Adenosine A2A Receptors Mediate Coronary Microvascular Dilation to Adenosine: Role of Nitric Oxide and ATP-Sensitive Potassium Channels
Adenosine A2A Receptors Mediate Coronary Microvascular Dilation to Adenosine: Role of Nitric Oxide and ATP-Sensitive Potassium Channels
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发表时间：
1999-11
影响因子：
3.5
通讯作者：
T. Hein;L. Belardinelli;L. Kuo
中科院分区：
文献类型：
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作者：
T. Hein;L. Belardinelli;L. Kuo
腺苷是一种有效的血管扩张剂，在调节冠状动脉微血管直径中发挥重要作用。尽管最近已经克隆了多种腺苷受体亚型，但具体的腺苷受体亚型和冠状微循环中腺苷血管舒张的潜在机制仍然未知。因此，在本研究中，我们确定了冠状动脉扩张腺苷的受体亚型，并研究了一氧化氮 (NO) 和 ATP 敏感钾 (K ATP ) 通道在这种血管舒张反应中的作用。猪冠状动脉（原位 50-100 μm）被分离、插管并在不流动的情况下加压，用于体外研究。小动脉出现基础张力，并以浓度依赖性方式扩张至腺苷和腺苷受体激动剂 (2 S )- N 6 -[2-内降冰片基]腺苷 (A 1 )、2-[ p -(2-羧乙基)]苯乙基-氨基-5'- N -乙基羧酰胺腺苷 (CGS21680; A 2A )、N 6 -(3-碘苄基)腺苷-5′-N-甲基糖醛酰胺(A 3 )和N-乙基羧酰胺腺苷（非选择性腺苷受体激活）。选择性 A 2A 受体拮抗剂 4-(2-[7-氨基-2-(2-呋喃基)[1,2,4]-三唑并[2,3-a][1,3,5]三嗪-5-基氨基]乙基)苯酚减弱腺苷和所有测试的腺苷受体激动剂的血管舒张作用，表明血管舒张反应主要由 A 2A 受体介导。腺苷和 CGS21680 诱导的扩张以类似的方式通过内皮去除和 NO 合酶抑制剂 NG-硝基-L-精氨酸甲酯减弱。在裸露血管中，腺苷和 CGS21680 诱导的扩张几乎被 K ATP 通道抑制剂格列本脲消除。选择性 A 2A 激动剂 CGS21680 在机制上模拟腺苷反应引起的血管舒张。总的来说，我们的结果表明冠状动脉向腺苷的扩张主要由 A 2A 受体介导。该受体亚型的激活通过内皮释放 NO 和平滑肌打开 K ATP 通道引起血管舒张。
Adenosine is a potent vasodilator that plays an important role in the regulation of coronary microvascular diameter. Although multiple adenosine receptor subtypes have been recently cloned, the specific adenosine receptor subtypes and the underlying mechanisms responsible for the vasodilation to adenosine in the coronary microcirculation remain unknown. Therefore, in the present study we determined the receptor subtypes for coronary arteriolar dilation to adenosine and investigated the role of nitric oxide (NO) and ATP-sensitive potassium (K ATP ) channels in this vasodilatory response. Pig coronary arterioles (50–100 μm in situ) were isolated, cannulated, and pressurized without flow for in vitro study. Arterioles developed basal tone and dilated in a concentration-dependent manner to adenosine and to adenosine receptor agonists (2 S )- N 6 -[2-endo-norbornyl]adenosine (A 1 ), 2-[ p -(2-carboxyethyl)]phenylethyl-amino-5′- N -ethylcarboxamidoadenosine (CGS21680; A 2A ), N 6 -(3-iodobenzyl)adenosine-5′- N -methyluronamide (A 3 ), and N -ethylcarboxamidoadenosine (nonselective adenosine receptor activation). The selective A 2A receptor antagonist 4-(2-[7-amino-2-(2-furyl)[1,2,4]-triazolo[2,3- a ][1,3,5]triazin-5-yl amino]ethyl)phenol attenuated vasodilation to adenosine and to all adenosine receptor agonists tested, suggesting that the vasodilatory responses were primarily mediated by A 2A receptors. Adenosine- and CGS21680-induced dilations were attenuated in a similar manner by endothelial removal and by the NO synthase inhibitor N G -nitro-l-arginine methyl ester. In denuded vessels, both adenosine- and CGS21680-induced dilations were nearly abolished by the K ATP channel inhibitor glibenclamide. The selective A 2A agonist CGS21680 mechanistically mimics the vasodilation in response to adenosine. Collectively, our results suggest that the dilation of coronary arterioles to adenosine is mediated predominantly by A 2A receptors. Activation of this receptor subtype elicits vasodilation by endothelial release of NO and by the smooth muscle opening of K ATP channels.