Targeted disruption of the β2 adrenergic receptor gene

beta-Adrenergic receptors (beta-ARs) are members of the superfamily of G-protein-coupled receptors that mediate the effects of catecholamines in the sympathetic nervous system. Three distinct beta-AR subtypes have been identified (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 inactivate selectively the beta 2-AR gene in mice. Based on intercrosses of heterozygous knockout (beta 2-AR +/-) mice, there is no prenatal lethality associated with this mutation. Adult knockout mice (beta 2-AR -/-) appear grossly normal and are fertile. Their resting heart rate and blood pressure are normal, and they have a normal chronotropic response to the beta-AR agonist isoproterenol, The hypotensive response to isoproterenol, however, is significantly blunted compared with wild type mice. Despite this defect in vasodilation, beta 2-AR -/- mice can still exercise normally and actually have a greater total exercise capacity than wild type mice. At comparable workloads, beta 2-AR -/- mice had a lower respiratory exchange ratio than wild type mice suggesting a difference in energy metabolism. beta 2-AR -/- mice become hypertensive during exercise and exhibit a greater hypertensive response to epinephrine compared with wild type mice. In summary, the primary physiologic consequences of the beta 2-AR gene disruption are observed only during the stress of exercise and are the result of alterations in both vascular tone and energy metabolism.