Altered role of smooth muscle endothelin receptors in coronary endothelin-1 and α1-adrenoceptor-mediated vasoconstriction in Type 2 diabetes
Altered role of smooth muscle endothelin receptors in coronary endothelin-1 and α1-adrenoceptor-mediated vasoconstriction in Type 2 diabetes
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DOI：
10.1152/ajpheart.00566.2007
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发表时间：
2007-10-01
影响因子：
4.8
通讯作者：
Klabunde, R. E.
中科院分区：
文献类型：
--
作者：
Bender, S. B.;Klabunde, R. E.
血管张力和血流的调节涉及许多局部和全身血管控制信号之间的相互作用，其中许多信号被2型糖尿病（T2D）改变。血管对内皮素-1 （ET-1）的反应是由内皮素A型（ETA）和B型（ETB）受体介导的，这两种受体与α(1)-肾上腺素受体（α (1)-AR）相互作用。T2D时ETA和ETB受体表达及血浆ET-1水平升高；然而，这是否会影响冠状动脉α (1)-AR功能尚未被研究。因此，我们在小鼠T2D模型中检测了ETA和ETB受体抑制对冠状血管收缩对ET-1和α (1)-AR激活的影响。在对照组和饮食诱导的T2D C57BL/ 6J小鼠离体小鼠心脏中检测冠状动脉血管反应。分别在一氧化氮合酶抑制剂n -omega-硝基- l -精氨酸甲酯（L-NAME）单独存在或与选择性ETA或ETB受体抑制剂BQ-123和BQ-788联合存在的情况下，研究了对ET-1和选择性α (1)-AR激动剂苯肾上腺素（PE）的反应。血管对ET-1的收缩增强，而ETB受体阻断降低了T2D心脏的基底冠状动脉张力，而ETA受体阻断则没有。在L-NAME存在的情况下，ETA受体抑制可以减弱两组的ET-1血管收缩，而ETB抑制仅在对照心脏中消除了这种反应。此外，在L-NAME治疗后，ETA抑制增强了T2D心脏中α (1)- ar介导的血管收缩，而不是对照组。因此，在该模型中，冠状动脉ET-1反应性增强主要通过平滑肌ETB受体介导，而与α (1)-ARs的相互作用仅通过ETA受体亚型介导。
Regulation of vascular tone and blood flow involves interactions between numerous local and systemic vascular control signals, many of which are altered by Type 2 diabetes (T2D). Vascular responses to endothelin-1 (ET-1) are mediated by endothelin type A (ETA) and type B (ETB) receptors that have been implicated in cross talk with alpha(1)-adrenoceptors (alpha(1)-AR). ETA and ETB receptor expression and plasma ET-1 levels are elevated in T2D; however, whether this influences coronary alpha(1)-AR function has not been examined. Therefore, we examined the effect of ETA and ETB receptor inhibition on coronary vasoconstriction to ET-1 and alpha(1)-AR activation in a mouse model of T2D. Coronary vascular responses were examined in isolated mouse hearts from control and diet-induced T2D C57BL/ 6J mice. Responses to ET-1 and the selective alpha(1)-AR agonist phenylephrine (PE) were examined alone and in the presence of the nitric oxide synthase inhibitor N-omega-nitro-L-arginine methyl ester (L-NAME) alone or in combination with selective ETA or ETB receptor inhibitors BQ-123 and BQ-788, respectively. Vasoconstriction to ET-1 was enhanced, whereas ETB, but not ETA, receptor blockade reduced basal coronary tone in T2D hearts. In the presence of L-NAME, ETA receptor inhibition attenuated ET-1 vasoconstriction in both groups, whereas ETB inhibition abolished this response only in control hearts. In addition, ETA inhibition enhanced alpha(1)-AR-mediated vasoconstriction in T2D, but not control, hearts following L-NAME treatment. Therefore, in this model, enhanced coronary ET-1 responsiveness is mediated primarily through smooth muscle ETB receptors, whereas the interaction with alpha(1)-ARs is mediated solely through the ETA receptor subtype.