Critical role for the α-1B adrenergic receptor at the sympathetic neuroeffector junction

Academic Article

Abstract

  • The α-1 adrenergic receptors (α1ARs) are critical in sympathetically mediated vasoconstriction. The specific role of each α1AR subtype in regulating vasoconstriction remains highly controversial. Limited pharmacological studies suggest that differential α1AR responses may be the result of differential activation of junctional versus extrajunctional receptors. We tested the hypothesis that the α1BAR 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 α1BAR 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 α1BAR 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 α1AR mesenteric microvascular contractile responses to endogenous norepinephrine (NE; elicited by electrical field stimulation 10 Hz) was markedly depressed in α1BAR 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 α1BAR KO and WT mice (22.4±7.3% versus 33.4±4.3%; NS). Collectively, these results demonstrate a critical role for the α1BAR in baroreceptor-mediated adrenergic signaling at the vascular neuroeffector junction. Moreover, α1BARs modulate inotropic responses to baroreceptor activation. The critical role for α1BAR in neuroeffector regulation of vascular tone and myocardial contractility has profound clinical implications for designing therapies for orthostatic intolerance.
  • Authors

    Published In

  • Hypertension  Journal
  • Digital Object Identifier (doi)

    Author List

  • Townsend SA; Jung AS; Hoe YSG; Lefkowitz RY; Khan SA; Lemmon CA; Harrison RW; Lee KH; Barouch LA; Cotecchia S
  • Start Page

  • 776
  • End Page

  • 782
  • Volume

  • 44
  • Issue

  • 5