Anesthesia Center for Critical Care Medicine, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School , Boston, Massachusetts.
Department of Ecology and Evolutionary Biology, University of California , Santa Cruz, California.
Am J Physiol Regul Integr Comp Physiol. 2019 Jun 1;316(6):R704-R715. doi: 10.1152/ajpregu.00283.2018. Epub 2019 Mar 20.
Nitric oxide (NO) is a potent vasodilator, which improves perfusion and oxygen delivery during tissue hypoxia in terrestrial animals. The vertebrate dive response involves vasoconstriction in select tissues, which persists despite profound hypoxia. Using tissues collected from Weddell seals at necropsy, we investigated whether vasoconstriction is aided by downregulation of local hypoxia signaling mechanisms. We focused on NO-soluble guanylyl cyclase (GC)-cGMP signaling, a well-known vasodilatory transduction pathway. Seals have a lower GC protein abundance, activity, and capacity to respond to NO stimulation than do terrestrial mammals. In seal lung homogenates, GC produced less cGMP (20.1 ± 3.7 pmol·mg protein·min) than the lungs of dogs (-80 ± 144 pmol·mg protein·min less than seals), sheep (-472 ± 96), rats (-664 ± 104) or mice (-1,160 ± 104, < 0.0001). Amino acid sequences of the GC enzyme α-subunits differed between seals and terrestrial mammals, potentially affecting their structure and function. Vasoconstriction in diving Weddell seals is not consistent across tissues; perfusion is maintained in the brain and heart but decreased in other organs such as the kidney. A NO donor increased median GC activity 49.5-fold in the seal brain but only 27.4-fold in the kidney, consistent with the priority of cerebral perfusion during diving. expression was high in the seal brain, which could improve NO production and vasodilatory potential. Conversely, expression was high in the seal renal artery, which may increase cGMP breakdown and vasoconstriction in the kidney. Taken together, the results of this study suggest that alterations in the NO-cGMP pathway facilitate the diving response.
一氧化氮（NO）是一种有效的血管扩张剂，可在陆生动物组织缺氧时改善灌注和氧气输送。脊椎动物潜水反应涉及选择性组织的血管收缩，尽管存在严重缺氧，但这种收缩仍持续存在。本研究使用在尸检时收集的威德尔海豹组织，研究局部缺氧信号机制的下调是否有助于血管收缩。我们专注于一氧化氮可溶性鸟苷酸环化酶（GC）-环鸟苷酸（cGMP）信号转导，这是一种众所周知的血管扩张转导途径。与陆生哺乳动物相比，海豹的 GC 蛋白丰度、活性和对 NO 刺激的反应能力较低。在海豹肺匀浆中，GC 产生的 cGMP 较少（20.1±3.7 pmol·mg 蛋白·min），比狗肺（比海豹少 80±144 pmol·mg 蛋白·min）、绵羊肺（-472±96 pmol·mg 蛋白·min）、大鼠肺（-664±104 pmol·mg 蛋白·min）或小鼠肺（-1160±104 pmol·mg 蛋白·min，<0.0001）少。GC 酶α亚基的氨基酸序列在海豹和陆生哺乳动物之间存在差异，这可能影响其结构和功能。潜水威德尔海豹的血管收缩在不同组织之间并不一致；大脑和心脏的灌注得到维持，但肾脏等其他器官的灌注减少。在海豹大脑中，NO 供体使 GC 活性中位数增加了 49.5 倍，但在肾脏中仅增加了 27.4 倍，这与潜水时大脑灌注的优先级一致。在海豹大脑中，表达水平较高，这可以提高 NO 的产生和血管扩张潜力。相反，在海豹肾动脉中，表达水平较高，这可能会增加肾脏中的 cGMP 分解和血管收缩。综上所述，本研究结果表明，NO-cGMP 途径的改变促进了潜水反应。
