronotropic response to the beta-AR agonist i
soproterenol, The hypotensive response to isoproterenol, however, is signif
icantly blunted compared with wild type mice. Despite this defect in vasodi
lation, beta 2-AR -/- mice can still exercise normally and actually have a
greater total exercise capacity than wild type mice. At comparable workload
s, beta 2-AR -/- mice had a lower respiratory exchange ratio than wild type
mice suggesting a difference in energy metabolism. beta 2-AR -/- mice beco
me hypertensive during exercise and exhibit a greater hypertensive response
to epinephrine compared with wild type mice. In summary, the primary physi
ologic consequences of the beta 2-AR gene disruption are observed only duri
ng the stress of exercise and are the result of alterations in both vascula
r tone and energy metabolism.