Bender S B, Klabunde R E
Department of Biomedical Sciences, Ohio University College of Osteopathic Medicine, Athens, Ohio 45701, USA.
Am J Physiol Heart Circ Physiol. 2007 Oct;293(4):H2281-8. doi: 10.1152/ajpheart.00566.2007. Epub 2007 Jul 27.
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 (ET(A)) and type B (ET(B)) receptors that have been implicated in cross talk with alpha(1)-adrenoceptors (alpha(1)-AR). ET(A) and ET(B) 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 ET(A) and ET(B) 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 ET(A) or ET(B) receptor inhibitors BQ-123 and BQ-788, respectively. Vasoconstriction to ET-1 was enhanced, whereas ET(B), but not ET(A), receptor blockade reduced basal coronary tone in T2D hearts. In the presence of l-NAME, ET(A) receptor inhibition attenuated ET-1 vasoconstriction in both groups, whereas ET(B) inhibition abolished this response only in control hearts. In addition, ET(A) 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 ET(B) receptors, whereas the interaction with alpha(1)-ARs is mediated solely through the ET(A) receptor subtype.
血管张力和血流的调节涉及众多局部和全身血管控制信号之间的相互作用，其中许多信号在2型糖尿病（T2D）中会发生改变。血管对内皮素-1（ET-1）的反应由A型内皮素受体（ET(A)）和B型内皮素受体（ET(B)）介导，这些受体与α1肾上腺素能受体（α1-AR）存在相互作用。T2D患者体内ET(A)和ET(B)受体表达以及血浆ET-1水平均升高；然而，这是否会影响冠状动脉α1-AR功能尚未得到研究。因此，我们在T2D小鼠模型中研究了ET(A)和ET(B)受体抑制对冠状动脉对ET-1的收缩反应以及α1-AR激活的影响。我们对来自对照和饮食诱导的T2D C57BL/6J小鼠的离体心脏进行了冠状动脉血管反应检测。单独以及在一氧化氮合酶抑制剂N(ω)-硝基-L-精氨酸甲酯（L-NAME）单独存在或与选择性ET(A)或ET(B)受体抑制剂BQ-123和BQ-788联合存在的情况下，检测了对ET-1和选择性α1-AR激动剂去氧肾上腺素（PE）的反应。T2D心脏中对ET-1的血管收缩反应增强，而ET(B)受体阻断可降低基础冠状动脉张力，ET(A)受体阻断则无此作用。在L-NAME存在的情况下，ET(A)受体抑制可减弱两组中ET-1的血管收缩反应，而ET(B)受体抑制仅在对照心脏中消除了该反应。此外，在L-NAME处理后，ET(A)受体抑制增强了T2D心脏而非对照心脏中α1-AR介导的血管收缩反应。因此，在该模型中，冠状动脉对ET-1反应性增强主要通过平滑肌ET(B)受体介导，而与α1-AR的相互作用仅通过ET(A)受体亚型介导。
