Townsend Seth A, Jung Albert S, Hoe Yen Shi Gillian, Lefkowitz Rafael Y, Khan Shakil A, Lemmon Christoper A, Harrison Robert W, Lee Kwanghho, Barouch Lili A, Cotecchia Susanna, Shoukas Artin A, Nyhan Daniel, Hare Joshua M, Berkowitz Dan E
Department of Anesthesiology/Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Hypertension. 2004 Nov;44(5):776-82. doi: 10.1161/01.HYP.0000145405.01113.0e. Epub 2004 Oct 4.
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.
α1肾上腺素能受体（α1ARs）在交感神经介导的血管收缩中起关键作用。每种α1AR亚型在调节血管收缩中的具体作用仍存在高度争议。有限的药理学研究表明，α1AR反应的差异可能是接头处受体与接头外受体差异激活的结果。我们检验了α1BAR亚型在介导交感神经接头处神经传递中起关键作用的假设。我们在α1BAR基因敲除（KO）小鼠及其野生型（WT）同窝小鼠中测量了对降压刺激（通过短暂双侧颈动脉闭塞[TBCO]诱导）的体内综合心血管反应。在WT小鼠中，解剖颈动脉并去除主动脉压力感受器缓冲神经的神经支配后，TBCO产生了显著的升压和正性肌力作用。在α1BAR KO小鼠中，这两种反应均明显减弱（收缩压变化46±8与11±2 mmHg；收缩末期压力-容积关系[ESPVR]的变化百分比36±7%与12±2%；WT与KO；P<0.003）。与WT相比，α1BAR KO小鼠中肠系膜微血管对去甲肾上腺素（NE；由10 Hz电场刺激引发）的体外α1AR收缩反应明显降低（12.4±1.7%与21.5±1.2%；P<0.001）。相比之下，α1BAR KO和WT小鼠对外源性NE的反应相似（22.4±7.3%与33.4±4.3%；无显著性差异）。总体而言，这些结果证明了α1BAR在压力感受器介导的血管神经效应器接头处肾上腺素能信号传导中的关键作用。此外，α1BAR调节对压力感受器激活的正性肌力反应。α1BAR在血管张力和心肌收缩力的神经效应器调节中的关键作用对设计体位性不耐受的治疗方法具有深远的临床意义。
