Targeted disruption of the beta2 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 (beta1-AR, beta2-AR, and beta3-AR). In order to define further the role of the different beta-AR subtypes, we have used gene targeting to inactivate selectively the beta2-AR gene in mice. Based on intercrosses of heterozygous knockout (beta2-AR +/-) mice, there is no prenatal lethality associated with this mutation. Adult knockout mice (beta2-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, beta2-AR -/- mice can still exercise normally and actually have a greater total exercise capacity than wild type mice. At comparable workloads, beta2-AR -/- mice had a lower respiratory exchange ratio than wild type mice suggesting a difference in energy metabolism. beta2-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 beta2-AR gene disruption are observed only during the stress of exercise and are the result of alterations in both vascular tone and energy metabolism.
Chruscinski
A J
AJ
Department of Molecular and Cellular Physiology, Stanford University, Stanford, California 94305, USA.
Rohrer
D K
DK
Schauble
E
E
Desai
K H
KH
Bernstein
D
D
Kobilka
B K
BK
D000818:Animals; D001794:Blood Pressure; D002320:Cardiovascular Physiological Phenomena / Q000187:drug effects; D004734:Energy Metabolism; D004837:Epinephrine / Q000494:pharmacology; D018390:Gene Targeting; D006339:Heart Rate; D006973:Hypertension; D020120:Iodocyanopindolol / Q000494:pharmacology; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016296:Mutagenesis; D010805:Physical Conditioning, Animal / Q000502:physiology*; D011412:Propanolamines / Q000494:pharmacology; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics* / Q000502:physiology*; D012119:Respiration; D014664:Vasodilation
D011412:Propanolamines; D018343:Receptors, Adrenergic, beta-2; C026777:ICI 118551; D020120:Iodocyanopindolol; D007545:Isoproterenol; D004837:Epinephrine