Adenosine receptor inhibition with theophylline attenuates the skin blood flow response to local heating in humans
Adenosine receptor inhibition with theophylline attenuates the skin blood flow response to local heating in humans
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DOI：
10.1113/expphysiol.2010.053538
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发表时间：
2010-09-01
影响因子：
2.7
通讯作者：
Wong, Brett J.
中科院分区：
文献类型：
--
作者：
Fieger, Sarah M.;Wong, Brett J.
人体皮肤局部加热后，皮肤血管舒张的机制仍然没有得到解决。腺苷受体激活已显示通过一氧化氮诱导血管舒张，并且人体皮肤局部加热的平台期的相当大一部分已显示依赖于一氧化氮。本研究的目的是探讨腺苷受体激活在人体皮肤热充血中的潜在作用。6名受试者在前臂腹侧配备了4根微透析纤维。将部位随机分配接受以下四种治疗之一：（1）乳酸林格氏溶液作为对照;（2）4 mm茶碱，一种竞争性、非选择性A（1）/A（2）腺苷受体拮抗剂;（3）10 mm N ω-硝基-L-精氨酸甲酯（l-NAME）抑制NO合酶;或（4）4 mm茶碱+ 10 mm l-NAME组合。基线测量后，以1 ℃（10 s）-1的速率将每个部位从33 ℃的基线温度局部加热至42 ℃，并通过激光多普勒血流仪（LDF）监测皮肤血流。皮肤血管传导性（CVC）计算为LDF除以平均动脉压，并通过局部加热至43 ℃和输注28 mm硝普钠标准化为最大值（CVCmax）。与对照部位（81 +/-2%CVCmax;分别为P < 0.01和P < 0.001）相比，茶碱（68 +/-2%CVCmax）和l-NAME部位（54 +/-5%CVCmax）的初始峰值显著降低。与对照组和茶碱部位相比，茶碱+ l-NAME（52 +/-5%CVCmax）组合降低了初始峰，但与l-NAME部位相比无显著差异。与对照部位（94 +/-2%CVCmax;所有条件下P < 0.001）相比，茶碱（77 +/-2%CVCmax）、l-NAME（60 +/-2%CVCmax）和茶碱+ l-NAME（53 +/-1%CVCmax）的继发平台期减弱。与单独使用茶碱（P <0.001）和l-NAME（P < 0.05）相比，联合使用l-NAME和茶碱（P <0.001）可进一步降低继发平台。这些数据表明，腺苷受体活化直接有助于皮肤热充血，如茶碱部位的初始峰和次级平台降低所证明的。这些数据进一步表明，一部分的NO反应可能是由腺苷受体激活解释，然而，一个相当大的一部分的NO反应是独立的腺苷受体激活。
Mechanisms underlying the robust cutaneous vasodilatation in response to local heating of human skin remain unresolved. Adenosine receptor activation has been shown to induce vasodilatation via nitric oxide, and a substantial portion of the plateau phase to local heating of human skin has been shown to be dependent on nitric oxide. The purpose of this study was to investigate a potential role for adenosine receptor activation in cutaneous thermal hyperaemia in humans. Six subjects were equipped with four microdialysis fibres on the ventral forearm. Sites were randomly assigned to receive one of the following four treatments: (1) lactated Ringer solution to serve as a control; (2) 4 mm theophylline, a competitive, non-selective A(1)/A(2) adenosine receptor antagonist; (3) 10 mm N omega-nitro-l-arginine methyl ester (l-NAME) to inhibit NO synthase; or (4) combined 4 mm theophylline + 10 mm l-NAME. Following baseline measurements, each site was locally heated from a baseline temperature of 33 degrees C to 42 degrees C at a rate of 1 degrees C (10 s)-1, and skin blood flow was monitored via laser-Doppler flowmetry (LDF). Cutaneous vascular conductance (CVC) was calculated as LDF divided by mean arterial pressure and normalized to maximal values (CVCmax) via local heating to 43 degrees C and infusion of 28 mm sodium nitroprusside. The initial peak was significantly reduced in theophylline (68 +/- 2% CVCmax) and l-NAME sites (54 +/- 5% CVCmax) compared with control sites (81 +/- 2% CVCmax; P < 0.01 and P < 0.001, respectively). Combined theophylline + l-NAME (52 +/- 5% CVCmax) reduced the initial peak compared with control and theophylline sites, but was not significantly different compared with l-NAME sites. The secondary plateau was attenuated in theophylline (77 +/- 2% CVCmax), l-NAME (60 +/- 2% CVCmax) and theophylline + l-NAME (53 +/- 1% CVCmax) compared with control sites (94 +/- 2% CVCmax; P < 0.001 for all conditions). The secondary plateau was reduced in l-NAME compared with theophylline sites (P < 0.001), and combined theophylline + l-NAME further reduced the secondary plateau compared with theophylline- (P < 0.001) and l-NAME-only sites (P < 0.05). These data suggest that adenosine receptor activation directly contributes to cutaneous thermal hyperaemia, as evidenced by the reduced initial peak and secondary plateau in theophylline sites. These data further suggest that a portion of the NO response may be explained by adenosine receptor activation; however, a substantial portion of the NO response is independent of adenosine receptor activation.