Critical role for the alpha-1B adrenergic receptor at the sympathetic neuroeffector junction.
The alpha-1 adrenergic receptors (alpha(1)ARs) are critical in sympathetically mediated vasoconstriction. The specific role of each alpha(1)AR subtype in regulating vasoconstriction remains highly controversial. Limited pharmacological studies suggest that differential alpha(1)AR responses may be the result of differential activation of junctional versus extrajunctional receptors. We tested the hypothesis that the alpha(1B)AR subtype is critical in mediating sympathetic junctional neurotransmission. We measured in vivo integrated cardiovascular responses to a hypotensive stimulus (induced via transient bilateral carotid occlusion [TBCO]) in alpha(1B)AR knockout (KO) mice and their wild-type (WT) littermates. In WT mice, after dissection of the carotid arteries and denervation of aortic baroreceptor buffering nerves, TBCO produced significant pressor and positive inotropic effects. Both responses were markedly attenuated in alpha(1B)AR KO mice (change systolic blood pressure 46+/-8 versus 11+/-2 mm Hg; percentage change in the end-systolic pressure-volume relationship [ESPVR] 36+/-7% versus 12+/-2%; WT versus KO; P<0.003). In vitro alpha(1)AR mesenteric microvascular contractile responses to endogenous norepinephrine (NE; elicited by electrical field stimulation 10 Hz) was markedly depressed in alpha(1B)AR KO mice compared with WT (12.4+/-1.7% versus 21.5+/-1.2%; P<0.001). In contrast, responses to exogenous NE were similar in alpha(1B)AR KO and WT mice (22.4+/-7.3% versus 33.4+/-4.3%; NS). Collectively, these results demonstrate a critical role for the alpha(1B)AR in baroreceptor-mediated adrenergic signaling at the vascular neuroeffector junction. Moreover, alpha(1B)ARs modulate inotropic responses to baroreceptor activation. The critical role for alpha(1B)AR in neuroeffector regulation of vascular tone and myocardial contractility has profound clinical implications for designing therapies for orthostatic intolerance.
Townsend
Seth A
SA
Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Jung
Albert S
AS
Hoe
Yen Shi Gillian
YS
Lefkowitz
Rafael Y
RY
Khan
Shakil A
SA
Lemmon
Christoper A
CA
Harrison
Robert W
RW
Lee
Kwanghho
K
Barouch
Lili A
LA
Cotecchia
Susanna
S
Shoukas
Artin A
AA
Nyhan
Daniel
D
Hare
Joshua M
JM
Berkowitz
Dan E
DE
D000818:Animals; D017704:Baroreflex / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology*; D002339:Carotid Arteries / Q000502:physiology; D016893:Carotid Stenosis / Q000503:physiopathology; D066298:In Vitro Techniques; D008638:Mesenteric Arteries / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009451:Neuroeffector Junction / Q000502:physiology*; D009638:Norepinephrine / Q000494:pharmacology / Q000502:physiology; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000502:physiology*; D014661:Vasoconstriction / Q000502:physiology*
C547717:Adra1b protein, mouse; D018340:Receptors, Adrenergic, alpha-1; D009638:Norepinephrine