Up-regulation of arginase activity contributes to attenuated reflex cutaneous vasodilatation in hypertensive humans
Up-regulation of arginase activity contributes to attenuated reflex cutaneous vasodilatation in hypertensive humans
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DOI：
10.1113/jphysiol.2007.128959
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发表时间：
2007-06-01
影响因子：
5.5
通讯作者：
Kenney, W. Larry
中科院分区：
文献类型：
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作者：
Holowatz, Lacy A.;Kenney, W. Larry
反射性皮肤血管舒张依赖于一氧化氮 (NO)，一氧化氮在高血压 (HTN) 中会减弱。精氨酸酶可能会被 HTN 上调，HTN 优先代谢 L-精氨酸 (L-arg)，与 NO 合酶 (NOS) 介导的途径竞争并限制 NO 合成。我们假设 HTN 皮肤中 NO 依赖性血管舒张作用会减弱，单独使用精氨酸酶抑制 (A-I) 或同时补充 L-精氨酸会增强血管舒张作用。将五根微透析纤维置于 8 名未接受药物治疗的 HTN（平均动脉压 (MAP)，112 +/- 1 mmHg）受试者和 9 名年龄匹配的血压正常 (AMN)（MAP：87 +/- 1 mmHg）男性和女性受试者的皮肤中，用作：对照（C，林格溶液）、NOS 抑制（NOS-I，10 mM L-NAME）、A-I（5 mM BEC + 5 mM）去甲-NOHA）、补充 L-arg（L-arg、10 mM L-arg）以及组合 A-I + L-arg。通过使用注水套装将口腔温度 (T-or) 提高 1.0 摄氏度来诱导反射性血管舒张。通过激光多普勒血流计测量每个部位的红细胞通量。计算皮肤血管电导（CVC = 通量/MAP）并标准化为最大 CVC（28 mM SNP + 局部加热至 43 摄氏度）。对照和 NOS-I 位点之间的 Delta%CVCmax 计算为 C 和 NOS-I 位点之间的差异。与 AMN 受试者相比，HTN 受试者的最大 CVC 减弱了约 25%（P < 0.001）。自始至终，各组之间的全身发热 %CVCmax 没有差异（HTN，43 +/- 3%CVCmax 与 AMN，45 +/- 3%CVCmax，P > 0.05）。 NOS-I 显着降低了两组的 %CVCmax，但 HTN 组的 %CVCmax 更大（HTN，32 +/- 4%CVCmax 与 AMN，23 +/- 3%CVCmax，P < 0.05）。 HTN 组中对照和 NOS-I 位点之间的 Delta%CVCmax 在 Delta T 或 > 0.5 摄氏度时减弱（与 AMN 相比，P < 0.001）。单独使用 A-I 仅在 HTN 组中增加了 %CVCmax（HTN，65 +/- 5%CVCmax 与 AMN，48 +/- 3%CVCmax，P < 0.05）。单独使用 L-Arg 并不影响任一组的 %CVCmax（HTN，49 +/- 5%CVCmax 与 AMN，49 +/- 3%CVCmax，P > 0.05）。与各自的对照位点相比，组合的 A-I + L-arg 增加了两个受试者组的 %CVCmax（HTN，60 +/- 7%CVCmax 与 AMN，61 +/- 3%CVCmax，与各自的对照位点相比，均 P < 0.05）。 HTN 会减弱血管舒张作用，因为 NO 依赖性血管舒张作用减少，而精氨酸酶抑制可增强血管舒张作用，但补充 L-arg 则不然，这表明 HTN 可以上调精氨酸酶。
Reflex cutaneous vasodilatation is dependent on nitric oxide (NO), which is diminished in hypertension (HTN). Arginase may be up-regulated with HTN, which preferentially metabolizes L-arginine (L-arg), competing with NO-synthase (NOS)-mediated pathways and limiting NO synthesis. We hypothesized that NO-dependent vasodilatation would be attenuated in HTN skin, and arginase inhibition (A-I) alone or with concurrent L-arginine supplementation, would augment vasodilatation. Five microdialysis fibres were placed in skin of eight unmedicated subjects with HTN (mean arterial pressure (MAP), 112 +/- 1 mmHg) and nine age-matched normotensive (AMN) (MAP: 87 +/- 1 mmHg) men and women to serve as: control (C, Ringer solution), NOS inhibited (NOS-I, 10 mM L-NAME), A-I (5 mM BEC + 5 mM nor-NOHA), L-arg supplemented (L-arg, 10 mM L-arg), and combined A-I + L-arg. Reflex vasodilatation was induced by using a water-perfused suit to increase oral temperature (T-or) 1.0 degrees C. Red cell flux was measured by laser-Doppler flowmetry over each site. Cutaneous vascular conductance was calculated (CVC = flux/MAP) and normalized to maximal CVC (28 mM SNP + local heating to 43 degrees C). The Delta%CVCmax between the control and NOS-I site was calculated as the difference between C and NOS-I sites. Maximal CVC was attenuated in the HTN subjects by similar to 25% compared with AMN subjects (P < 0.001). Throughout, whole body heating %CVCmax was not different between the groups (HTN, 43 +/- 3%CVCmax versus AMN, 45 +/- 3%CVCmax, P > 0.05). NOS-I significantly decreased %CVCmax in both groups but %CVCmax was greater in the HTN group (HTN, 32 +/- 4%CVCmax versus AMN, 23 +/- 3%CVCmax, P < 0.05). The Delta%CVCmax between the control and NOS-I sites was attenuated at Delta T-or > 0.5 degrees C in the HTN group (P < 0.001 versus AMN). A-I alone augmented %CVCmax only in the HTN group (HTN, 65 +/- 5%CVCmax versus AMN, 48 +/- 3%CVCmax, P < 0.05). L-Arg alone did not affect %CVCmax in either group (HTN, 49 +/- 5%CVCmax versus AMN, 49 +/- 3%CVCmax, P > 0.05). Combined A-I + L-arg augmented %CVCmax in both subject groups compared with their respective control sites (HTN, 60 +/- 7%CVCmax versus AMN, 61 +/- 3%CVCmax, both P < 0.05 versus respective control sites). Vasodilatation is attenuated with HTN due to decreased NO-dependent vasodilatation and can be augmented with arginase inhibition but not L-arg supplementation, suggesting that arginase is up-regulated with HTN.