Differential cardiovascular regulatory activities of the α1B- and α1D-adrenoceptor subtypes
Differential cardiovascular regulatory activities of the α1B- and α1D-adrenoceptor subtypes
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DOI：
10.1124/jpet.102.048553
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发表时间：
2003-06-01
影响因子：
3.5
通讯作者：
Piascik, MT
中科院分区：
文献类型：
--
作者：
Chalothorn, D;McCune, DF;Piascik, MT
α (1B)-和α (1D)-肾上腺素受体（ARs）对心脏和血管功能的调节已经在两种转基因小鼠中进行了评估，一种是过表达组成型活性α (1B)-AR突变(α (1B)-AR (C128F))，另一种是α (1D)-AR敲除系。使用表达组成活性α (1B)-AR的小鼠的优势在于受体具有强直活性，从而避免使用可激活所有亚型的非选择性激动剂。在表达α (1B)-AR（C128F）的动物心脏中，与非转基因对照动物相比，丝裂原活化蛋白激酶、细胞外信号调节激酶和c-Jun n-末端激酶的活性显著升高。过表达α (1B)-AR（C128F）的小鼠超声心动图显示收缩功能障碍和心室尺寸增加。在α (1B)-AR（C128F）表达动物的离体灌注心脏或左心室切片中，异丙肾上腺素增加收缩力或增加cAMP水平的能力显著降低。与对心脏的显著作用相反，α (1B)-AR的组成性激活对苯肾上腺素诱导离体主动脉血管平滑肌收缩的能力几乎没有影响。在α (1D)-AR基因敲除小鼠中，苯肾上腺素刺激冠状血管收缩的能力减弱。在α (1D)-AR敲除动物中，没有发现对心脏收缩功能的负面影响。这些结果表明α (1)- ar调节了不同的生理过程。α (1B)-AR似乎参与心脏生长和收缩功能的调节，而α (1D)-AR则与平滑肌收缩和全身动脉血压的调节有关。
The regulation of cardiac and vascular function by the alpha(1B)- and alpha(1D)-adrenoceptors (ARs) has been assessed in two lines of transgenic mice, one over-expressing a constitutively active alpha(1B)-AR mutation (alpha(1B)- AR(C128F)) and the other an alpha(1D)-AR knockout line. The advantage of using mice expressing a constitutively active alpha(1B)-AR is that the receptor is tonically active, thus avoiding the use of nonselective agonists that can activate all subtypes. In hearts from animals expressing alpha(1B)-AR(C128F), the activities of the mitogen-activated protein kinases, extracellular signal-regulated kinase, and c-Jun N-terminal kinase were significantly elevated compared with nontransgenic control animals. Mice over-expressing the alpha(1B)-AR(C128F) had echocardiographic evidence of contractile dysfunction and increases in chamber dimensions. In isolated-perfused hearts or left ventricular slices from alpha(1B)-AR(C128F)-expressing animals, the ability of isoproterenol to increase contractile force or increase cAMP levels was significantly decreased. In contrast to the prominent effects on the heart, constitutive activation of the alpha(1B)-AR had little effect on the ability of phenylephrine to induce vascular smooth muscle contraction in the isolated aorta. The ability of phenylephrine to stimulate coronary vasoconstriction was diminished in alpha(1D)-AR knockout mice. In alpha(1D)-AR knockout animals, no negative effects on cardiac contractile function were noted. These results show that the alpha(1)-ARs regulate distinctly different physiologic processes. The alpha(1B)-AR appears to be involved in the regulation of cardiac growth and contractile function, whereas the alpha(1D)-AR is coupled to smooth muscle contraction and the regulation of systemic arterial blood pressure.