Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
Eur Heart J. 2015 Nov 14;36(43):3023-30. doi: 10.1093/eurheartj/ehv365. Epub 2015 Jul 28.
We assessed whether acute intra-arterial infusion of exogenous ghrelin can improve endothelial dysfunction by restoring nitric oxide (NO) availability in the forearm microcirculation of essential hypertensive patients. The effect of ghrelin on endothelial dysfunction (pressurized myograph), vascular oxidative stress generation (fluorescent dihydroethidium), and phosphorylation of p47phox (western blot), an index of NAD(P)H oxidase activation, in isolated small arteries taken from essential hypertensive patients (subcutaneous biopsy) were also investigated.
In 18 normotensive control subjects and 18 essential hypertensive patients, we studied the forearm blood flow (strain-gauge plethysmography) response to intra-arterial acetylcholine, repeated under NO synthase inhibitor N(G)-monomethyl-l-arginine (l-NMMA) or the antioxidant ascorbic acid. The protocol was repeated at the end of exogenous ghrelin intra-arterial infusion. In hypertensive patients, ghrelin normalized the blunted response to acetylcholine, restored the inhibiting effect of l-NMMA and abrogated the potentiating effect of ascorbic acid on acetylcholine. In controls, ghrelin failed to modify these vascular responses. In hypertensive patients, ghrelin decreased venous levels of malondialdehyde, lipoperoxide, and interleukin-6, and concomitantly increased endogenous antioxidant capacity. Small vessels from hypertensive patients showed an enhanced intravascular oxidative stress, which was strongly and similarly decreased by incubation with ghrelin, the NAD(P)H oxidase inhibitor gp91 ds-tat, or both. Ghrelin also normalized the overexpression of p47 phosphorylation and restored the NO availability in small vessels from hypertensive patients.
Exogenous ghrelin increases endothelial dysfunction by restoring NO availability in the forearm microcirculation of essential hypertensive patients, an effect ascribable to an antioxidant effect via inhibition of NAD(P)H oxidase activation.
我们评估了外源性生长激素释放肽（ghrelin）急性动脉内输注是否可以通过恢复一氧化氮（NO）的可用性来改善原发性高血压患者前臂微循环中的内皮功能障碍。我们还研究了 ghrelin 对内皮功能障碍（加压肌描记法）、血管氧化应激产生（荧光二氢乙啶）以及 NAD(P)H 氧化酶激活的 p47phox 磷酸化（western blot）的影响，这些指标是从原发性高血压患者（皮下活检）分离的小动脉中获得的。
在 18 名正常血压对照者和 18 名原发性高血压患者中，我们研究了前臂血流（应变计体积描记法）对动脉内乙酰胆碱的反应，在重复给予 NO 合酶抑制剂 N(G)-单甲基-l-精氨酸（l-NMMA）或抗氧化剂抗坏血酸时进行。在结束外源性 ghrelin 动脉内输注后，重复该方案。在高血压患者中，ghrelin 使乙酰胆碱反应减弱恢复正常，恢复了 l-NMMA 的抑制作用，并消除了抗坏血酸对乙酰胆碱的增强作用。在对照者中，ghrelin 未能改变这些血管反应。在高血压患者中，ghrelin 降低了静脉血丙二醛、脂质过氧化物和白细胞介素-6 的水平，同时增加了内源性抗氧化能力。高血压患者的小血管显示出增强的血管内氧化应激，这种应激通过孵育 ghrelin、NAD(P)H 氧化酶抑制剂 gp91 ds-tat 或两者同时使用而强烈且相似地降低。ghrelin 还使高血压患者小血管中 p47 磷酸化的过表达正常化并恢复了 NO 的可用性。
外源性 ghrelin 通过恢复原发性高血压患者前臂微循环中 NO 的可用性来增加内皮功能障碍，这种作用归因于通过抑制 NAD(P)H 氧化酶激活的抗氧化作用。
