Department of Anesthesiology and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21287-6568, USA.
Eur J Appl Physiol. 2010 Sep;110(2):395-404. doi: 10.1007/s00421-010-1514-7. Epub 2010 May 29.
Emerging evidence suggests that nitric oxide (NO) plays a pivotal role in the mechanism of vascular hyporesponsiveness contributing to microgravity-induced orthostatic intolerance. The cellular and enzymatic source of the NO, however, remains controversial. In addition, the time course of the endothelial-dependent contribution remains unstudied. We tested the hypotheses that the change in vasoresponsiveness seen in acute (3-day) hindlimb unweighted (HLU) animals is due to an endothelium-dependent mechanism and that endothelial-dependent attenuation in vasoreactivity is due to endothelial nitric oxide synthase (NOS-3) dependent activation. Vasoreactivity was investigated in rat aortic rings following acute HLU treatment. Dose responsiveness to norepinepherine (NE) was depressed after 3-day HLU [1,338 +/- 54 vs. 2,325 +/- 58 mg at max (NE), HLU vs. C, P < 0.001]. However, removal of the endothelium restored the vascular contractility to that of C. In addition, 1H-oxadiazole quinoxalin-1-one (ODQ), a soluble guanylyl cyclase inhibitor, restored the reduced vasoconstrictor responses to phenylephrine (PE) seen in 3-day HLU rings (1.30 +/- 0.10 vs. 0.53 +/- 0.07 g, HLU + ODQ vs. HLU, P = 0.0001). Ca(+) dependent nitric oxide synthase (NOS) activity was increased, as was vascular NO products as a result of HLU. While NOS-3 expression was not increased in HLU rats, phosphorylation of NOS-3 at serine-1177 (an activator of NOS-3) was increased while phosphorylation of serine-495 (an inactivator of NOS-3) was decreased. These findings demonstrate that changes in vasoresponsiveness in the acute HLU model of microgravity are due to an upregulation of the endothelial-dependent NO/cGMP pathway through NOS phosphorylation.
新出现的证据表明，一氧化氮（NO）在血管低反应性的机制中起关键作用，导致微重力引起的直立不耐受。然而，NO 的细胞和酶源仍存在争议。此外，内皮依赖性贡献的时间过程仍未得到研究。我们测试了以下假设：急性（3 天）后肢失重（HLU）动物中观察到的血管反应性变化是由于内皮依赖性机制，并且血管反应性的内皮依赖性衰减是由于内皮型一氧化氮合酶（NOS-3）依赖性激活。在急性 HLU 处理后，研究了大鼠主动脉环的血管反应性。在 3 天 HLU 后，去甲肾上腺素（NE）的剂量反应性降低[1,338 +/- 54 对 2,325 +/- 58 mg 最大（NE），HLU 对 C，P < 0.001]。然而，去除内皮恢复了血管收缩性到 C 的水平。此外，1H-恶二唑喹喔啉-1-酮（ODQ），一种可溶性鸟苷酸环化酶抑制剂，恢复了在 3 天 HLU 环中观察到的对苯肾上腺素（PE）的减少的血管收缩反应[1.30 +/- 0.10 对 0.53 +/- 0.07 g，HLU + ODQ 对 HLU，P = 0.0001]。由于 HLU，Ca（+）依赖性一氧化氮合酶（NOS）活性增加，血管 NO 产物增加。虽然 HLU 大鼠中 NOS-3 表达没有增加，但 NOS-3 的丝氨酸-1177 磷酸化（NOS-3 的激活剂）增加，而 NOS-3 的丝氨酸-495 磷酸化（NOS-3 的失活剂）减少。这些发现表明，微重力急性 HLU 模型中血管反应性的变化是由于内皮依赖性 NO/cGMP 途径通过 NOS 磷酸化的上调所致。
