Human Cardiovascular Physiology Laboratory, Department of Health and Exercise Science, Vascular Physiology Research Group, Colorado State University, Fort Collins, CO 80523-1582, USA.
J Physiol. 2011 Apr 15;589(Pt 8):1979-90. doi: 10.1113/jphysiol.2011.205013. Epub 2011 Feb 21.
We tested the hypothesis that nitric oxide (NO) and vasodilating prostaglandins (PGs) contribute independently to hypoxic vasodilatation, and that combined inhibition would reveal a synergistic role for these two pathways in the regulation of peripheral vascular tone. In 20 healthy adults, we measured forearm blood flow (Doppler ultrasound) and calculated forearm vascular conductance (FVC) responses to steady-state (SS) isocapnic hypoxia (O₂ saturation 85%). All trials were performed during local α- and β-adrenoceptor blockade (via a brachial artery catheter) to eliminate sympathoadrenal influences on vascular tone and thus isolate local vasodilatory mechanisms. The individual and combined effects of NO synthase (NOS) and cyclooxygenase (COX) inhibition were determined by quantifying the vasodilatation from rest to SS hypoxia, as well as by quantifying how each inhibitor reduced vascular tone during hypoxia. Three hypoxia trials were performed in each subject. In group 1 (n = 10), trial 1, 5 min of SS hypoxia increased FVC from baseline (21 ± 3%; P < 0.05). Infusion of N(G)-nitro-L-arginine methyl ester (L-NAME) for 5 min to inhibit NOS during continuous SS hypoxia reduced FVC by -33 ± 3% (P < 0.05). In Trial 2 with continuous NOS inhibition, the increase in FVC from baseline to SS hypoxia was similar to control conditions (20 ± 3%), and infusion of ketorolac for 5 min to inhibit COX during continuous SS hypoxia reduced FVC by -15 ± 3% (P < 0.05). In Trial 3 with combined NOS and COX inhibition, the increase in FVC from baseline to SS hypoxia was abolished (3%; NS vs. zero). In group 2 (n = 10), the order of NOS and COX inhibition was reversed. In trial 1, five minutes of SS hypoxia increased FVC from baseline (by 24 ± 5%; P < 0.05), and infusion of ketorolac during SS hypoxia had minimal impact on FVC (-4 ± 3%; NS). In Trial 2 with continuous COX inhibition, the increase in FVC from baseline to SS hypoxia was similar to control conditions (27 ± 4%), and infusion of L-NAME during continuous SS hypoxia reduced FVC by -36 ± 7% (P < 0.05). In Trial 3 with combined NOS and COX inhibition, the increase in FVC from baseline to SS hypoxia was abolished (~3%; NS vs. zero). Our collective findings indicate that (1) neither NO nor PGs are obligatory to observe the normal local vasodilatory response from rest to SS hypoxia; (2) NO regulates vascular tone during hypoxia independent of the COX pathway, whereas PGs only regulate vascular tone during hypoxia when NOS is inhibited; and (3) combined inhibition of NO and PGs abolishes local hypoxic vasodilatation (from rest to SS hypoxia) in the forearm circulation of healthy humans during systemic hypoxia.
我们检验了这样一个假设，即一氧化氮（NO）和血管舒张性前列腺素（PGs）独立地促进缺氧性血管舒张，并且联合抑制将揭示这两种途径在调节外周血管张力中的协同作用。在 20 名健康成年人中，我们测量了前臂血流量（多普勒超声）并计算了前臂血管传导性（FVC）对稳态（SS）等碳酸缺氧（O₂饱和度约为 85%）的反应。所有试验均在局部α和β肾上腺素能受体阻断（通过肱动脉导管）下进行，以消除血管紧张度对血管紧张度的交感肾上腺影响，从而分离局部血管舒张机制。通过量化从休息到 SS 缺氧的血管舒张以及量化每个抑制剂在缺氧期间如何降低血管紧张度，确定了一氧化氮合酶（NOS）和环氧化酶（COX）抑制的个体和联合作用。在每个受试者中进行了三次缺氧试验。在第 1 组（n = 10）中，在试验 1 中，5 分钟的 SS 缺氧将 FVC 从基线增加（21 ± 3%；P < 0.05）。在连续 SS 缺氧期间持续输注 N（G）-硝基-L-精氨酸甲酯（L-NAME）5 分钟以抑制 NOS，将 FVC 降低了-33 ± 3%（P < 0.05）。在持续 NOS 抑制的试验 2 中，FVC 从基线到 SS 缺氧的增加与对照条件相似（20 ± 3%），并且在连续 SS 缺氧期间输注酮咯酸持续 5 分钟以抑制 COX，将 FVC 降低了-15 ± 3%（P < 0.05）。在联合 NOS 和 COX 抑制的试验 3 中，FVC 从基线到 SS 缺氧的增加被消除（3%；与零相比无差异）。在第 2 组（n = 10）中，NOS 和 COX 抑制的顺序被颠倒。在试验 1 中，SS 缺氧 5 分钟将 FVC 从基线增加（增加 24 ± 5%；P < 0.05），并且在 SS 缺氧期间输注酮咯酸对 FVC 的影响最小（-4 ± 3%；无差异）。在持续 COX 抑制的试验 2 中，FVC 从基线到 SS 缺氧的增加与对照条件相似（27 ± 4%），并且在连续 SS 缺氧期间输注 L-NAME 将 FVC 降低了-36 ± 7%（P < 0.05）。在联合 NOS 和 COX 抑制的试验 3 中，FVC 从基线到 SS 缺氧的增加被消除（3%；与零相比无差异）。我们的综合研究结果表明，（1）在从休息到 SS 缺氧的正常局部血管舒张反应中，NO 和 PGs 都不是必需的；（2）NO 独立于 COX 途径调节缺氧时的血管紧张度，而 PGs 仅在 NOS 抑制时调节缺氧时的血管紧张度；（3）在全身缺氧期间，联合抑制 NO 和 PGs 会消除健康人前臂循环中的局部缺氧性血管舒张（从休息到 SS 缺氧）。
